For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

Little is known about people who write to criminals incar­cerated for a violent crime. However, existence of Web sites such as WriteAPrisoner.com, Meet-An-Inmate.com, and PrisonPenPals.com suggests some appetite among the public for corresponding with the incarcerated. Writers of letters might be drawn to the “bad boy” image of prison­ers. Furthermore, much has been written of the willingness of some battered women to remain in an abusive domestic relationship, leading them to correspond with their abusers even after those abusers are incarcerated.^1,2

To our knowledge, no examination of letters written to a mass murderer has been published. Therefore, we catego­rized and analyzed 784 letters sent to a high-profile male mass murderer whose crime was committed during the past decade. Here is a description of the study and what we found, as well as discussion of how our findings might offer utility in a psychiatric practice.

Goals of the study
We hypothesized that a large percentage of those letters could be classified as “Romantic,” given the lay percep­tion that it is women who write to mass murderers. We also sought to evaluate follow-up letters sent by these writers to test the assumption that their individual goals would be con­stant over time.

We performed this study in the hope that the research could assist psychiatric practitioners in treating patients who seek to associate with a violent person (see “Treatment considerations,”). We thought it might be helpful for practitioners to get a better understanding of the nature of people who write to a violent offender or express a desire to do so.

Methods of study
Two authors (R.S.J. and D.P.G.) evaluated 819 letters that had been written by non-incarcerated, non-family adults to 1 mass murderer. The initial letter and follow-up letters written by each unique writer (n = 333) were categorized as follows:
   • state or country from which the letter was sent
   • age
   • sex
   • number of letters sent by each writer
   • whether a photograph was enclosed
   • whether additional items were enclosed (eg, gifts, drawings)
   • whether the letter was rejected by prison authorities
   • the writer’s purpose.

The study was approved by the insti­tutional review board of Baylor College of Medicine.

Letters were assigned to 1 of 5 categories:

Acquaintance letters sought ongoing cor­respondence relationship with the murderer. They focused largely on conveying informa­tion about the writer.

Show of support letters also sought an ongoing correspondence relationship with the murderer, but instead focused on him, not the writer.

Romance letters used words that conveyed romantic or non-platonic affection.

Spiritual letters gave advice to the mur­derer with a religious tone.

Words of wisdom letters offered advice but lacked a religious tone.

Given the nonstandardized nature of categorization and the lack of a formal questionnaire, we were unable to perform an exploratory factor analysis on our cat­egorizations. Inter-rater reliability of letter categorization was 0.79.

Results: Writer profiles, purpose for writing
In all, we reviewed 819 letters:
   • Thirty-five letters were excluded because they were written by family mem­bers, children, or other prisoners
   • Of the remaining 784 letters, there were 333 unique writers
   • Two-hundred sixty letters were writ­ten by women, 61 by men; 2 were co-written by both sexes; sex could not be determined for 10.

Women were more likely than men to write a letter (P = .014) and to write ≥3 letters (P = .001). The age of the writer was deter­mined for 117 (35.1%) letters; mean age was 27.8 (± 8.9) years (range, 18 to 59 years).

The purpose of the letters differed by sex (P < .001) but not by the writer’s age (P = .058). Women were more likely than men to write letters categorized as “Acquaintance,” “Romance,” and “Show of support”; in con­trast, men were more likely than women to write a letter categorized as “Spiritual”  (Table 1). Approximately 95% of let­ters were handwritten. Letters averaged 3 pages (range, 1 to 16 pages).

Two-hundred sixteen writers wrote a single letter; 53 wrote 2 letters; 18 wrote 3 let­ters; 11 wrote 4 letters; 30 wrote 5 to 10 let­ters; and 9 wrote 11 to 43 letters. The purpose of follow-up letters was associated with the age of the writer (P < .001) and with the writ­er’s sex (P < .001). Women were more likely to write “Show of support” and “Romance” follow-up letters; men were more likely to write “Spiritual” follow-up letters (Table 2).

Results suggested that the purpose of the initial letter was a reasonable predictor of the purpose of follow-up letters (P < .001) (Table 3). The murderer never responded to any letters. Letters were most often writ­ten from his state of incarceration; next, from contiguous states; then, from non-contiguous states; and, last, from interna­tional locations (P < .001).

Of the initial letters from writers who wrote ≥10, 60% were categorized as “Acquaintance” and 20% as “Romance.” The writer who wrote the most letters (43) moved during the course of her letter-writing to live in the same state as the murderer; she stated in her letters that she did so to be closer to him and to be able to attend his court hearings. Four other writers, each of whom wrote >5 letters, stated that they had traveled to the murderer’s state of incarcera­tion to attend some of his hearings in person.

Composite examples of more common categories of letters
Names and other pertinent identifying information have been changed.

Acquaintance. Hi, Steve. I’ve been follow­ing your case and just wanted to write you so that maybe we could be friends or keep in touch since you’re probably pretty bored. I’m a 27-year-old college student studying market­ing and working at Applebee’s as a waitress (for now) until I can land my dream job. I’ve enclosed a picture of me and my dachshund along with a photo of my favorite beach in the world. Write me back if you want. Jenny.

Show of support. Steve: I’ve been really wor­ried about you since first seeing you on TV. You look different lately and I hope they’re treating you OK and feeding you decent food. In case they’re not, I’ve enclosed a little something to buy yourself a treat. Just know that there are many of us that care about you and are really pulling for you to be strong in this tough situ­ation you’re in. Yours truly, Karen.

Romance. Dearest Steven: My mind has been filled with thoughts of you and of us since I last saw you in my dreams! Be strong, because you are going to beat this once they understand that you are not responsible for what happened! Don’t you see, sweetie, the system failed you, and now you’re caught up in something that you will soon overcome. When I think of the day that you get released, and how we’ll be able to settle down some­where together, it gets me incredibly excited. You and I are meant to be together, because I understand you and can help you get better. I love you, Steven! Please write me back so that I know we’re on the same page about our plans for the future. Love, ♥ Your sweetie, Rachel.

Spiritual. Dear Child of God: The Lord has a plan for you. I know that things right now might be confusing, and you’re in a black place, but He is there right beside you. If you need some reading materials to give you com­fort, just let me know and I can get a Bible to you along with some other books to give you solace and strengthen your walk with Him. God forgives you and he loves you so much! Much love in Christ, Mary.

Discussion
Given that the mass murderer in this study was a young man, it is not surpris­ing that 78% of writers of initial letters were women. However, it is interesting that, among women’s initial letters, 44% were “Acquaintance” letters and only 15% were categorized as “Romance.”

Given the severity of the murderer’s crime, it is remarkable that he received only 1 “Hate mail” letter.

Initial “Spiritual” letters were more likely to be followed by letters of the same category than any other category; “Romance” letters were a close second. This demonstrates the consistent efforts of writers in these 2 categories. Highly persis­tent writers (≥10 letters) were most likely to fall into “Acquaintance” and “Romance” categories. The persistence of these writers is remarkable, in view of the fact that none of their letters were answered. We hypoth­esize that the killer did not reply because he had no interest in correspondence.

Similarities to stalking. Given that 9 writ­ers wrote >10 letters each and 2 wrote >20 each, elements of their behavior are not unlike what is seen in stalkers.³ Consistent with the stalking literature and Mullen et al4 stalker typology, many writers in this study appeared to seek intimacy with the perpetrator through “Romance” or “Show of support” letters, and might be akin to Mullen’s so-called intimacy-seeking stalker. Such stalkers’ behavior arises out of loneliness, with a strong desire for a rela­tionship with the target; a significant per­centage of such stalkers suffer a delusional disorder.

Mullen’s so-called incompetent suitor stalker is similar to the intimacy-seeking type but, instead, has an interest in a short-term relationship and is far less persistent in his (her) stalking behavior⁴; this type might apply to the writers in this study who wrote >1 but <10 letters.

Two additional observations also are notable when trying to characterize people who write letters: (1) A high percentage of people who stalk a celebrity suffer a psy­chotic disorder^5,6; (2) 4 letter-writers trav­eled, and 1 relocated, to the murderer’s state of incarceration to attend his hearings and be closer to him.

This study has limitations:
   • categorization of letters is inherently subjective and the categories themselves were created by the researchers
   • the nature and categorization of such letters might vary considerably with the age and sex of the violent criminal; our findings in this case are not generalizable.

Last, researchers who plan to study writers of letters to incarcerated criminals should consider sending a personality test and other questionnaires to those writers to understand this population better.

Treatment considerations
Psychiatrists treating patients who seek a romantic attachment with a violent person should consider psychotherapy as a means of treating possible character pathology. The desire for romance with a violent crimi­nal was greater among repeat writers (20%) than in initial letters (15%), suggesting that people who have a strong inclination to associate with a violent person might benefit from exploring romantic feelings in therapy. Specifically, therapists would be wise to explore with such patients the possibility that they experienced violence or verbal abuse in childhood or adulthood.

To the extent that evidence of prior abuse exists, a diagnosis of posttraumatic stress disorder (PTSD) might be appro­priate; specialized therapy for men and women with a history of abuse might be indicated. It is important to provide vali­dation for patients who are victims when they describe their abuse, and to stress that they did nothing to provoke the violence. Furthermore, investigation of why the patient feels drawn romantically toward a violent criminal is helpful, as well as an examination of how such behavior is self-defeating.

There might be value in having patients keep a journal in lieu of actually sending letters; there is evidence that “journaling” can reduce substance use recidivism.⁷ This work can be performed in conjunction with group or individual psychotherapy that addresses any history of abuse and subse­quent PTSD.

Many patients are reluctant to discuss their romantic feelings toward a violent criminal until the psychiatrist has estab­lished a strong doctor−patient relationship. Last, clinicians should not hesitate to refer these patients to a therapist who specializes in domestic violence.

Related Resource
• Marazziti D, Falaschi V, Lombardi A, et al. Stalking: a neuro­biological perspective. Riv Psichiatr. 2015;50(1):12-18.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Little is known about people who write to criminals incar­cerated for a violent crime. However, existence of Web sites such as WriteAPrisoner.com, Meet-An-Inmate.com, and PrisonPenPals.com suggests some appetite among the public for corresponding with the incarcerated. Writers of letters might be drawn to the “bad boy” image of prison­ers. Furthermore, much has been written of the willingness of some battered women to remain in an abusive domestic relationship, leading them to correspond with their abusers even after those abusers are incarcerated.^1,2

To our knowledge, no examination of letters written to a mass murderer has been published. Therefore, we catego­rized and analyzed 784 letters sent to a high-profile male mass murderer whose crime was committed during the past decade. Here is a description of the study and what we found, as well as discussion of how our findings might offer utility in a psychiatric practice.

Goals of the study
We hypothesized that a large percentage of those letters could be classified as “Romantic,” given the lay percep­tion that it is women who write to mass murderers. We also sought to evaluate follow-up letters sent by these writers to test the assumption that their individual goals would be con­stant over time.

We performed this study in the hope that the research could assist psychiatric practitioners in treating patients who seek to associate with a violent person (see “Treatment considerations,”). We thought it might be helpful for practitioners to get a better understanding of the nature of people who write to a violent offender or express a desire to do so.

Methods of study
Two authors (R.S.J. and D.P.G.) evaluated 819 letters that had been written by non-incarcerated, non-family adults to 1 mass murderer. The initial letter and follow-up letters written by each unique writer (n = 333) were categorized as follows:
   • state or country from which the letter was sent
   • age
   • sex
   • number of letters sent by each writer
   • whether a photograph was enclosed
   • whether additional items were enclosed (eg, gifts, drawings)
   • whether the letter was rejected by prison authorities
   • the writer’s purpose.

The study was approved by the insti­tutional review board of Baylor College of Medicine.

Letters were assigned to 1 of 5 categories:

Acquaintance letters sought ongoing cor­respondence relationship with the murderer. They focused largely on conveying informa­tion about the writer.

Show of support letters also sought an ongoing correspondence relationship with the murderer, but instead focused on him, not the writer.

Romance letters used words that conveyed romantic or non-platonic affection.

Spiritual letters gave advice to the mur­derer with a religious tone.

Words of wisdom letters offered advice but lacked a religious tone.

Given the nonstandardized nature of categorization and the lack of a formal questionnaire, we were unable to perform an exploratory factor analysis on our cat­egorizations. Inter-rater reliability of letter categorization was 0.79.

Results: Writer profiles, purpose for writing
In all, we reviewed 819 letters:
   • Thirty-five letters were excluded because they were written by family mem­bers, children, or other prisoners
   • Of the remaining 784 letters, there were 333 unique writers
   • Two-hundred sixty letters were writ­ten by women, 61 by men; 2 were co-written by both sexes; sex could not be determined for 10.

Women were more likely than men to write a letter (P = .014) and to write ≥3 letters (P = .001). The age of the writer was deter­mined for 117 (35.1%) letters; mean age was 27.8 (± 8.9) years (range, 18 to 59 years).

The purpose of the letters differed by sex (P < .001) but not by the writer’s age (P = .058). Women were more likely than men to write letters categorized as “Acquaintance,” “Romance,” and “Show of support”; in con­trast, men were more likely than women to write a letter categorized as “Spiritual”  (Table 1). Approximately 95% of let­ters were handwritten. Letters averaged 3 pages (range, 1 to 16 pages).

Two-hundred sixteen writers wrote a single letter; 53 wrote 2 letters; 18 wrote 3 let­ters; 11 wrote 4 letters; 30 wrote 5 to 10 let­ters; and 9 wrote 11 to 43 letters. The purpose of follow-up letters was associated with the age of the writer (P < .001) and with the writ­er’s sex (P < .001). Women were more likely to write “Show of support” and “Romance” follow-up letters; men were more likely to write “Spiritual” follow-up letters (Table 2).

Results suggested that the purpose of the initial letter was a reasonable predictor of the purpose of follow-up letters (P < .001) (Table 3). The murderer never responded to any letters. Letters were most often writ­ten from his state of incarceration; next, from contiguous states; then, from non-contiguous states; and, last, from interna­tional locations (P < .001).

Of the initial letters from writers who wrote ≥10, 60% were categorized as “Acquaintance” and 20% as “Romance.” The writer who wrote the most letters (43) moved during the course of her letter-writing to live in the same state as the murderer; she stated in her letters that she did so to be closer to him and to be able to attend his court hearings. Four other writers, each of whom wrote >5 letters, stated that they had traveled to the murderer’s state of incarcera­tion to attend some of his hearings in person.

Composite examples of more common categories of letters
Names and other pertinent identifying information have been changed.

Acquaintance. Hi, Steve. I’ve been follow­ing your case and just wanted to write you so that maybe we could be friends or keep in touch since you’re probably pretty bored. I’m a 27-year-old college student studying market­ing and working at Applebee’s as a waitress (for now) until I can land my dream job. I’ve enclosed a picture of me and my dachshund along with a photo of my favorite beach in the world. Write me back if you want. Jenny.

Show of support. Steve: I’ve been really wor­ried about you since first seeing you on TV. You look different lately and I hope they’re treating you OK and feeding you decent food. In case they’re not, I’ve enclosed a little something to buy yourself a treat. Just know that there are many of us that care about you and are really pulling for you to be strong in this tough situ­ation you’re in. Yours truly, Karen.

Romance. Dearest Steven: My mind has been filled with thoughts of you and of us since I last saw you in my dreams! Be strong, because you are going to beat this once they understand that you are not responsible for what happened! Don’t you see, sweetie, the system failed you, and now you’re caught up in something that you will soon overcome. When I think of the day that you get released, and how we’ll be able to settle down some­where together, it gets me incredibly excited. You and I are meant to be together, because I understand you and can help you get better. I love you, Steven! Please write me back so that I know we’re on the same page about our plans for the future. Love, ♥ Your sweetie, Rachel.

Spiritual. Dear Child of God: The Lord has a plan for you. I know that things right now might be confusing, and you’re in a black place, but He is there right beside you. If you need some reading materials to give you com­fort, just let me know and I can get a Bible to you along with some other books to give you solace and strengthen your walk with Him. God forgives you and he loves you so much! Much love in Christ, Mary.

Discussion
Given that the mass murderer in this study was a young man, it is not surpris­ing that 78% of writers of initial letters were women. However, it is interesting that, among women’s initial letters, 44% were “Acquaintance” letters and only 15% were categorized as “Romance.”

Given the severity of the murderer’s crime, it is remarkable that he received only 1 “Hate mail” letter.

Initial “Spiritual” letters were more likely to be followed by letters of the same category than any other category; “Romance” letters were a close second. This demonstrates the consistent efforts of writers in these 2 categories. Highly persis­tent writers (≥10 letters) were most likely to fall into “Acquaintance” and “Romance” categories. The persistence of these writers is remarkable, in view of the fact that none of their letters were answered. We hypoth­esize that the killer did not reply because he had no interest in correspondence.

Similarities to stalking. Given that 9 writ­ers wrote >10 letters each and 2 wrote >20 each, elements of their behavior are not unlike what is seen in stalkers.³ Consistent with the stalking literature and Mullen et al4 stalker typology, many writers in this study appeared to seek intimacy with the perpetrator through “Romance” or “Show of support” letters, and might be akin to Mullen’s so-called intimacy-seeking stalker. Such stalkers’ behavior arises out of loneliness, with a strong desire for a rela­tionship with the target; a significant per­centage of such stalkers suffer a delusional disorder.

Mullen’s so-called incompetent suitor stalker is similar to the intimacy-seeking type but, instead, has an interest in a short-term relationship and is far less persistent in his (her) stalking behavior⁴; this type might apply to the writers in this study who wrote >1 but <10 letters.

Two additional observations also are notable when trying to characterize people who write letters: (1) A high percentage of people who stalk a celebrity suffer a psy­chotic disorder^5,6; (2) 4 letter-writers trav­eled, and 1 relocated, to the murderer’s state of incarceration to attend his hearings and be closer to him.

This study has limitations:
   • categorization of letters is inherently subjective and the categories themselves were created by the researchers
   • the nature and categorization of such letters might vary considerably with the age and sex of the violent criminal; our findings in this case are not generalizable.

Last, researchers who plan to study writers of letters to incarcerated criminals should consider sending a personality test and other questionnaires to those writers to understand this population better.

Treatment considerations
Psychiatrists treating patients who seek a romantic attachment with a violent person should consider psychotherapy as a means of treating possible character pathology. The desire for romance with a violent crimi­nal was greater among repeat writers (20%) than in initial letters (15%), suggesting that people who have a strong inclination to associate with a violent person might benefit from exploring romantic feelings in therapy. Specifically, therapists would be wise to explore with such patients the possibility that they experienced violence or verbal abuse in childhood or adulthood.

To the extent that evidence of prior abuse exists, a diagnosis of posttraumatic stress disorder (PTSD) might be appro­priate; specialized therapy for men and women with a history of abuse might be indicated. It is important to provide vali­dation for patients who are victims when they describe their abuse, and to stress that they did nothing to provoke the violence. Furthermore, investigation of why the patient feels drawn romantically toward a violent criminal is helpful, as well as an examination of how such behavior is self-defeating.

There might be value in having patients keep a journal in lieu of actually sending letters; there is evidence that “journaling” can reduce substance use recidivism.⁷ This work can be performed in conjunction with group or individual psychotherapy that addresses any history of abuse and subse­quent PTSD.

Many patients are reluctant to discuss their romantic feelings toward a violent criminal until the psychiatrist has estab­lished a strong doctor−patient relationship. Last, clinicians should not hesitate to refer these patients to a therapist who specializes in domestic violence.

Related Resource
• Marazziti D, Falaschi V, Lombardi A, et al. Stalking: a neuro­biological perspective. Riv Psichiatr. 2015;50(1):12-18.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Little is known about people who write to criminals incar­cerated for a violent crime. However, existence of Web sites such as WriteAPrisoner.com, Meet-An-Inmate.com, and PrisonPenPals.com suggests some appetite among the public for corresponding with the incarcerated. Writers of letters might be drawn to the “bad boy” image of prison­ers. Furthermore, much has been written of the willingness of some battered women to remain in an abusive domestic relationship, leading them to correspond with their abusers even after those abusers are incarcerated.^1,2

To our knowledge, no examination of letters written to a mass murderer has been published. Therefore, we catego­rized and analyzed 784 letters sent to a high-profile male mass murderer whose crime was committed during the past decade. Here is a description of the study and what we found, as well as discussion of how our findings might offer utility in a psychiatric practice.

Goals of the study
We hypothesized that a large percentage of those letters could be classified as “Romantic,” given the lay percep­tion that it is women who write to mass murderers. We also sought to evaluate follow-up letters sent by these writers to test the assumption that their individual goals would be con­stant over time.

We performed this study in the hope that the research could assist psychiatric practitioners in treating patients who seek to associate with a violent person (see “Treatment considerations,”). We thought it might be helpful for practitioners to get a better understanding of the nature of people who write to a violent offender or express a desire to do so.

Methods of study
Two authors (R.S.J. and D.P.G.) evaluated 819 letters that had been written by non-incarcerated, non-family adults to 1 mass murderer. The initial letter and follow-up letters written by each unique writer (n = 333) were categorized as follows:
   • state or country from which the letter was sent
   • age
   • sex
   • number of letters sent by each writer
   • whether a photograph was enclosed
   • whether additional items were enclosed (eg, gifts, drawings)
   • whether the letter was rejected by prison authorities
   • the writer’s purpose.

The study was approved by the insti­tutional review board of Baylor College of Medicine.

Letters were assigned to 1 of 5 categories:

Acquaintance letters sought ongoing cor­respondence relationship with the murderer. They focused largely on conveying informa­tion about the writer.

Show of support letters also sought an ongoing correspondence relationship with the murderer, but instead focused on him, not the writer.

Romance letters used words that conveyed romantic or non-platonic affection.

Spiritual letters gave advice to the mur­derer with a religious tone.

Words of wisdom letters offered advice but lacked a religious tone.

Given the nonstandardized nature of categorization and the lack of a formal questionnaire, we were unable to perform an exploratory factor analysis on our cat­egorizations. Inter-rater reliability of letter categorization was 0.79.

Results: Writer profiles, purpose for writing
In all, we reviewed 819 letters:
   • Thirty-five letters were excluded because they were written by family mem­bers, children, or other prisoners
   • Of the remaining 784 letters, there were 333 unique writers
   • Two-hundred sixty letters were writ­ten by women, 61 by men; 2 were co-written by both sexes; sex could not be determined for 10.

Women were more likely than men to write a letter (P = .014) and to write ≥3 letters (P = .001). The age of the writer was deter­mined for 117 (35.1%) letters; mean age was 27.8 (± 8.9) years (range, 18 to 59 years).

The purpose of the letters differed by sex (P < .001) but not by the writer’s age (P = .058). Women were more likely than men to write letters categorized as “Acquaintance,” “Romance,” and “Show of support”; in con­trast, men were more likely than women to write a letter categorized as “Spiritual”  (Table 1). Approximately 95% of let­ters were handwritten. Letters averaged 3 pages (range, 1 to 16 pages).

Two-hundred sixteen writers wrote a single letter; 53 wrote 2 letters; 18 wrote 3 let­ters; 11 wrote 4 letters; 30 wrote 5 to 10 let­ters; and 9 wrote 11 to 43 letters. The purpose of follow-up letters was associated with the age of the writer (P < .001) and with the writ­er’s sex (P < .001). Women were more likely to write “Show of support” and “Romance” follow-up letters; men were more likely to write “Spiritual” follow-up letters (Table 2).

Results suggested that the purpose of the initial letter was a reasonable predictor of the purpose of follow-up letters (P < .001) (Table 3). The murderer never responded to any letters. Letters were most often writ­ten from his state of incarceration; next, from contiguous states; then, from non-contiguous states; and, last, from interna­tional locations (P < .001).

Of the initial letters from writers who wrote ≥10, 60% were categorized as “Acquaintance” and 20% as “Romance.” The writer who wrote the most letters (43) moved during the course of her letter-writing to live in the same state as the murderer; she stated in her letters that she did so to be closer to him and to be able to attend his court hearings. Four other writers, each of whom wrote >5 letters, stated that they had traveled to the murderer’s state of incarcera­tion to attend some of his hearings in person.

Composite examples of more common categories of letters
Names and other pertinent identifying information have been changed.

Acquaintance. Hi, Steve. I’ve been follow­ing your case and just wanted to write you so that maybe we could be friends or keep in touch since you’re probably pretty bored. I’m a 27-year-old college student studying market­ing and working at Applebee’s as a waitress (for now) until I can land my dream job. I’ve enclosed a picture of me and my dachshund along with a photo of my favorite beach in the world. Write me back if you want. Jenny.

Show of support. Steve: I’ve been really wor­ried about you since first seeing you on TV. You look different lately and I hope they’re treating you OK and feeding you decent food. In case they’re not, I’ve enclosed a little something to buy yourself a treat. Just know that there are many of us that care about you and are really pulling for you to be strong in this tough situ­ation you’re in. Yours truly, Karen.

Romance. Dearest Steven: My mind has been filled with thoughts of you and of us since I last saw you in my dreams! Be strong, because you are going to beat this once they understand that you are not responsible for what happened! Don’t you see, sweetie, the system failed you, and now you’re caught up in something that you will soon overcome. When I think of the day that you get released, and how we’ll be able to settle down some­where together, it gets me incredibly excited. You and I are meant to be together, because I understand you and can help you get better. I love you, Steven! Please write me back so that I know we’re on the same page about our plans for the future. Love, ♥ Your sweetie, Rachel.

Spiritual. Dear Child of God: The Lord has a plan for you. I know that things right now might be confusing, and you’re in a black place, but He is there right beside you. If you need some reading materials to give you com­fort, just let me know and I can get a Bible to you along with some other books to give you solace and strengthen your walk with Him. God forgives you and he loves you so much! Much love in Christ, Mary.

Discussion
Given that the mass murderer in this study was a young man, it is not surpris­ing that 78% of writers of initial letters were women. However, it is interesting that, among women’s initial letters, 44% were “Acquaintance” letters and only 15% were categorized as “Romance.”

Given the severity of the murderer’s crime, it is remarkable that he received only 1 “Hate mail” letter.

Initial “Spiritual” letters were more likely to be followed by letters of the same category than any other category; “Romance” letters were a close second. This demonstrates the consistent efforts of writers in these 2 categories. Highly persis­tent writers (≥10 letters) were most likely to fall into “Acquaintance” and “Romance” categories. The persistence of these writers is remarkable, in view of the fact that none of their letters were answered. We hypoth­esize that the killer did not reply because he had no interest in correspondence.

Similarities to stalking. Given that 9 writ­ers wrote >10 letters each and 2 wrote >20 each, elements of their behavior are not unlike what is seen in stalkers.³ Consistent with the stalking literature and Mullen et al4 stalker typology, many writers in this study appeared to seek intimacy with the perpetrator through “Romance” or “Show of support” letters, and might be akin to Mullen’s so-called intimacy-seeking stalker. Such stalkers’ behavior arises out of loneliness, with a strong desire for a rela­tionship with the target; a significant per­centage of such stalkers suffer a delusional disorder.

Mullen’s so-called incompetent suitor stalker is similar to the intimacy-seeking type but, instead, has an interest in a short-term relationship and is far less persistent in his (her) stalking behavior⁴; this type might apply to the writers in this study who wrote >1 but <10 letters.

Two additional observations also are notable when trying to characterize people who write letters: (1) A high percentage of people who stalk a celebrity suffer a psy­chotic disorder^5,6; (2) 4 letter-writers trav­eled, and 1 relocated, to the murderer’s state of incarceration to attend his hearings and be closer to him.

This study has limitations:
   • categorization of letters is inherently subjective and the categories themselves were created by the researchers
   • the nature and categorization of such letters might vary considerably with the age and sex of the violent criminal; our findings in this case are not generalizable.

Last, researchers who plan to study writers of letters to incarcerated criminals should consider sending a personality test and other questionnaires to those writers to understand this population better.

Treatment considerations
Psychiatrists treating patients who seek a romantic attachment with a violent person should consider psychotherapy as a means of treating possible character pathology. The desire for romance with a violent crimi­nal was greater among repeat writers (20%) than in initial letters (15%), suggesting that people who have a strong inclination to associate with a violent person might benefit from exploring romantic feelings in therapy. Specifically, therapists would be wise to explore with such patients the possibility that they experienced violence or verbal abuse in childhood or adulthood.

To the extent that evidence of prior abuse exists, a diagnosis of posttraumatic stress disorder (PTSD) might be appro­priate; specialized therapy for men and women with a history of abuse might be indicated. It is important to provide vali­dation for patients who are victims when they describe their abuse, and to stress that they did nothing to provoke the violence. Furthermore, investigation of why the patient feels drawn romantically toward a violent criminal is helpful, as well as an examination of how such behavior is self-defeating.

There might be value in having patients keep a journal in lieu of actually sending letters; there is evidence that “journaling” can reduce substance use recidivism.⁷ This work can be performed in conjunction with group or individual psychotherapy that addresses any history of abuse and subse­quent PTSD.

Many patients are reluctant to discuss their romantic feelings toward a violent criminal until the psychiatrist has estab­lished a strong doctor−patient relationship. Last, clinicians should not hesitate to refer these patients to a therapist who specializes in domestic violence.

Related Resource
• Marazziti D, Falaschi V, Lombardi A, et al. Stalking: a neuro­biological perspective. Riv Psichiatr. 2015;50(1):12-18.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

Lab mouse

The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.

Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.

Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.

Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.

“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.

These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.

“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.

So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.

Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and proliferation, hematopoietic stem cell function, and blood formation.

“We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” Dr Reya said.

To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.

In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.

Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great translational interest as a target for antibody-mediated therapy.

“There’s been great progress in pediatric leukemia research and treatment over the last few years,” Dr Reya said. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Micrograph showing TTP

Image by Erhabor Osaro

Researchers say they have uncovered a new avenue for therapeutic intervention in thrombotic thrombocytopenic purpura (TTP).

The team discovered how autoimmune antibodies in a TTP patient recognize and bind to ADAMTS13.

They believe this knowledge could help them alter ADAMTS13 to produce a therapeutic enzyme that can elude recognition by autoimmune antibodies yet still retain its ability to cleave von Willebrand factor.

Such an enzyme could be given to TTP patients in the hospital to speed recovery and cut the cost of treatment.

Long Zheng, MD, PhD, of the University of Alabama at Birmingham, and his colleagues described this work in PNAS.

The researchers found that 5 small loops in ADAMTS13’s amino acid sequence are necessary for autoantibodies to bind to ADAMTS13.

Cutting or substituting several amino acids out of any of the 5 loops prevented binding. Small deletions in a loop also left the enzyme unable to cleave von Willebrand factor.

“This was really surprising,” Dr Zheng said. “It’s like a table with 5 legs. If you take 1 away, it should still stand, but, somehow, it collapsed. This suggests that you need the coordinated activity of all 5.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor.

Analyses of autoantibodies from 23 more TTP patients revealed that most use the same binding site. This suggests modifying the ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

Dr Zheng and his colleagues first isolated messenger RNAs that code single chains of variable regions of monoclonal antibodies from B cells collected from patients with acquired TTP.

The team used phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies were then expressed in E coli cells, purified, and biochemically characterized.

Three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen exchange with deuterium on each amino acid residue except proline.

After the reaction was stopped, the protein was cut into small pieces (or peptide fragments) and run through high-performance liquid chromatography for separation and mass spectrometry for identification.

Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the 3 high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients.

The results show that this particular binding epitope is common among patients with acquired autoimmune TTP.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Charles M. Rubin, MD

Photo courtesy of University

of Chicago Medicine

Charles M. Rubin, MD, an associate professor of pediatrics at the University of Chicago Medicine, has passed away at the age of 62.

Dr Rubin died while at work on July 17.

He had just arrived at the pediatric clinic at the University of Chicago Medicine Comprehensive Cancer Center at Silver Cross Hospital in New Lenox when his heart stopped.

Resuscitation efforts were unsuccessful.

An authority on pediatric cancers, Dr Rubin had a particular interest in brain tumors and cancer occurring in children with genetic syndromes. He combined experience in basic laboratory research on the genetics of cancer with broad clinical expertise.

“I can’t put into words how much I respected him,” said colleague Tara Henderson, MD, associate professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago’s Comer Children’s Hospital.

“He was amazingly knowledgeable, compassionate, and thoughtful—traits at the core of our program. I take his influence with me as I care for my patients. He could also be funny, with a dry, quiet sense of humor. We never knew when it was coming. We miss him dearly.”

Dr Rubin was born February 10, 1953, in Long Branch, New Jersey. He earned his bachelor’s degree from the University of Pennsylvania in 1975 and his medical degree from Tufts University School of Medicine in 1979.

Dr Rubin completed his pediatric residency at the Children’s Hospital of Philadelphia in 1982, followed by a fellowship in pediatric hematology/oncology at the University of Minnesota in 1985.

He went to the University of Chicago in 1985 as a cytogenetics and molecular biology fellow in the laboratory of Janet Rowley, MD, an internationally recognized pioneer in understanding the genetics of cancer.

Dr Rubin joined the faculty as an assistant professor of pediatrics and medicine and a member of the university’s Cancer Research Center in 1987. In 1991, he and adult oncologist Funmi Olopade, MD, co-founded the university’s Cancer Risk Clinic.

“Chuck Rubin was one of the finest individuals I have ever known,” said Michelle Le Beau, PhD, a former colleague in the Rowley laboratory and now director of the University of Chicago Medicine Comprehensive Cancer Center.

“He was a consummate academician and physician who blended compassion and sensitivity with brilliant clinical acumen. His dedication to his family, his patients, and the University of Chicago was selfless and unparalleled. It was a privilege to work with him and an honor to learn from his example.”

Although Dr Rubin continued to work closely with his basic-science colleagues, contributing to more than 50 original reports in academic journals, his interests increasingly focused on patient care.

At the same time, he took on several administrative roles. He served as course director for pediatric grand rounds and the medical center’s pediatric tumor board.

He directed the pediatric hematology/oncology fellowship for 7 years and the pediatric neuro-oncology program for 10 years. He also volunteered for medical staff positions in various educational and rehabilitative summer camps for children with cancer.

Dr Rubin was a leader in the University of Chicago Medicine’s efforts to take a research-driven approach to pediatric cancer care into the community, serving as director of pediatric hematology/oncology outreach since 2008.

Dr Rubin is survived by his wife, Gretchen; their 4 daughters, Elizabeth, Jane, Lucy, and Claire; brothers Michael, Peter, and Richard; and many nieces and nephews.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Genome testing

Photo courtesy of NIGMS

Investigators have identified a single nucleotide polymorphism (SNP) that seems to confer shorter survival in patients with multiple myeloma (MM).

The group found a significant association between survival and a SNP near the gene FOPNL on chromosome 16p13.

On average, MM patients with this SNP (rs72773978) died 1 to 3 years sooner than patients without it.

The investigators pinpointed the SNP via genome-wide association studies and verified its impact on survival in patient populations from North America and Europe.

The research, which is published in Nature Communications, included 1635 MM patients.

“This is the largest study of inherited genetics and myeloma survival to date,” said Nicola Camp, PhD, of the Huntsman Cancer Institute in Salt Lake City, Utah.

“We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this. The ability to stratify patients based on their genetic make-up opens the door to personalizing their treatment and care.”

For this study, Dr Camp and her colleagues first conducted a meta-analysis of 306 MM patients treated at University of California, San Francisco and 239 patients treated at the Mayo Clinic.

The investigators found a significant association between rs72773978 and survival. Patients with the minor allele had an increased risk of mortality compared to patients who were homozygous for the major allele (hazard ratio=2.65).

The team then conducted a replication meta-analysis of 1090 MM cases, including 772 European patients from the IMMEnSE consortium and 318 from the Utah cohort. Again, there was a significant association between rs72773978 and survival (hazard ratio=1.34).

Although the investigators don’t yet understand why the SNP is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification.

Analyses of the different MM patient datasets showed that individuals with the worst outcomes have abnormal amounts of FOPNL and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.

“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis,” said Elad Ziv, MD, of the University of California, San Francisco.

“If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression. Such knowledge could ultimately lead to better therapies.”

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

Time-lapse images of

apoptosis in cancer cells

For the first time, researchers have synthesized compounds that induce rapid apoptosis in leukemic cells.

The team synthesized several members of the family of dimeric nuphar alkaloids, which are compounds previously isolated from the yellow pond lily.

These structurally complex molecules have proven capable of inducing apoptosis in human leukemia cell lines faster than any other small molecule tested to date.

The researchers were also able to synthesize some related structures that they predict might exist in nature but have not yet been found.

Their work is published in Angewandte Chemie International Edition.

“We anticipate that these compounds will serve as useful tools for dissecting an important, but as yet undefined, step in the regulation of apoptosis,” said study author Jimmy Wu, PhD, of Dartmouth College in Hanover, New Hampshire.

The research also provides a means to a steady supply of the active compounds for further study.

Preliminary biological tests conducted by Alan Eastman, PhD, also of Dartmouth College, suggest the compounds, both the naturally occurring ones and those predicted to exist in nature, are capable of inducing extremely rapid apoptosis in leukemic cells.

“Studies to clarify the biological mechanism by which they operate are ongoing,” Dr Wu said.

He noted that there have been 2 reports that attempt to explain the molecules’ mechanism of action. But these are incomplete, and more research is required to fully reveal how these compounds work.

“A better understanding of the biological basis of how the dimeric nuphar alkaloids can so rapidly induce cell death may lead to novel points of intervention for the design of prospective therapeutics,” Dr Wu concluded.

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”

A conceptual image of the

zebrafish used in the study

Image by Jonathan Henninger

and Vera Binder

Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).

The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.

The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.

“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.

“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”

Dr Zon and his colleagues described their work with EETs in Nature.

EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.

In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.

The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.

The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.

The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.

“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”

That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.

“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”

In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.

EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.

After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.

“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”