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1.  Allogeneic Hematopoietic Cell Transplantation for Advanced Polycythemia Vera and Essential Thrombocythemia 
Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69%for ET and 67%for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus- host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47%and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.
PMCID: PMC3499973  PMID: 22449610
Transplantation; PV; ET
2.  The involvement of Galectins in the modulation of the JAK/STAT pathway in myeloproliferative neoplasia 
In patients with myeloproliferative neoplasia (MPN) the development of fibrosis and increased vessel density correlate with poor prognosis. The JAK2V617F mutation constitutively activates JAK2, which phosphorylates signal transducer activator of transcription (STAT), up-regulating vascular endothelial growth factor (VEGF), which might be responsible for angiogenesis in MPN. Galectins are involved in the development of fibrosis and angiogenesis and might also be involved in activation of the JAK/STAT pathway in MPN.
106 MPN patients, 36 essential thrombocythemia (ET), 25 polycythemia vera (PV) and 45 primary myelofibrosis (PMF), were analyzed for the expression pattern of galectin-1, galectin-3, pSTAT3, pSTAT5 and MVD by immunostaining of bone marrow biopsy sections followed by automated image analysis. The JAK2 mutational status was analysed through real time PCR in blood samples.
The expression of galectin-1 was significantly higher in all MPN patients compared to normal controls. Galectin-3 was expressed more in PV patients. MVD was significantly higher in all MPN patients and correlated with galectin-1 and pSTAT5 expression. pSTAT5 expression showed a trend of higher expression in patients carrying the JAK2V617F mutation as well as in PV patients. PMF patients and all JAK2V617F positive patients showed a significantly higher pSTAT3 expression compared to control and ET patients.
The findings suggest the involvement of galectin-1 in MPN development, regardless of the subtype. Furthermore involvement of galectin-3 in PV development, pSTAT5 in that of PV and JAK2V617F positive patients and angiogenesis, as well as pSTAT3 is involved in the pathogenesis of PMF.
PMCID: PMC3384397  PMID: 22762031
MPN; myeloproliferative neoplasia; galectin; JAK; STAT; angiogenesis; MVD
Patients with chemorefractory mantle cell lymphoma (MCL) have poor prognosis. We used the CIBMTR database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced intensity/non-myeloablative conditioning (RIC/NST), during 1998–2010. We analyzed non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients received MA, and 128 underwent RIC/NST. Median ages are 54 and 59 years for MA and RIC/NST allo-HCT recipients, respectively. Median follow-up after MA and RIC/NST allo-HCT is 35 months and 43 months, respectively. At 3 years, comparing MA with RIC/NST allo-HCT, no significant differences were found in terms of NRM (47% vs. 43%; p-value=0.68), relapse/progression (33% vs. 32%; p-value=0.89), PFS (20% vs. 25%; p=0.53), and OS (25% vs. 30%; p-value=0.45). On multivariate analysis no significant differences were observed in NRM, relapse, PFS and OS between MA and RIC/NST allo-HCT; however, receiving a bone marrow or T-cell depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Despite a refractory disease state, approximately a fourth of MCL patients can attain durable remissions after allo-HCT. Conditioning regimen intensity did not influence the outcomes of patients after allo HCT.
PMCID: PMC3640440  PMID: 23333532
Mantle cell lymphoma; allogeneic transplantation; chemotherapy unresponsive; graft-versus-host disease
Using CIBMTR data we compared the transplant outcomes of patients with chronic myeloid leukemia (CML) who were non-smokers (NS) and past or current smokers (PCS). There were 2193 NS and 625 PCS who received matched sibling and unrelated donor allografts for CML in first chronic phase. We looked for dose effects and identified low and high dose smoking groups (≥10 pack years, >1 pack per day). Outcomes were adjusted for known prognostic variables including the EBMT risk score. In multivariate analyses of sibling allograft recipients, relapse risk was higher (RR 1.67, p=0.003) in smokers than NS but the dose effects were not consistent. High dose smokers experienced a 50% TRM vs. 28% in the NS group at 5 years on univariate analysis and the RR was 1.57 (p=0.005) on multivariate analysis. Overall survival at 5 years was 68% in NS vs. 62% in the low dose smoking group vs. 50% in the high dose smoking group (p<0.001). Smoking did not significantly affect outcomes in unrelated donor recipients but numbers were smaller. High dose smoking is associated with a reduction in overall survival in patients having sibling allografts for CML. A prospective study with detailed demographic, pulmonary function and quality of life data would improve our understanding of this issue.
PMCID: PMC2768519  PMID: 19747636
smoking effect; hematopoietic cell transplantation; outcomes; chronic myeloid leukemia; dose effect
5.  Randomized clinical trial of an intensive nursing-based pain education program for cancer outpatients suffering from pain 
Supportive Care in Cancer  2008;17(8):1089-1099.
The prevalence of pain in patients with cancer is still too high. Factors relating to ineffective pain treatment fall into three categories: the health care system, professional care providers, and patients. In patients, various barriers lead to noncompliance. Previous educational interventions have increased their knowledge of pain and decreased short-term pain levels. In this randomized controlled trial, the authors investigated how an intensive home-based education program given by nurses affected short-term and long-term pain levels.
Materials and methods
One hundred and twenty cancer patients were randomized to receive either the pain education program (PEP) or usual care. Pain, knowledge, quality of life, anxiety, and depression were measured at baseline and after 4 and 8 weeks. In the intervention group, effects on symptom levels were communicated to the treating physician.
The level of pain had decreased at 4 weeks, but not at 8 weeks. Significant decreases in pain only persisted in those patients with a high pain score at baseline. Knowledge of pain significantly increased in the intervention group. No correlation was found between increased pain knowledge and decreased pain levels.
The PEP given by nurses lowered pain intensity levels in cancer patients and increased their knowledge of pain. More attention should be paid to patient education and to communication between patients and health professionals regarding pain and pain management.
PMCID: PMC2707949  PMID: 19104843
Randomized clinical trial; Pain education program; Cancer outpatients; Pain; Pain management
6.  The Granularity of Medical Narratives and Its Effect on the Speed and Completeness of Information Retrieval 
Abstract Objective: Using electronic rather than paper-based record systems improves clinicians' information retrieval from patient narratives. However, few studies address how data should be organized for this purpose. Information retrieval from clinical narratives containing free text involves two steps: searching for a labeled segment and reading its content. The authors hypothesized that physicians can retrieve information better when clinical narratives are divided into many small, labeled segments (“high granularity”).
Design: The study tested the ability of 24 internists and 12 residents at a teaching hospital to retrieve information from an electronic medical record—in terms of speed and completeness—when using different granularities of clinical narratives. participants solved, without time pressure, predefined problems concerning three voluminous, inpatient case records. To mitigate confounding factors, participants were randomly allocated to a sequence that was balanced by patient case and learning effect.
Results: Compared with retrieval from undivided notes, information retrieval from problem-partitioned notes was 22 percent faster (statistically significant), whereas retrieval from notes divided into organ systems was only 11 percent faster (not statistically significant). Subdividing segments beyond organ systems was 13 percent slower (statistically significant) than not subdividing. Granularity of medical narratives affected the speed but not the completeness of information retrieval.
Conclusion: Dividing voluminous free-text clinical narratives into labeled segments makes patient-related information retrieval easier. However, too much subdivision slows retrieval. Study results suggest that a coarser granularity is required for optimal information retrieval than for structured data entry. Validation of these conclusions in real-life clinical practice is recommended.
PMCID: PMC61337  PMID: 9824804
7.  Salvage Second Hematopoietic Cell Transplantation in Myeloma 
Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM.
PMCID: PMC3816739  PMID: 23298856
Second autologous; transplantation; Multiple myeloma; Relapsed multiple myeloma
8.  Outcome of Lower-Intensity Allogeneic Transplantation in non-Hodgkin Lymphoma After Autologous Transplant Failure 
We studied the outcome of allogeneic transplantation after lower-intensity conditioning regimens (reduced-intensity [RIC] and non-myeloablative [NST]) in non-Hodgkin lymphoma (NHL) relapsing after autologous transplantation. Non-relapse mortality (NRM), lymphoma progression/relapse, progression-free survival (PFS) and overall survival (OS) were analyzed in 263 NHL patients. All had relapsed after a prior autologous transplant and then received allogeneic transplantation from related (n = 26) or unrelated donors (n= 237) after RIC (n = 128) or NST (n = 135), and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2006. Median follow-up of survivors was 68 months (range, 3–111). Three-year NRM was 44% (95% CI, 37%–50%). Lymphoma progression/relapse at three years was 35% (95% CI, 29%–41%). Three-year probabilities of PFS and OS were 21% (95% CI, 16%–27%) and 32% (95% CI, 27%–38%) respectively. Superior performance score, longer interval between transplants, total-body irradiation-based conditioning regimen and lymphoma remission at transplantation correlated with improved PFS. Allogeneic transplantation after lower-intensity conditioning is associated with significant NRM, but can result in long-term PFS. We describe a quantitative risk model based on pretransplant risk factors in order to identify those likely to benefit from this approach.
PMCID: PMC3376237  PMID: 22198543
Non-Hodgkin Lymphoma; Allogeneic; Relapse
9.  Classifying Cytogenetics in Patients with AML in Complete Remission Undergoing Allogeneic Transplantation: A CIBMTR Study 
Cytogenetics play a major role in determining the prognosis of patients with AML. However, the existing cytogenetics classifications were developed on chemotherapy-treated patients and may not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the CIBMTR who underwent HCT for AML in first or second CR between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival (OS). We then defined a new schema specifically applicable to HCT patients using this patient cohort. Under this CIBMTR schema, inv(16) is favorable, complex karyotype (4+ abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5y OS 64%, 18%, and 50%, respectively, p=0.0001). This schema stratified patients into 3 groups with similar non-relapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applied to patients regardless of their disease status (CR1 or CR2), donor type (MRD or URD), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.
PMCID: PMC3224672  PMID: 21810400
AML; cytogenetics; stem cell transplantation
10.  Dietary Acrylamide Intake and the Risk of Lymphatic Malignancies: The Netherlands Cohort Study on Diet and Cancer 
PLoS ONE  2012;7(6):e38016.
Acrylamide, a probable human carcinogen, is present in many everyday foods. Since the finding of its presence in foods in 2002, epidemiological studies have found some suggestive associations between dietary acrylamide exposure and the risk of various cancers. The aim of this prospective study is to investigate for the first time the association between dietary acrylamide intake and the risk of several histological subtypes of lymphatic malignancies.
The Netherlands Cohort Study on diet and cancer includes 120,852 men and women followed-up since September 1986. The number of person years at risk was estimated by using a random sample of participants from the total cohort that was chosen at baseline (n  = 5,000). Acrylamide intake was estimated from a food frequency questionnaire combined with acrylamide data for Dutch foods. Hazard ratios (HRs) were calculated for acrylamide intake as a continuous variable as well as in categories (quintiles and tertiles), for men and women separately and for never-smokers, using multivariable-adjusted Cox proportional hazards models.
After 16.3 years of follow-up, 1,233 microscopically confirmed cases of lymphatic malignancies were available for multivariable-adjusted analysis. For multiple myeloma and follicular lymphoma, HRs for men were 1.14 (95% CI: 1.01, 1.27) and 1.28 (95% CI: 1.03, 1.61) per 10 µg acrylamide/day increment, respectively. For never-smoking men, the HR for multiple myeloma was 1.98 (95% CI: 1.38, 2.85). No associations were observed for women.
We found indications that acrylamide may increase the risk of multiple myeloma and follicular lymphoma in men. This is the first epidemiological study to investigate the association between dietary acrylamide intake and the risk of lymphatic malignancies, and more research into these observed associations is warranted.
PMCID: PMC3377662  PMID: 22723843
We determined treatment-related mortality (TRM), progression free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n=21) or non-Hodgkin lymphoma (NHL, n=19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range, 16–61) and 22 (58%) patients had a Karnofsky performance score less than 90. HCT2 was performed >1 year after HCT1 in 82%. The probability of TRM at day 100 was 15% (95% CI, 3–22%). The 1, 3 and 5 yr probabilities of PFS were 50% (95% CI, 34–66%), 36% (95% CI, 21–52%) and 30% (95% CI, 16–46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50–79%), 36% (95% CI, 22–52%) and 30% (95% CI, 17–46%), respectively. At a median follow up of 72 months (range, 12–124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower TRM than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options.
PMCID: PMC3353768  PMID: 18640574
second autologous transplant; non-Hodgkin lymphoma; Hodgkin lymphoma
12.  Pregnancy After Hematopoietic-cell Transplantation: A Report From the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR) 
Preservation of fertility after hematopoietic-cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the CIBMTR between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N=99) and non-malignant disorders (N=79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative allogeneic HCT (12 women, 50 men) and non-myeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were myeloablative in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5-10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or myeloablative conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.
PMCID: PMC3017731  PMID: 20659574
Allogeneic hematopoietic-cell transplantation; Autologous hematopoietic-cell transplantation; Pregnancy; Fertility Preservation
Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease free survival after allogeneic hematopoietic cell transplantation. In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft versus host disease prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day transplant related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5 year overall survival rates were 37%, 30%, and 40% respectively. Disease-free survival rates were 33%, 27% and 22% respectively. Disease-free survival for patients receiving reduced intensity transplants was comparable, 39% for HLA identical sibling donors and 17% for unrelated donors at three years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival in about one-third of patients.
PMCID: PMC2908949  PMID: 19879949
Myelofibrosis; allogeneic transplantation
We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients age ≥ 18 years undergoing first autologous (n=837) or myeloablative allogeneic hematopoietic cell transplant (HCT) (n=79) between 1995–2003 reported to the CIBMTR. Median follow-up was 81 months for allogeneic HCT vs. 60 months for autologous. Allogeneic HCT recipients were more likely to have high risk disease features including higher stage, more prior chemotherapy regimens and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (RR 4.88, 95% CI, 3.21–7.40, p<0.001), treatment failure (RR 2.06, 95% CI, 1.54–2.75, p<0.001) and mortality (RR 2.75, 95% CI, 2.03–3.72, p<0.001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73–1.72, p=0.59). In fact, for 1 year survivors, no significant differences were observed for TRM, progression, progression-free or overall survival. Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance and earlier year of transplant. In a cohort of mainly high risk DLBCL patients, upfront myeloablative allogeneic HCT while associated with increased early mortality was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.
PMCID: PMC2929576  PMID: 20053330
unrelated; allogeneic transplantation; Hodgkin Lymphoma
To compare the clinical outcomes of older (age ≥ 55 years) non-Hodgkin’s lymphoma (NHL) patients with younger NHL patients (< 55 years) receiving autologous hematopoietic cell transplantation (HCT) while adjusting for patient-, disease-, and treatment-related variables. We compared autologous HCT outcomes in 805 NHL patients age ≥ 55 years to 1,949 NHL patients < 55 years during the years 1990–2000 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). In multivariate analysis, older patients with aggressive histologies were 1.86 times [95% confidence interval (CI) 1.43–2.43, p<0.001] more likely than younger patients to experience treatment-related mortality. Relative death risks were 1.33 times (CI 1.04–1.71, p=0.024) and 1.50 times (CI 1.33–169, p<0.001) higher in older compared to younger patients with follicular grade I/II and aggressive histologies, respectively. Autologous HCT in older NHL patients is feasible but most disease-related outcomes are statistically inferior to younger patients. Studies addressing supportive care particular to older patients who are most likely to benefit from this approach are recommended.
PMCID: PMC2638759  PMID: 19041053
non-Hodgkin’s lymphoma; autologous HCT; relapse; second complete remission; elderly
Reduced intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in Follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for follicular lymphoma in 208 recipients reported to the Center for International Blood and Marrow Transplant Research between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N=120) or reduced-intensity (RIC; N=88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 mo (4–96 mo) after myeloablative conditioning versus 35 mo (4–82 mo) after RIC (p<0.001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63–79%) and 62 (51–72%; p=0.15) and progression free survival (PFS), 67 (58–75%) and 55 (44–65%; p=0.07) respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment related mortality (TRM), lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (RR=2.97, p=0.04) RIC has become the de facto standard in allogeneic HSCT for FL and appears to result in similar long term outcomes. Although disease free survival is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.
PMCID: PMC2531158  PMID: 18215784
Follicular Lymphoma; Allogeneic; Nonmyeloablative

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