Significant Adverse Risk Factor Research Articles

Impact of Pretransplant Cytogenetics and Marrow Remission Status on Outcome of Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation Conditioned with Busulfan and Fludarabine

BACKGROUND: The purpose of this study was to determine the impact of cytogenetics and remission status on outcome of allogeneic stem cell transplantation (alloSCT) conditioned with busulfan and fludarabine based regimens for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).METHODS: We retrospectively collected data on all consecutive patients (pts) who received busulfan and fludarabine with alloSCT at MD Anderson Cancer Center for AML and MDS between January 2001 and December 2007. All pts received busulfan and fludarabine in myeloablative (busulfan 130 mg/m2 for 4 days and fludarabine 40 mg/m2 for 4 days) or reduced intensity doses. ATG was added to the regimen for unrelated and mismatched related donor transplants. Pts in first complete remission (CR) or advanced CR (2nd or 3rd CR) and also pts with morphologic remission but platelet count <100,000/mcl (termed “marrow remission”) were included. Pts were divided into subgroups according to cytogenetic abnormalities based on the MRC, SWOG, CALGB, and the recently described Dana-Farber (DF) categorization systems. Cox's regression analysis was used to evaluate the impact of the prognostic factors on overall survival (OS), progression free survival (PFS) and non-relapse mortality (NRM). The cumulative incidence of NRM was estimated considering progression of disease as a competing risk.RESULTS: 215 pts were included in the analysis with a median age 47 (range 13–69). Four pts were less than 18 years old and 117 (54%) were older than 45 years. Diagnoses were AML (n=176), MDS (n=14) and AML evolving from MDS (n=25). Disease status at alloSCT was; first CR (n=111), advanced CR (n=65) and marrow remission (n=39). Donors were matched related (n= 114), matched unrelated (n=86), 1 antigen mismatched related (n=7), or 1 antigen mismatched unrelated (n=6). Stem cell source was bone marrow (n=84) or peripheral blood (n=131). Median follow-up time of surviving pts was 36 months (range 1.6–85). The 3 years actuarial probabilities of OS and PFS were 59% and 51%, respectively. The 3 years cumulative incidence of NRM was 22%. On univariate analysis, adverse cytogenetics according to the DF scoring system (but not the MRC, SWOG and CALGB classifications) was associated with a significantly lower OS (HR=1.8, P=0.03) and PFS (HR=1.7, P=0.02). Three year PFSs for pts in CR with favorable, intermediate or adverse cytogenetics were 58%, 56% and 49%, respectively (Figure 1). In addition, pts in marrow remission compared to those who were in first or advanced CR with full platelet recovery prior to transplant had a significantly poorer OS (41 vs 63 % at 3 yrs, HR=2.1, P=0.01), and PFS (33 vs 55% at 3 yrs, HR=1.9, P=0.01). Outcomes were comparable for pts in first and advanced CR (Figure 2). AML evolving from MDS was a significant adverse risk factor for OS (HR=1.9, P=0.04) but not for PFS (HR=1.6, P=0.08). On multivariate analysis, pts had the highest mortality rate if they had both a marrow remission and adverse cytogenetics, classified according to the DF system (HR (OS)=3.4, P<0.001; and HR (PFS)=3.2, P<0.001). A diagnosis of AML evolving from MDS remained as a significant adverse factor for OS on multivariate analysis (HR=2.1; P=0.01). Significant adverse prognostic factors for NRM on univariate and multivariate analysis included alloSCT later than one year after diagnosis (HR=2; P= 0.02) and AML evolving from MDS (HR=2.6; P=0.01). There was no impact of cytogenetics on the rate of NRM.CONCLUSION: Cytogenetic characteristics and remission status before alloSCT correlate with transplantation outcome in MDS or AML pts conditioned with busulfan and fludarabine. This regimen with alloSCT produced improved outcomes compared to published results with standard chemotherapy for pts in the intermediate and high risk cytogenetic groups. [Display omitted] [Display omitted]

Spinal Cord Stimulation for Chronic Pain: Causes of Long-Term Paddle-Lead Failure

Objectives. This study is to evaluate long-term lead failure in spinal cord stimulation. Materials and Methods. One hundred and seven patients with permanently implanted spinal cord stimulators were studied for 14years. All suspected paddle-lead failures were studied prospectively using preoperative radiography and intraoperative electric interrogation. Lead failure was defined as complete loss of electric stimulation due to lead malfunction. Primary lead failure was defined as first lead failure after permanent implantation of a new lead and recurrent lead failure was defined as any lead failure after any lead replacement. Results. Primary lead failure occurred in 14.9% and recurrent lead failure in 56.2%. Two (12.5%) of the primary failures and two (22.2%) of the recurrent failures were due to lead fractures. The mean time to primary lead failure was 37.9months and to recurrent lead failure was 23.7months. Conclusion. The incidence of primary lead failure remains low at 14.9% in the long run, but it is a significant adverse risk factor for recurrent paddle-lead failure. Great care should be undertaken to prevent lead failures by appropriate anchoring.

Allogeneic HSCT for Hematologic Malignancies in 145 Patients - Identical Biologic Prognostic Factors Affect Outcome Despite Different Conditioning Regimen Intensities.

Analysis of pre-transplant variables affecting the outcome of allogeneic HSCT after 100 mg/m2 melphalan (± 50 mg/kg cyclophosphamide depending upon prior autograft) in 91 adult patients with hematologic malignancies identified refractory disease, poor performance status (ECOG 2/3), elevated LDH, and donor age >45 years as significant adverse prognostic factors affecting overall survival (OS) (Mehta et al. ASH 2006, BMT 2006). GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched siblings) or tacrolimus-mycophenolate (other donors). The patients were treated at NU. The outcome of 54 patients with hematologic malignancies treated at UIC with more intensive conditioning regimens was studied to see if the prognostic factors identified at NU were applicable to them. The conditioning regimens at UIC comprised 12.8 mg/kg IV busulfan + 120–160 mg/m2 fludarabine (n=36) or 140 mg/m2 melphalan + 150 mg/m2 fludarabine (n=18). Tacrolimus and methotrexate were used for GVHD prophylaxis. While the characteristics of the two patient populations were significantly different (especially diagnosis), transplant-related mortality and relapse rates were not significantly different for the two centers. As the table below shows, chemorefractory disease, poor performance status, and elevated LDH were adverse risk factors for OS in both groups of patients.VariableMel100 (NU)BuFlu/Mel140 (UIC)(OS)RR (95% CI)PRR (95% CI)PRefractory disease3.0 (1.7–5.0)0.00014.5 (1.8–11.4)0.002Performance status 2/33.9 (2.2–6.8)<0.00016.0 (2.0–17.8) 0.001Elevated LDH2.1 (1.3–3.5)0.0044.2 (1.7–10.8)0.003Donor age >451.9 (1.2–3.2) *0.0090.24 (0.06–1.03) *0.06*Note the disparity - unfavorable in the NU group and favorable in the UIC groupHowever, donor age >45, an adverse risk factor in the NU population, appeared to be a borderline favorable factor in the UIC population. HLA mismatch was found to be an additional significant adverse risk factor in the combined population when it did not reach statistical significance in either group individually. The figures below shows the effect of the number of adverse risk factors (excluding donor age) on DFS and OS in the entire group of 145 patients (P<0.0001 for each). We conclude that biologic disease-related risk factors such as chemorefractoriness and elevated LDH, and patient-related risk factors such as poor performance status appear to be applicable to allograft recipients irrespective of the intensity of the underlying transplant procedure. The reason for the disparate effect of donor age in the two groups of patients is unclear, and needs to be studied further. [Display omitted] [Display omitted]

Lactate Dehydrogenase (LDH) Level Predicts the Outcome of Patients with Acute Myelogenous Leukemia (AML) Following HLA-Matched Sibling Bone Marrow Transplant (BMT).

Active disease (ActDis), poor-risk cytogenetics, and older age have historically been considered the most important adverse risk factors for survival after BMT for AML. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 43 years (range 19 to 62). The median LDH level at the time of BMT was 204 U/L (range 93–1555 U/L; normal 100–220 U/L). Forty-one patients were in either first (n= 30) or second complete remission (n=11; CR). 46 patients with ActDis were treated. The 87 patients were then classified according to the SWOG/ECOG (Blood 96:4075, 2000), MRC (Blood 92:2322, 1998), and CALGB (Blood 100:4325, 2002) cytogenetic classification systems. With a median follow-up of 56.0 months (range 4.5–107.8 months), the median relapse-free survival is 13.5 months for patients in CR1 and 4.1 months for patients in CR2. The relapse-free survival of patients with ActDis was 5.5 months. A Cox proportional hazards analysis that included gender, age, LDH, disease status, cytogenetic risk group, preparative regimen, source of stem cells, and CMV status was performed for overall and relapse-free survival. Significant risk factors for shorter survival in univariate analysis included male gender, LDH >330 U/L (but not LDH >220 U/L or per 100 U/L increase), and peripheral stem cells as a source of hematopoietic reconstitution (n = 7). Surprisingly, a male donor to a male recipient was also an adverse risk factor (p<0.001). However, in multivariable analysis, only LDH >330 U/L (p=0.002), source of stem cells (p=0.019), and male donor to male recipient (p<0.001) remained as significant adverse risk factors. In fact, patients with ActDis and an LDH ≤ 330 U/L had similar survival to patients treated in remission, while patients with ActDis and LDH > 330 U/L had significantly worse survival as shown below. We conclude that high LDH (>1.5X upper limit of normal) is a significant adverse risk factor for survival after BMT for AML and predicts outcome better than more traditional risk factors such as age, disease status, and cytogenetic risk profile. [Display omitted]

Uniform Approach Better Defines Natural History of Transient Myeloproliferative Disorder (TMD) in Down Syndrome (DS) Neonates: Outcomes from Children' Oncology Group (COG) Study A2971.

TMD is solely found in DS infants in the first few months of life & is distinguished from congenital AML primarily by its spontaneous resolution. A2971, the largest study of TMD conducted to date, defines the natural history of this disorder by utilizing uniform observation & treatment guidelines. A total of 136 DS patients (pts) <90 days (d) of age were enrolled from 1999–2004 with median follow-up of 745d(0–2187). Pts were assigned to observation(n=110) or intervention(n=26) arms based upon clinical severity. Median age at diagnosis was 5d(0–58) with median hematologic values of WBC 32,800(4,800 – 259,100), hemoglobin 15(5–22.5), platelets 125K(10–958K), peripheral blasts 25%(0–92) & bone marrow blasts 15%(0–95). Hepatomegaly (HM) was seen in 59%, splenomegaly in 39%, & pleural or pericardial effusion in 10% & 19%. Pts required intervention due to hyperviscosity(11%), blast count >100,000/μl(25%), organomegaly(OM) with respiratory(resp) compromise(43%), CHF(11%), hydrops fetalis(21%), liver dysfunction(43%), renal dysfunction(14%), or DIC(25%). For pts who required intervention(n=29, 21%), 9 pts(31%) received leukopheresis/exchange transfusion (Leuk/Exch). 26(90%) pts received low-dose AraC (3.33 mg/kg/24 hrs continuous infusion on days 0–4) for OM, organ dysfunction causing resp compromise, or continued symptoms after Leuk/Exch. Among all pts, 3-year overall survival(OS) was 77 ± 8% & event-free survival(EFS) was 73 ± 9%. 28 deaths were noted (15 related, 12 unrelated to TMD or therapy, 1 unknown). Median time to TMD resolution (defined as resolution of peripheral/ bone marrow blasts, OM, effusions & organ dysfunction) was 46d(7–757). Peripheral blast resolution was attained in a median of 35d (2–147). To date, 16 pts (12%), including 4 treated with AraC, developed AML/MDS at a median time of 355d(118–888). We identified 3 distinct groups of TMD pts: low risk (without palpable HM or hepatic dysfunction, n=52, 38%), intermediate risk (HM with non-life threatening hepatic dysfunction, n=55, 40%), & high risk (WBC>100K or life threatening cardio-resp compromise due to TMD, n=29, 21%). The OS for low, intermediate & high risk groups was 92 ± 8%, 82 ± 11% & 49 ± 20% and EFS was 83 ± 11%, 64 ± 15% & 36 ± 19%, respectively(p<0.001 for low vs high & intermediate vs high risk groups for OS & EFS). WBC >100K (Hazards Ratio-HR 3.57, p=0.004) & presence of hepatomegaly (HR 3.6, p=0.009) were significant adverse risk factors for OS in univariate analyses. This study confirms that most TMD pts undergo spontaneous resolution of disease without intervention, further clarifies the natural history of TMD, & provides baseline comparisons for upcoming COG trials.

2361: The Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy (PORT) and Pathologic Risk Groups in Patients With Head and Neck Cancer (HNC)

2361: The Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy (PORT) and Pathologic Risk Groups in Patients With Head and Neck Cancer (HNC)

Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients

To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.

Prognostic relevance of P-cadherin expression in melanocytic skin tumours analysed by high-throughput tissue microarrays

Aim: To investigate whether protein expression or cellular localisation of P-cadherin is associated with clinicopathological characteristics in benign and malignant melanocytic skin tumours. Experimental design: P-cadherin expression and the Ki-67...

A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors.

The goal of this multi-institutional retrospective study of children with intracranial ependymoma was to identify risk factors associated with unfavorable overall survival (OS) and event-free survival (EFS). Clinical data, including demographics, tumor location, spread, histology, details of surgery, radiation treatment, and chemotherapy were collected. Clinical characteristics and univariate and multivariate analyses of risk factors for OS and EFS are presented. Eleven U.S. institutions contributed 83 patients treated from 1987 to 1991. The OS at 5 and 7 years was 57% and 46%, and EFS at 5 and 7 years was 42% and 33%. Patients 3 years of age or younger differed from the older group by more common infratentorial location, less common gross total resection (GTR), and postoperative use of chemotherapy rather than radiation. This younger group of patients had worse survival (P < 0.01) than the older age group. Other than young age, less than GTR and World Health Organization (WHO) II grade 3 histology were significant adverse risk factors for EFS in univariate and multivariate analyses. OS shared the same adverse risk factors except for histology in multivariate analysis, which was only of borderline significance (P = 0.05). Progression at the original tumor location, present in 89% of patients, was the major pattern of tumor recurrence. Adjuvant chemotherapy in the group older than 3 years or craniospinal radiation in M0 patients did not significantly change EFS. Adverse outcome in childhood intracranial ependymoma is related to age (3 years or younger), histology (grade 3), and degree of surgical resection (less than GTR). New approaches, particularly for local tumor control in younger patients, are needed to improve survival.

Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies

Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P=0.008), age >10 years (P=0.02), and have a leukocyte count > or =50,000/L (P <0.0001). Nearly all Ph+ (96.7%) and Ph (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD =1.2%), respectively (P <0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL.

Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies

BACKGROUND Children with Philadelphia (Ph) chromosome positive (+) acute lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment failure. In this report, the authors assessed the outcome of Ph+ ALL in a large cohort of children treated on contemporary intensive chemotherapy protocols of the Children's Cancer Group (CCG). METHODS This study included 1322 children enrolled between 1988-1995 on CCG risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty patients had a t(9;22)(q34;q11) translocation and were referred to as Ph+; 1292 were Ph negative(-). Outcome analyses used standard life table methods. RESULTS Compared with Ph- ALL patients, Ph+ ALL patients were more likely to be black (P = 0.008), age >10 years (P = 0.02), and have a leukocyte count ≥50,000/L (P < 0.0001). Nearly all Ph+ (96.7%) and Ph- (98.3%) patients achieved remission after induction therapy, yet event free survival outcome was significantly worse for Ph+ patients compared with Ph- patients, with 4-year estimates of 20.1% (standard deviation [SD] = 9.1%) and 75.8% (SD = 1.2%), respectively (P < 0.0001). This difference was maintained among patients regardless of presenting leukocyte count, age, or early response to therapy. Ten Ph+ patients underwent bone marrow transplantation (BMT) at the time of first remission; six of these patients remained event free at the time of analysis, and represent the majority (six of eight) of patients surviving event free. CONCLUSIONS The findings of the current study confirm that Ph chromosome positivity represents a significant independent adverse risk factor for childhood ALL that has not been abrogated by current intensive chemotherapy programs. BMT at the time of first remission, as well as other alternative strategies employing biotherapeutic agents, should be considered in future front-line trials for pediatric patients with Ph+ ALL. Cancer 1998;83:2030-2039. © 1998 American Cancer Society.

Preventing postoperative recurrence of Crohn's disease

Risk factors for recurrence of Crohn's disease and the evidence for progress in reducing recurrence following resection were reviewed. A Medline based literature review was carried out. Only smoking has been confirmed as a significant adverse risk factor for recurrence. Evidence for differing recurrence rates in fibrostenosing disease and perforating disease is inconclusive, but such a classification along with the endoscopic findings of recurrence may have a place in the analysis of therapeutic trials. Minimal resectional surgery with clearing of only macroscopic disease seems to be justified, with no clear benefits from different anastomotic techniques. Recent trials offer encouraging evidence of the usefulness of 5-aminosalicylic acid, particularly higher-dose regimens started early after resection, although the long-term benefits are uncertain. The oral steroid, budesonide, offers a potent treatment with minimal side-effects, but evidence of its prevention of recurrence is presently weak.