Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Donor T-cell chimerism and early post-transplant cytomegalovirus viremia in patients treated with myeloablative allogeneic hematopoietic stem cell transplant.

BACKGROUND: Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia. METHODS: We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia. RESULTS: CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06). CONCLUSION: We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population.

Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.

Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Patients mobilizing large numbers of CD34+ cells ('super mobilizers') have improved survival in autologous stem cell transplantation for lymphoid malignancies.

The cellular composition of an autologous graft may influence autologous stem cell transplantation (ASCT) outcome. Etoposide (VP) plus filgrastim (G) frequently mobilizes high numbers of CD34+ cells for autologous transplantation. We investigated whether patients collecting high numbers of CD34+ cells ('super mobilizers') have a better outcome than other patients. We reviewed 350 consecutive adult patients with NHL or Hodgkin's lymphoma receiving an ASCT from January 1994 to December 2005, mobilized with VP+G. Super mobilizers were defined as collecting a minimum of 8 x 10(6) CD34+ cells/kg. Two hundred and three patients were super mobilizers, while 147 collected between 2.0 and 7.95 CD34+ cells/kg. Super mobilizers were younger and more likely to have received two or fewer prior chemotherapy regimens (80 versus 63%, P<0.001). Median CD34+ cell dose for the super mobilizing group was 13.7 x 10(6) versus 4.4 x 10(6)/kg in the standard collecting group. The super mobilizer group had a superior overall survival (P=0.006). In multivariable analysis, favorable disease status and younger age at transplant, and super mobilization were associated with improved survival. We conclude that patients had an improved ASCT outcome if large numbers of CD34+ cells were mobilized and infused. The explanation for this observation is unknown.

Elevated lactate dehydrogenase is an adverse predictor of outcome in HLA-matched sibling bone marrow transplant for acute myelogenous leukemia.

Prognostic factors for survival following allogeneic BMT for AML include age, disease status and cytogenetic risk classification. Lactate dehydrogenase (LDH) levels have not been studied as a potential risk factor. We reviewed our experience with BMT for AML and included LDH at the time of admission in an analysis of prognostic factors for survival. We found that LDH >330 U/l (1.5 times the upper limit of normal at our institution), older age, active disease, peripheral stem cell graft and male-to-male transplant were significant adverse predictors of survival. After accounting for LDH, other factors such as disease status and cytogenetics were not significantly associated with the outcome of BMT. All but one patient with an LDH >330 U/l had active disease. However, when patients in CR were excluded, LDH >330 U/l remained a significant adverse predictor of overall survival (hazard ratio 2.70, 95% confidence interval 1.41-5.16, P=0.003). We conclude that LDH is an important adverse risk factor for survival and should be included in future studies of risk performed on larger patient cohorts.

Survival of AML patients receiving HLA-matched sibling donor allogeneic bone marrow transplantation correlates with HLA-Cw ligand groups for killer immunoglobulin-like receptors.

The reactivity of natural killer cells and some T-cell populations is regulated by killer immunoglobulin-like receptors (KIR) interactions with target cell HLA class I molecules. Such interactions have been suggested to influence outcomes after allogeneic hematopoietic stem cell transplantation, particularly for myeloid malignancies and with T-cell depletion. Donor KIR genotypes and recipient HLA KIR ligands were analyzed in 60 AML patients receiving T-cell replete, HLA-matched-related donor allogeneic bone marrow transplants. Patients were categorized according to their HLA inhibitory KIR ligand groups by determining whether or not they expressed: HLA-A3 or -A11; HLA-Bw4 and HLA-Cw groups (homozygous C1, homozygous C2 or heterozygous C1/C2). Heterozygous C1/C2 patients had significantly worse survival than those homozygous for C1 or C2 (5.8 vs 43.5 months, respectively, P=0.018) and the C1/C2 group had a higher relapse rate (47 vs 31%, respectively, P=0.048). Multivariate analysis found C1/C2 status to be an independent predictor for mortality (P=0.007, HR 2.54, confidence interval 1.29-5.00). C1/C2 heterozygosity was also associated with a delayed time to platelet engraftment, particularly for those with concurrent HLA-Bw4 expression (P=0.003). Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK- and T-cell populations involved in graft vs leukemia responses.

Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma.

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

Downregulation of topoisomerase IIbeta in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest.

Among the topoisomerase (topo) II isozymes (alpha and beta), topo IIbeta has been suggested to regulate differentiation. In this study, we examined the role of topo IIbeta in all-trans retinoic acid (ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo IIbeta activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo IIbeta-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo IIbeta. Gene expression profiling led to the identification of peroxiredoxin 2 (PRDX2) as a candidate gene that was downregulated in topo IIbeta-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo IIbeta-deficient cells correlated with increased accumulation of reactive oxygen species (ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo IIbeta-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo IIbeta in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo IIbeta induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo IIbeta and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.

Allogeneic BMT and patient eligibility based on psychosocial criteria: a survey of BMT professionals.

BMT professionals were compared regarding their willingness to proceed with allogeneic BMT given select psychosocial issues. A questionnaire was sent to 660 physician members of ASBMT, 92 social work members of BMT Special Interest Group, Association of Oncology Social Work, and 626 nurse members of BMT Special Interest Group, Oncology Nursing Society; 597 responded with a response rate of 43.5%. Items included background information, followed by 17 case vignettes; each represented a different psychosocial issue to which respondents indicated whether or not they would recommend proceeding with allogeneic BMT. In every vignette, at least 10% of respondents indicated they would not proceed. In six vignettes, at least 64% indicated do not proceed: suicidal ideation (86.8%), uses addictive illicit drugs (81.7%), history of noncompliance (80.5%), no lay caregiver (69.3%), alcoholic (64.8%), and mild dementia/Alzheimer's (64.4%). In 10 vignettes, at least 73% indicated proceed. On four vignettes, professional subgroups differed in their recommendation on whether or not to proceed with allogeneic BMT. Qualitative data suggest that this decision is contingent on the perceived acuity, severity, and currency of the psychosocial issue, patient ability to comply with treatment given the issue, and its manageability as a risk factor for treatment related vulnerability and outcomes.

Risk factors for recurrent Clostridium difficile infection in allogeneic hematopoietic cell transplant recipients.

Clostridium difficile infection (CDI) is one of the leading causes of hospital-acquired infections in recent times. Hematopoietic stem cell transplantation (HSCT) confers increased risk for CDI because of prolonged hospital stay, immunosuppression, the need to use broad-spectrum antibiotics and a complex interplay of preparative regimen and GvHD-induced gut mucosal damage. Our study evaluated risk factors (RF) for recurrent CDI in HSCT recipients given the ubiquity of traditional RF for CDI in this population. Of the 499 allogeneic HSCT recipients transplanted between 2005 and 2012, 61 (12%) developed CDI within 6 months before transplant or 2 years after transplant and were included in the analysis. Recurrent CDI occurred in 20 (33%) patients. One year incidence of CDI recurrence was 31%. Multivariable analyses identified the number of antecedent antibiotics other than those used to treat CDI as the only significant RF for recurrence (hazard ratio 1.96, 95% confidence interval 1.09-3.52, P=0.025). Most recurrences occurred within 6 months of the first CDI, and the recurrence of CDI was associated with a trend for increased risk of mortality. This prompts the need for further investigation into secondary prophylaxis to prevent recurrent CDI.

Association of socioeconomic status with autologous hematopoietic cell transplantation outcomes for lymphoma.

Socioeconomic status (SES) is an important determinant of disparities in health care. The association of SES with outcomes in autologous hematopoietic cell transplantation (AHCT) has not been described previously. We conducted a retrospective cohort study of 687 AHCT recipients with lymphoma transplanted between 2003 and 2013. Patients were categorized into low (<$50 000/year) and high SES (⩾$50 000/year). A greater proportion of low SES patients lived farther away from our center (median 54 vs 28 miles), belonged to a racial minority (12 vs 3%), had poorer performance status (4 vs 1%) and had high-risk disease at AHCT (9 vs 5%). Median follow-up was 53 months. In univariable analysis, low SES patients had significantly higher relapse mortality and lower OS and PFS. This was confirmed on multivariable analysis for relapse mortality (HR for high vs low SES: 0.74 (95% confidence interval (CI), 0.54-0.99), P=0.05), OS (HR 0.74 (0.58-0.95), P=0.02) and PFS (HR 0.77 (0.63-0.95), P=0.02). In multivariable analysis of ⩾1-year progression-free survivors, high SES patients had better OS (HR 0.73, P=0.05 vs low SES) that was primarily driven by a trend toward lower risk of non-relapse mortality (HR 0.62, P=0.06). SES is associated with outcomes of AHCT in patients with lymphoma.

Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy.

PURPOSE: A phase II trial of accelerated fractionation radiation with concurrent cisplatin and paclitaxel chemotherapy was performed to investigate the role of the paclitaxel, when substituted for fluorouracil (5-FU), in the chemoradiotherapy of esophageal cancer. PATIENTS AND METHODS: Patients with an esophageal ultrasound stage of T(3) or N(1) or M(1) (nodal) esophageal cancer were treated with two courses of a cisplatin infusion (20 mg/m(2)/d for 4 days) and paclitaxel (175 mg/m(2) over 24 hours) concurrent with a split course of accelerated fractionation radiation (1.5 Gy bid to a total dose of 45 Gy). Surgical resection was performed 4 to 6 weeks later followed by a single identical postoperative course of chemoradiotherapy (24 Gy) in patients with significant residual tumor at surgery. Toxicity and results of this treatment were retrospectively compared with our previous 5-FU and cisplatin chemoradiotherapy experience. RESULTS: Between September 1995 and July 1997, 40 patients were entered onto this study. Although dysphagia proved worse in our 5-FU-treated patients, profound leukopenia and a need for unplanned hospitalization were significantly more common in the paclitaxel group. Thirty-seven patients (93%) proved resectable for cure. The 3-year projected overall survival is 30%, locoregional control is 81%, and distant metastatic disease control is 44%. When compared with a similarly staged cohort of 5-FU-treated patients, there was no advantage for any survival function studied. CONCLUSION: This paclitaxel-based treatment regimen for locoregionally advanced esophageal cancer produced increased toxicity with no improvement in results when compared with our previous 5-FU experience. Paclitaxel-based treatments must be carefully and prospectively studied before their incorporation into the standard management of esophageal cancer.

Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy.

PURPOSE: A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy. PATIENTS AND METHODS: Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study. RESULTS: Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P =.89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P =.002). CONCLUSION: An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.

Influence of a randomized clinical trial on practice by participating investigators: lessons from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). CAVEAT I and II Investigators.

OBJECTIVES: We sought to determine whether the results of the first Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) influenced subsequent practice patterns among the investigators. BACKGROUND: CAVEAT-I demonstrated that directional coronary atherectomy (DCA) resulted in higher rates of early complications at a higher cost and with no clinical benefit. We sought to determine whether these results influenced subsequent use of procedures among CAVEAT-I investigators. METHODS: We compared the results of a week-long registry of all coronary interventions performed at 35 CAVEAT-I sites in 1994 with those of a similar registry obtained in 1992 before the trial, the results of which were published in 1993. For control purposes, the use of procedures was studied at 24 additional sites to provide insight into practice at hospitals not participating in the trial. A total of 1,465 interventions were analyzed. RESULTS: Ninety-four percent of CAVEAT-I sites responded. Utilization rates differed between CAVEAT-I and CAVEAT-I follow-up (p < 0.001). Balloon angioplasty decreased from 83.8% to 68.5%, DCA increased slightly from 10.7% to 14.1%, and the use of other devices increased from 5.4% to 17.5%. Stand-alone balloon use was more prevalent at nonparticipating control sites than at sites that took part in CAVEAT-I (p < 0.001). CONCLUSIONS: Paradoxically, despite the negative findings of CAVEAT-I, there was a noteworthy trend toward an increase in the use of DCA and other devices at CAVEAT-I sites. Our findings suggest that among investigators in the trial, there may have been a lack of influence of trial data on clinical practice patterns 1 year after publication of the results. Ethics of protocol: Both CAVEAT I and II were approved by the Institutional Review Board at each study site.

The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.

BACKGROUND: Colorectal cancer in primary sclerosing cholangitis patients with ulcerative colitis is mostly right-sided where concentrations of carcinogenic secondary bile acids are highest. AIM: To investigate whether ursodeoxycholic acid could be chemopreventive for colorectal cancer. METHODS: A historical cohort study was performed on primary sclerosing cholangitis patients with ulcerative colitis where the 28 patients (cases) who were treated with ursodeoxycholic acid for at least 6 months (mean 3.4 +/- 2.7 years) were compared with the 92 patients (controls) who were not treated with ursodeoxycholic acid. The primary outcomes were colorectal cancer and dysplasia. The secondary outcome was overall mortality. RESULTS: The cumulative incidence of dysplasia or cancer was not significantly different between cases and controls (P = 0.17 by log-rank test). The adjusted relative risk for cases of developing dysplasia or cancer was 0.59 (95% CI 0.26-1.36). The cumulative mortality was significantly different between groups (P = 0.02 by log-rank test). The adjusted relative risk for cases of death was 0.44 (95% CI 0.22-0.90). CONCLUSION: In ulcerative colitis patients with primary sclerosing cholangitis, ursodeoxycholic acid did not reduce the risk of developing cancer or dysplasia. However, ursodeoxycholic acid may reduce mortality.

Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection.

Engraftment syndrome (ES) following autologous hematopoietic stem cell transplantation (AHSCT) is characterized by fever and rash. In January 2002, we instituted steroid prophylaxis for ES from day +4 to +14. This study was conducted to assess whether this practice increased the risk of infection. In total, 194 consecutive patients were reviewed, 111 did not receive steroid prophylaxis (group A), and 83 did (group B). Initial antimicrobial prophylaxis was the same in both groups. There were no significant differences between groups in age, gender, race, prior radiation therapy, number of prior chemotherapy regimens, disease status at transplant, mobilization regimen, days of leukopheresis, CD34(+) cell dose, and days to platelet and neutrophil engraftment. Group B had significantly fewer patients with non-Hodgkin's lymphoma and multiple myeloma, shorter median duration from diagnosis to transplant, lower risk of ES, and shorter mean length of hospital stay. The incidence of early and late microbiologically confirmed infections was not significantly different between groups. Types of infections and types of organisms identified were similar in both groups. Hospital readmission rates were similar in both groups. Steroid prophylaxis significantly decreases the risk of ES following AHSCT, and is associated with shortened hospitalization, without increasing risk of infection.

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens.

The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.