Shannon Smiley

Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adenocarcinoma

Activation of the epidermal growth factor receptor (EGFR) has a role in oncogenesis and may correlate with prognosis. The aim of this study was to examine EGFR expression in esophageal adenocarcinoma and correlate EGFR status with pathologic and clinical prognostic features. An exploratory retrospective review of 38 patients with surgically resected esophageal adenocarcinoma was performed. All patients underwent an esophagogastrectomy with regional lymphadenectomy; 24 patients underwent primary resection and 14 patients had surgery after preoperative chemoradiation therapy. Immunohistochemical analysis was performed on paraffin-embedded tissue samples using an EGFR monoclonal antibody. Low- and moderate-grade tumors were positive for EGFR expression in 2 of 15 patients; poorly differentiated tumors were positive for EGFR expression in 13 of 23 patients (p = 0.02). The median survival was 35 months (confidence interval [CI]: 29–40) for EGFR negative patients (n = 23) and 16 months (CI: 10–22) for EGFR positive patients (n = 13) (p = 0.10). Disease recurred in 3 of 21 EGFR negative patients and 6 of 13 EGFR positive patients (p = 0.06). Poorly differentiated adenocarcinomas of the esophagus demonstrated higher EGFR expression compared to low-grade tumors based upon immunohistochemical analysis. A trend toward improved disease-free and overall survival was seen in EGFR negative patients.

High prevalence of early-onset osteopenia/osteoporosis after allogeneic stem cell transplantation and improvement after bisphosphonate therapy

Osteopenia/osteoporosis (O/O) has been associated with allogeneic stem cell transplantation (alloSCT). We retrospectively reviewed 102 patients undergoing a first alloSCT from 2000 to 2005 at our center to evaluate the prevalence of O/O ⩽6 and >6 months post-alloSCT. Fifty-six patients did not have a dual energy X-ray absorptiometry (DXA) scan following alloSCT. Approximately half (n=13/27) of those with a first DXA scan ⩽6 months post-alloSCT had O/O and a similar rate (n=9/19) was seen in those with a first DXA scan >6 months. There were no significant differences in patient characteristics between the normal and O/O groups. The dual femur (DF) appeared to be more vulnerable to alloSCT-induced bone mineral density (BMD) loss than the lumbar spine (LS), regardless of screening time. O/O patients were treated with bisphosphonates and 41% had a repeat DXA scan post-treatment. No patient developed jaw osteonecrosis and significant BMD improvement was seen at the LS (mean BMD, 1.03±0.13 vs 1.08±0.12, P=0.004) but not the DF (mean BMD, 0.84±0.06 vs 0.85±0.08, P=0.29), indicating BMD loss at the DF is more resistant than the LS to antiresorptive therapy. Our results demonstrate that O/O is an early and late complication post-alloSCT and bisphosphonate treatment reverses BMD loss at the LS.

A Deletion Polymorphism in Glutathione-S-Transferase Mu (GSTM1) and/or Theta (GSTT1) Is Associated with an Increased Risk of Toxicity after Autologous Blood and Marrow Transplantation

Toxicity after blood and marrow transplantation (BMT) has interindividual variability that may be explained by common genetic polymorphisms in critical pathways. The glutathione-S-transferase (GST) isoenzymes detoxify the reactive oxygen species generated by chemotherapy agents and radiation. We investigated whether deletion polymorphisms in 2 GST genes (GSTM1 and GSTT1) were associated with toxicity after autologous or allogeneic BMT. The study population was selected from 699 consecutive BMT patients from 2 centers in Buffalo, NY, and Moscow, Russia, of whom 321 (203 autologous, 118 allogeneic BMT) had available banked samples and amplifiable DNA. Fifty percent of patients were homozygous null for GSTM1, which did not vary by center; however, the GSTT1 homozygous null deletion polymorphism occurred more frequently in patients treated in Moscow (38% versus 18%, P < .001). Overall grade 2-4 regimen-related toxicity occurred in 56%, with nearly 1 in 5 patients having 2 or more organ systems affected. Among autologous BMT patients, a deletion polymorphism in 1 or both genes was significantly associated with increased occurrence of overall toxicity (71% versus 56%, P = .034) and mucositis (74% versus 55%, P = .006). GSTM1 and/or GSTT1 deletion polymorphisms were not associated with toxicity after allogeneic BMT. Future studies may allow for individualized genetic risk stratification.

Intensive conditioning regimen of etoposide (VP-16), cyclophosphamide and carmustine (VCB) followed by autologous hematopoietic stem cell transplantation for relapsed and refractory Hodgkin's lymphoma

Several high-dose therapy regimens are used for autologous hematopoietic stem cell transplantation (auto-HSCT) for relapsed and refractory Hodgkins lymphoma (HL) with variable disease response. An intensified regimen of etoposide (VP-16) 2400 mg/m2, cyclophosphamide 7200 mg/m2 and carmustine (BCNU) 600 mg/m2 (VCB) pre-auto-HSCT was developed to overcome disease recurrence. A total of 43 relapsed and refractory HL patients underwent auto-HSCT between January 1992 and December 2004. At day 100 there were 37 (86%) complete responses. A total of 40 patients survived beyond day 100, 14 of whom subsequently relapsed/progressed. At a median follow-up of 4.9 years (range 1.5–11.4 years), 26 patients (60%) are alive and disease free. Five-year actuarial event-free survival (EFS) was 53% (95% CI 35–70%) and median EFS was 5.9 years. Median progression-free and overall survivals have not been reached. EFS was reduced with an increasing number of prognostic factors (Karnofsky performance status, KPS <90, chemotherapy-resistant disease and ⩾3 chemotherapy regimens prior to transplant ⩽1 vs ⩾2; P=0.049). Grade III–IV regimen-related toxicity was 9% (n=4). The 1-year cumulative incidence of interstitial pneumonitis (IP) was 36%, however only two patients died of IP complications. Disease progression was the most common cause of death (n=10, 23%). Intensive VCB is an effective and well-tolerated preparative regimen for relapsed and refractory HL auto-HSCT.

Seeing What's Out of Sight: Wireless Capsule Endoscopy's Unique Ability to Visualize and Accurately Assess the Severity of Gastrointestinal Graft-versus-Host-Disease

Early recognition of gastrointestinal graft-versus-host disease (GI GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) is vital to initiation of therapy. However, the most common location, the small bowel (SB), is difficult to access with upper and lower endoscopy (UGE/LGE). Wireless capsule endoscopy (WCE) is a noninvasive technology allowing complete SB evaluation. The capsule location can also be tracked to identify motility derangements. From August 2006 to July 2007, 11 alloHSCT patients with GI symptoms underwent WCE, and visual grading was performed. UGE and LGE with biopsies were done when clinically indicated. All patients had evidence of probable acute GVHD (aGVHD) on WCE. WCE revealed lesions of greater severity than those seen by UGE or LGE in most patients. WCE demonstrated that 45% of patients had delayed gastric transit time. WCE is an excellent, noninvasive method for assessing GI GVHD, with the ability to more accurately assess the severity of GVHD, evaluate clinical symptoms, and follow response to treatment.

A Comparison of Measured Creatinine Clearance versus Calculated Glomerular Filtration Rate for Assessment of Renal Function before Autologous and Allogeneic BMT

Common blood and marrow transplantation (BMT) eligibility criteria include a minimum glomerular filtration rate (GFR) that may vary by regimen intensity. GFR is often estimated by measurement of creatinine clearance in a 24-hour urine collection (24-hr CrCl), an inconvenient and error-prone method that overestimates GFR. The study objectives were to determine which of 6 GFR calculations: Cockroft-Gault (CG), modified CG (mCG), Modification of Diet in Renal Disease 1 (MDRD1), MDRD2, Jelliffe, and Wright, consistently underestimated measured 24-hr CrCl pre-BMT. We retrospectively analyzed 98 consecutive allogeneic (n = 48) or autologous (n = 50) adult BMT patients from January 2006 to April 2007. All 6 formulas were significantly (P < .001) correlated with 24-hr CrCl with R = 0.64 (Wright), 0.63 (CG), 0.61 (mCG), 0.61 (Jelliffe), 0.54 (MDRD2), and 0.50 (MDRD1). When compared to the measured 24-hr CrCl, MDRD2 consistently underestimated it in the highest proportion of patients (66%, P < .001), compared with MDRD1 (65%, P < .001), Jelliffe (61%, P = NS), mCG (55%, P = NS), Wright (34%, P < .001), and CG (34%, P = .001). Measured 24-hr CrCl, pre-BMT serum Cr, and all 6 equations were not predictive of renal regimen-related toxicity (RRT) post-BMT. The Wright and CG formulas are closest to, but overestimate 24-hr CrCl in 66% of patients. In comparison, MDRD2 consistently underestimates 24-hr CrCl in 66%. Although MDRD2 is the most conservative formula, all 6 formulas gave reasonable estimates of GFR and any of the 6 equations can replace the measured 24-hr CrCl. Larger analyses and transplantation of patients with GFR <50 mL/min may better define subgroups at risk for renal RRT.

Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation

Background Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT. Methods and Findings We genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5–35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss. Conclusion Our data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings.

Detection of extra-medullary relapse of acute lymphoblastic leukemia by radiographic imaging following allogeneic hematopoietic SCT

Detection of extra-medullary relapse of acute lymphoblastic leukemia by radiographic imaging following allogeneic hematopoietic SCT

Human leukocyte antigen DR4 is associated with inferior progression-free survival following allogeneic hematopoietic stem cell transplantation for lymphoid malignancies

The Class II human leukocyte antigen (HLA) DRB1 antigen DR4 is associated with autoimmune disorders and response to cyclosporine immunosuppression in T-lymphoproliferative disorders. We retrospectively reviewed the role of HLA DR4 on outcomes in 77 related and 22 unrelated consecutive first HLA-matched alloHSCT patients with lymphoid malignancies treated between 1992 and 2003. HLA DRB1 typing was determined by molecular (n = 69) or serologic (n = 30) methods. The proportion of patients with one HLA DR4 antigen was 18% (18/99). At a median follow-up of 5.6 years, there were no significant differences in aGvHD, cGvHD and OS between the HLA DR4 positive versus negative patients in any disease or donor subgroups. Nine of 18 (50%) DR4 positive patients and 20 of 81 (25%) DR4 negative patients had disease progression post HSCT (p = 0.033). Progression-free survival (PFS) at 3 years was 29% in the DR4 positive group and 70% in the DR4 negative group (p = 0.004). In univariate and multivariate analyses, DR4 positivity was the only significant factor associated with PFS (RR = 3.2, p = 0.007). Our results suggest that in addition to the known role of HLA DRB1 disparity in mediating histocompatibility, HLA DR4 is associated with inferior PFS in patients with lymphoid malignancy undergoing alloHSCT.

Fatal Hyperacute Graft-versus-Host Disease following Denileukin Diftitox Treatment for Recurrent T Cell Lymphoma after Allogeneic Stem Cell Transplantation

Age in years (median, range) 45 (10-46) 32(13-56) .83 Conditioning regimen Myeloablative 4/5 (80%) 8/10 (80%) 1.0 Reduced intensity 1/5 (20%) 2/10 (20%) 1.0 aGVHD 1/5 (20%) 7/10 (70%) .12 Grade II-IV aGVHD 1/5 (20%) 1/10 (10%) 1.0 cGVHD 4/5 (80%) 8/10 (80%) 1.0 Extensive cGVHD 1/5 (20%) 1/10 (10%) 1.0 IST for cGVHD >3 years 3/5 (60%) 5/10 (50%) 1.0 Lamivudine treatment 3/5 (60%) — Lamivudine prophylaxis* 0 5/10 (50%) HBV vaccine after SCT 0 6/10 (60%) Donors with vaccination of HBV 1/5 (20%) 1/10 (10%) 1.0