Vitamin D deficiency (< 30 ng/mL serum vitamin D [25(OH)D3]) found in 239 of 311 (76.9%) cutaneous T-cell lymphoma (CTCL) patients was comparable to 238 controls including 127 of 169 (75.2%) of cancer controls and 46 of 69 (66.7%) of healthy controls (P = .05, .07). Supplementation With D2 or D3 corrected only about a third of patients' levels and did not affect response to therapy.Background: The purpose of this study was to determine the prevalence of vitamin D deficiency in CTCL patients and whether supplementation corrects vitamin D deficiency or treatment outcome. Patients and Methods: Three hundred eleven CTCL patients including 27/311 (8.7%) with Sezary syndrome (SS), 169 cancer controls, and 69 normal controls from the M.D. Anderson clinics had 25(OH)D3 levels determined and categorized as deficient (< 20 ng/mL), intufficient (20-29 ng/mL), or sufficient (>= 30 ng/mL). Clinical response was determined according to a change in percent body surface area involvement. Results: Low 25(OH)D3 (< 30 ng/rnL) levels were present in 76.9% of mycosis fungoides/SS patients, 75.2% of cancer controls, and 66.7% of healthy controls (P = .05, .07) and in 30% to 39% of historical normal controls. Correction of deficiency was successful in 35% or 55 of 156 patients who were given dealer's choice of either vitamin D2 at 50,000 IU orally (p.o.) biweekly or D3 1000 IU p.o. daily. Correction of vitamin D levels was noted in 27 of 100 (27%) patients given D3 and 28 of 56 (50%) given D2. Responses to standard CTCL therapy was similar among patients with corrected and persistently low levels (P = .51). Conclusion: To our knowledge, this is the first study of vitamin D status in CTCL patients. Vitamin D deficiency was present in CTCL and other cancer patients compared with normal and historical controls. Correction of vitamin D deficiency and type of vitamin D supplementation used did not affect the overall clinical disease response.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, because of high treatment-related mortality (TRM), its role is not well defined. Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of 2 reduced-intensity conditioning regimens; fludarabine 120 mg/m(2) melphalan 100 mg/m(2) (FM100) versus fludarabine 120 mg/m(2) melphalan 140 mg/m(2) (FM140) before allo-HCT from related or unrelated donors. Fifty patients underwent allo-HCT using FM100 (n = 23) or FM140 (n = 27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (P = .21), acute grade II to IV graft-versus-host disease (GVHD) (P = 1.0), chronic GVHD (P = .24), response rate (P = 1.0), TRM (13% versus 15%, P = 1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, P = .12, and median overall survival (OS), 35.1 versus 19.7 months, P = .38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (P = .08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), P = .24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with <VGPR, P = .05). OS was similar across all variables. We conclude that FM100 and FM140 may result in similar patient outcomes after allo-HCT for MM. (C) 2013 American Society for Blood and Marrow Transplantation.

Death due to melanoma in childhood (up to 20 y of age) is a rare event, with an average of 18 cases reported annually in the United States. In this study we evaluated 2 subgroups of high-risk melanocytic neoplasms in childhood, specifically atypical Spitz tumors (ASTs) with chromosomal copy number changes and conventional melanomas. We analyzed the clinical, histologic, and molecular features of all cases and performed the Fisher exact test, logistic regression, and multivariate analysis to evaluate features associated with aggressive clinical behavior in these cases. Among the ASTs, all of which had 1 or more chromosomal copy number aberrations, the presence of homozygous 9p21 deletions and a positive sentinel lymph node were each found to be correlated with tumor extension beyond the sentinel lymph node, with P-values of 0.046 and 0.01, respectively. Two patients with ASTs that had homozygous 9p21 deletions developed brain metastasis, one of whom died of disease. Among the 21 conventional melanomas, 3 patients developed distant metastasis and died of disease. Chromosomal copy number aberrations evaluated by fluorescence in situ hybridization were present in the majority of the cases (16/18). Among conventional melanomas, we did not identify any clinical, histologic, or molecular features associated with aggressive behavior. The presence of 8q24 gains was seen almost exclusively in 6 amelanotic small cell melanomas in children of whom 1 died of disease. Characteristic chromosomal copy number aberrations may occur in specific subtypes of melanocytic neoplasms in children and may help with the classification and prognostication of these rare tumors.

Risk assessment for atypical Spitz tumors remains an enigma for physicians. Many prognosticators including sentinel lymph node biopsy fail to show the same prognostic significance in these tumors as seen in conventional melanoma. We conducted a case-controlled collaborative study involving multiple major melanoma treatment centers in the United States and Australia. Sixty-four atypical Spitz tumors with 5 years of uneventful follow-up and 11 atypical Spitz tumors resulting in advanced locoregional disease, distant metastasis, or death were evaluated by fluorescence in situ hybridization using 2 probe sets targeting 6 chromosomal loci. Predetermined criteria were utilized to detect the presence or absence of copy number aberrations for each locus. Logistic regression analysis, Fisher exact test, and multivariate analysis were performed to determine chromosomal copy number aberrations with statistically significant association with aggressive clinical behavior. Gains in 6p25 or 11q13 and homozygous deletions in 9p21 had statistically significant association with aggressive clinical behavior with P-values of 0.02, 0.02, and <0.0001, respectively. In multivariate analysis, homozygous 9p21 deletion was highly associated with clinically aggressive behavior (P<0.0001) and death due to disease (P=0.003). Fluorescence in situ hybridization detecting a limited number of chromosomal copy number aberrations can provide clinically useful and statistically significant risk assessment for atypical Spitz tumors. Cases with homozygous 9p21 deletions have the greatest risk. Cases with 6p25 or 11q13 gains also have higher risk for aggressive clinical behavior than FISH-negative atypical Spitz tumors or cases with 6q23 deletions.

Determining risk assessment for aggressive behavior of atypical Spitz tumors (ASTs) remains a significant challenge for pathologists. Despite the presence of many concerning histological features such as tumor ulceration, expansile growth, dermal mitotic rate, and cytological atypia, the overwhelming majority of these tumors behave in an indolent fashion. Recently, we have noted that using cytogenetics, one can identify ASTs with high likelihood for aggressive behavior allowing for a clinically significant risk assessment. In this retrospective case-controlled study, we examined the clinical and histological features of 24 cases of ASTs that were found to have isolated copy number deletions in 6q23 when studied by probes targeting 6p25, 6q23, Cep6, 11q13, 9p21, and Cep9. Although 6 of 11 patients had a positive sentinel node biopsy, none of the patients developed tumor in a nonsentinel node, palpable adenopathy, in transit metastasis, or distant metastasis. Histopathologically, the tumors showed minimal pagetoid spread (P = 0.004) and trended toward a histological presentation with expansile nodular growth (P = 0.08) and focal ulceration (P = 0.19). Furthermore, we also depict and illustrate the challenges that may occur in accurately identifying 6q23 deletions using fluorescence in situ hybridization in ASTs.

PURPOSE:To investigate the prognostic value of the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) in patients who received transplantation admitted to the intensive care unit (ICU).PATIENTS AND METHODS:We investigated the association of HCT-CI with inpatient mortality and overall survival (OS) among 377 patients who were admitted to the ICU within 100 days of allogeneic stem-cell transplantation (ASCT) at our institution. HCT-CI scores were collapsed into four groups and were evaluated in univariate and multivariate analyses using logistic regression and Cox proportional hazards models.RESULTS:The most common pretransplantation comorbidities were pulmonary and cardiac diseases, and respiratory failure was the primary reason for ICU admission. We observed a strong trend for higher inpatient mortality and shorter OS among patients with HCT-CI values ≥ 2 compared with patients with values of 0 to 1 in all patient subsets studied. Multivariate analysis showed that patients with HCT-CI values ≥ 2 had significantly higher inpatient mortality than patients with values of 0 to 1 and that HCT-CI values ≥ 4 were significantly associated with shorter OS compared with values of 0 to 1 (hazard ratio, 1.74; 95% CI, 1.23 to 2.47). The factors associated with lower inpatient mortality were ICU admission during the ASCT conditioning phase or the use of reduced-intensity conditioning regimens. The overall inpatient mortality rate was 64%, and the 1-year OS rate was 15%. Among patients with HCT-CI scores of 0 to 1, 2, 3, and ≥ 4, the 1-year OS rates were 22%, 17%, 18%, and 9%, respectively.CONCLUSION:HCT-CI is a valuable predictor of mortality and survival in critically ill patients after ASCT.

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.

Abstract PEA-15 is 15-kDa serine-phosphoprotein that sequesters phospho-ERK from the nucleus to the cytoplasm. Previously, we showed that overexpression of PEA-15 had antitumor effects in both breast and ovarian cancer cells. We also reported that PEA-15 expression was associated with prolonged overall survival in patients with epithelial ovarian cancer, as found using a tissue microarray. Because PEA-15 has two major phosphorylation sites, Serine104 and Serine116, that are closely related to its biological function in regulating cell proliferation and survival, we sought to develop a more potent form of PEA-15 by modifying its two major phosphorylation sites. To determine which mutant form of PEA-15 is a more potent antitumor agent, we evaluated the function of double-mutated PEA-15 at Ser104 and Ser116; PEA-15-AA, in which residues were substituted with alanine (double-unphosphorylated form); and PEA-15-DD, in which residues were substituted with aspartic acid (double-phosphorylated form) were tested in vitro and in vivo in ovarian cancer cell lines. PEA-15-AA resulted in 85% inhibition of SKOV3.ip1 cell colony formation (P<0.001) under anchorage-independent conditions. Compared to vector control, PEA-15-AA reduced projection formation by about 80%-90% (P=0.01) under the 3D Matrigel culture condition and inhibition of cell migration by 60%-80% (P=0.02). Further, to determine the in vivo effect of PEA-15-AA, we injected control vector, PEA-15-AA, and PEA-15-DD stable transfectants of SKOV3.ip1 cells intraperitoneally into nude mice. We observed that PEA-15-AA strongly inhibited tumor formation and tumor size (6 of 15, P=0.02) compared to the control (9 of 10) or PEA-15-DD (16 of 16). Immunohistochemical data revealed that beta-catenin and CD-31 (endothelial cell marker) expression was significantly decreased in PEA-15-AA tumor tissues. These data show that the antitumor effect of PEA-15-AA was partially dependent on both the inhibition of beta-catenin expression and its nuclear translocalization. We next determined the clinical relevance of phosphorylated PEA-15 in patients with ovarian cancer using a human ovarian cancer tissue microarray. Our analysis showed that total double-phosphorylated PEA-15 expression at Ser104 and Ser116 was significantly higher in high-grade (II, P=0.002; III, P=0.001) ovarian tumor tissue than in adjacent normal ovarian tissue. These data indicate that PEA-15 in ovarian tumor cells exists predominantly in the double-phosphorylated form, PEA-15-DD. Further studies are warranted to determine the correlation between the phosphorylation status of PEA-15 and overall survival in patients with ovarian cancer. Taken together, our results suggest that PEA-15-AA has strong antitumor effects in vitro and in vivo that would justify its development as an effective therapeutic molecule in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5616. doi:1538-7445.AM2012-5616

BACKGROUND: The high prevalence of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma v-ras oncogene homolog (NRAS) mutations in melanoma provides a strong rationale to test the clinical efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in this disease. The authors hypothesized that the presence of BRAF or NRAS mutations would correlate with clinical benefit among patients who received treatment with combination regimens that included the MEK inhibitor selumetinib. METHODS: BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib). The clinical response rate and the time to progression (TTP) were assessed as a function of BRAF and NRAS mutation status. RESULTS: Among 18 patients analyzed, 9 patients (50%) harbored a BRAF mutation (8 had a valine-to-glutamic acid substitution at residue 600 [V600E]; 1 had an arginine nonsense mutation at residue 603 [R603]), 4 patients (22%) harbored an NRAS mutation (2 had a glutamine-to-arginine substitution at residue 61 [Q61R], 1 had a glutamine-to-lysine substitution at residue 61 [Q61K], and 1 had a glycine-to-lysine substitution at residue 12 [G12S]), and 5 patient (28%) had the wild type of both genes. These mutations were mutually exclusive. Among the 9 patients who had BRAF mutations, 5 patients (56%) achieved a partial response, and 4 patients (44%) achieved stable disease for at least 6 weeks. No patient with the wild-type BRAF gene achieved a clinical response (P = .01 vs patients with BRAF mutations). The presence of an NRAS mutation did not correlate with the clinical response rate. The presence of a BRAF mutation was correlated significantly with the TTP in a multivariate model (hazard ratio, 0.22; P = .02 vs wild-type BRAF). CONCLUSIONS: Higher response rates and longer TTP were observed with selumetinib-containing regimens in patients who had tumors that harbored a BRAF mutation compared with patients who had wild-type BRAF. Cancer 2013. (c) 2012 American Cancer Society.

Mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are the most common cutaneous T cell lymphomas (CTCL), but their etiology remains unknown. After patients were observed with hydrochlorothiazide (HCTZ)‐associated CTCL, HCTZ was examined as a putative chronic antigen in a cohort of prospectively staged patients.

Purpose: The purpose of this prospectively collected single center study cohort of 1,263 patients with mycosis fungoides (MF)/Sézary syndrome (SS) is to evaluate the significance of stage and risk of disease progression from initial presentation and to examine other prognostic factors. Patients and Methods: The prognostic variables effecting overall survival (OS) were examined in a unique prospective cohort of 1,263 patients with MF and SS seen by one investigator at MD Anderson Cancer Center (Houston, TX) from 1982 to 2009. Kaplan–Meier estimates were used to determine median OS, progression-free survival (PFS), and disease-specific survival (DSS). Cox proportional hazards regression model assessed prognostic factors. Results: Mean age at diagnosis was 55.33 years. Early mycosis fungoides (stage IA–IIA) represented 71.5% (903 of 1,263) and advanced (stage IIB–IVB) 28.5% (360 of 1,263) patients. Progression to a higher stage occurred in 147 patients (11.6%) of whom 112 (12%) were early and 35 (9.7%) advanced. Death from disease occurred in 102 of 1,263 (8.1%) patients. Median OS was 24.44 years, PFS was 16 years, and median DSS was not reached. OS and PFS were significantly better for early-stage patients with patches (T1a/T2a) than with patches/plaques (T1b/T2b). The PFS analyzed in 1,241 patients found that only 337 (27.2%) had disease progression or had died from disease. Risk factors associated with progression or deaths were advanced age, plaque stage, lactate dehydrogenase (LDH) level, and tumor area. Conclusions: Improved outcome of MF/SS, reflected by OS and PFS for all stages, may result from earlier diagnosis, new therapies, and aggressive treatment of infections. Clin Cancer Res; 18(18); 5051–60. ©2012 AACR.

BEAM is considered a standard HDC regimen for pts with Hodgkin's lymphoma (HL) who are candidates for an ASCT. However, pts with primary refractory tumors or high-risk relapse have poor outcomes after BEAM, underscoring the need for more active HDC combinations. We have developed a new HDC regimen of gemcitabine (Gem), busulfan (Bu) and melphalan (Mel) (Gem/Bu/Mel), exploiting their synergy based on DNA damage repair inhibition. At its MTD, Gem was infused at a fixed dose rate of 10 mg/m2/min (optimizing its intracellular activation) over 4.5 hours (d-8 and -3) (total dose 5,550 mg/m2), preceding the first doses of Bu or Mel. Bu was given as 4 daily doses (d-8 to -5) targeting AUC 4,000/d x4. Mel was given at 60 mg/m2/d x2 (d-3 and -2). We compared the subset of refractory HL pts of this study with all other refractory HL pts transplanted during the same period at our institution, who were eligible for this trial but either received BEAM off protocol or were enrolled in a separate trial of Bu/Mel. All of them met ≥1 of the following criteria: primary induction failure (PIF) (1 relapse. Pts with relapsed and non-refractory HL were excluded from this analysis. We analyzed 209 pts in these cohorts: 1) Gem/Bu/Mel (N = 89) (Jan 07-June 11), median f/u: 16 (3-57) mo; 2) BEAM (N = 83) (Jan 05-Aug 11), median f/u: 17 (2-56) mo; 3) Bu/Mel (N = 37) (Apr 05-Dec 07), median f/u: 36 (17-56) mo. The Gem/Bu/Mel cohort had substantially higher % PIF, >1 relapses, bulky tumors (>5 cm) at relapse/PD, extranodal disease at relapse/PD, PET+ tumors at HDC and PD at HDC.Table 1Clinical featuresGem/Bu/MelBEAMBu/MelP valueN898337Age, median (range)32 (19-61)36 (17-67)36 (20-63)0.7% PIF6446320.002% CR1 <6 mo8173860.2% prior xRT2730300.9% relapse within prior xRT field129110.8% >1 relapses4326220.02% bulky tumor at relapse3718220.009% B symptoms at relapse151480.6% extranodal disease at relapse5130320.01% PET+ at HDC5228270.001% PD at HDC2663<0.0001 Open table in a new tab The overall and CR rates were: Gem/Bu/Mel: 93% and 81%; BEAM: 93% and 66%; Bu/Mel: both 64%. Despite its worse prognostic features Gem/Bu/Mel pts had improved EFS (63% v 42% v 38%, P = 0.002) and OS (85% v 63% v 62%, P = 0.02) compared to BEAM or Bu/Mel. Gem/Bu/Mel was superior in both PET-and PET+ subsets. Cox regression models identified the use of a regimen other than GemBuMel [risk ratio 2.1 (95% CI, 1.3-3.5), P = 0.002], PET+ tumors at HDC [RR 1.9 (1.2-3.1), P = 0.002] and >1 prior relapse [RR 1.8 (1.1-2.9), P = 0.01] as independent adverse predictors of EFS. Despite its markedly worse prognostic features, refractory HL pts treated with the novel regimen Gem/Bu/Mel show superior outcome than contemporaneous pts receiving BEAM or Bu/Mel. A randomized trial of Gem/Bu/Mel vs BEAM is warranted.

We investigated the role of neoadjuvant/adjuvant therapies on survival for resectable biliary tract cancer. We hypothesized that neoadjuvant and adjuvant therapy should improve the survival probability in these patients.This was a retrospective review of a prospective database of patients resected for gallbladder cancer (GBC) and cholangiocarcinoma (CC). One hundred fifty-seven patients underwent resection for primary GBC (n = 63) and CC (n = 94). Fisher's exact test, Student's t test, the log-rank test, and a Cox proportional hazard model determined significant differences.The 5-year overall survival rate after resection of GBC and CC was 50.6 % and 30.4 %, respectively. Of the patients, 17.8 % received neoadjuvant chemotherapy, 48.7 % received adjuvant chemotherapy, while 15.8 % received adjuvant chemoradiotherapy. Patients with negative margins of at least 1 cm had a 5-year survival rate of 52.4 % (p < 0.01). Adjuvant therapy did not significantly prolong survival. Neoadjuvant therapy delayed surgical resection on average for 6.8 months (p < 0.0001). Immediate resection increased median survival from 42.3 to 53.5 months (p = 0.01).Early surgical resection of biliary tract malignancies with 1 cm tumor-free margins provides the best probability for long-term survival. Currently available neoadjuvant or adjuvant therapy does not improve survival.

Ipilimumab improves overall survival (OS) in patients with metastatic melanoma including those previously treated with high-dose interleukin-2 (HD IL-2). The primary objective of this study was to determine if clinical response or progression-free survival (PFS) to HD IL-2 could predict benefit to subsequent ipilimumab. The secondary objective was to further characterize the clinical benefit of ipilimumab in patients who have progressed on HD IL-2. We reviewed the records of all patients with metastatic melanoma who received HD IL-2 at MD Anderson Cancer Center or Beth Israel Deaconess Medical Center from 2003 to 2009 and further identified patients who also received ipilimumab after progressing on HD IL-2. OS to ipilimumab was calculated from the first dose of ipilimumab, determined by Kaplan-Meier analysis, and was compared in patients based on their prior clinical response and PFS to HD IL-2 using the log-rank test. Patients were grouped based on their prior response to HD IL-2 as follows: complete response and partial response, stable disease, and progressive disease. Patients were also grouped and compared by prior PFS to HD IL-2 in >60 days versus ≤60 days. A total of 208 patients with melanoma were treated with HD IL-2, 130 (63%) received additional systemic therapy after confirmed disease progression, and 48 (23%) received ipilimumab. The clinical benefit of ipilimumab was similar to previously published results (OS, 12.0 mo; PFS, 2.5 mo; response rate, 16.7%). Prior clinical response or PFS to HD IL-2 did not predict benefit to subsequent ipilimumab. Prospective trials of HD IL-2 followed by ipilimumab could potentially identify patients most likely to benefit from a sequential approach of HD IL-2 followed by ipilimumab.

Purpose: C-MET is over-expressed in metastatic melanoma and have copy number gains at chromosome 7 in late stages of melanoma progression. However, the presence of C-MET mutation is not well known in melanoma. We analyzed tumor samples of patients with malignant melanoma to identify the frequency and the clinicopathology of C-MET mutations. Methods: We identified 103 patients with metastatic mutation who underwent testing for c-MET mutation and reviewed the clinical data of these patients. The sequencing analyses were performed by Sequenom Assay, and the mutations were confirmed with Sanger Sequencing analysis. Clinical characteristics were correlated with C-MET mutation status, and a survival analysis was performed to identify significant associations. Results Among the 103 patients, eleven (11%) patients had melanoma harboring a C-MET mutation. Five (4.5%) patients had N375S mutation; two (1.8%) patients had R988C mutation; two (1.8%) had T1010I; one (1%) patient had H1112R and another patient had N375/T1010 mutation. A median age at diagnosis, sex, race and the status of ulceration at the primary site and the stages at diagnosis were similar between patients with a C-MET mutation and those with wild type. There were no significant differences in the overall survival from the time of stage IV diagnosis between the two groups, but there was a trend of a shorter median duration from the time of the initial diagnosis to distant metastases among patients with a C-MET mutation. (23.6 months vs. 15.9 months, p=0.09). Conclusions We found C-MET mutations in 11% of patients with malignant melanoma. There was a tendency to have distant metastasis at an earlier time in patients with a C-MET mutation. This is the first report describing the frequency and clinical characteristics of C-MET mutations in patients with malignant melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4588. doi:1538-7445.AM2012-4588

Background Multi-organ resection in patients with non-urothelial cancer may include segmental ureteral resection. The resulting ureteral defect can be reconstructed with a transureteroureterostomy (TUU); however, whether TUU is safe and effective in this patient group remains unclear. Objectives In the current retrospective analysis, we evaluated renal function before and after complex multi-organ resection that included TUU to determine whether TUU is safe and effective. Methods We retrospectively reviewed the charts of patients who underwent TUU between 1995 and 2011. Renal imaging studies performed before and after TUU were used to determine whether hydronephrosis was present in either kidney. Kidney function was assessed by measuring serum creatinine levels and calculating the estimated glomerular filtration rate (eGFR) before and after TUU. Results Twelve patients underwent TUU during multiorgan resection. Median follow-up time was 15 months. Three patients with cancer recurrence involving the TUU developed progressive hydronephrosis. Serum creatinine levels did not increase more than 0.5?mg/dl in any patient. Kidney function as assessed by eGFR was maintained in all patients (until the time of recurrence in the three patients with recurrence affecting the TUU). Conclusions TUU during multi-organ resection for non-urothelial malignancy is safe and effective. Long-term renal function is maintained in the majority of patients. J. Surg. Oncol. 2012; 106:6265. (C) 2012 Wiley Periodicals, Inc.

Abstract Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC. Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors. Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p<0.01), adjusted for lymphatic/vascular invasion. Although there is a trend that patients who used statin “H” had a longer time to death compared to patients who did not take statin, it did not reach statistical significance for OS (HR=0.80; 95% CI: 0.43–1.49; p=0.49) and DSS (HR=0.85; 95% CI: 0.46–1.57, p=0.59) after adjustment for lymphatic/vascular invasion, nuclear grade and surgery status within one year. Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.

Abstract Abstract 147 Background: Hematopoietic cell transplantation – specific comorbidity index (HCT-CI) based on pre-transplant comorbidities was shown to be predictive of survival and non-relapse mortality in patients undergoing allogeneic stem cell transplantation (ASCT). We assessed HCT-CI as a predictive instrument for survival in patients admitted to intensive care unit (ICU) early after ASCT. Methods: Patients older than 18 who were admitted to ICU between the preparative regimen initiation and post-transplant day 100 were included. Demographics, pre-transplant comorbidities, disease characteristics, transplant data, dates of transplantation, ICU admission, and last follow-up were gathered from institutional registries. Reason for ICU transfer, date and survival status at the time of hospital discharge were gathered from individual medical records. HCT-CI scores were calculated as previously described by Sorror et al. Patients who were transferred to a hospice and died within 7 days of the transfer were considered to have died in the hospital for the purpose of current analyses. Results: Of 3039 patients who underwent ASCT between June 2001 and December 2011 at MD Anderson Cancer Center, 377 patients (12%) were transferred to ICU within 100 days of the transplant. Disease and transplant characteristics of the patients are demonstrated in the Table. The most common reasons for ICU transfer were respiratory failure (n=230), septic shock (n=44), altered mental status (n=33), hemorrhage (excluding intracranial, n=28), and arrhythmias (n=20). Median age was 53 years with a range of 19–80. The most common pre-transplant comorbidities were pulmonary in 302 (80%) and cardiac in 73 patients (19%). Overall 240 patients (64%) died in the hospital. A comprehensive logistic regression model demonstrated HCT-CI score ≥3 to be associated with a higher risk of death in the hospital (Table). Patients with myeloproliferative diseases and those admitted to ICU during the preparative regimen had less risk of dying in the hospital while those who received ablative regimens had an increased risk. One-year overall survival (OS) rates were 22%, 16%, 16%, and 10% among patients with HCT-CI scores of 0–1, 2, 3, and ≥4, respectively. A Cox proportional hazards model demonstrated HCT-CI score of ≥4 to be a poor prognostic factor on OS (HR: 1.72, 95% CI: 1.21–2.44). The only other significant prognostic factor on OS was the age. Conclusion: Overall prognosis in patients who are transferred to ICU within 100 days of ASCT is poor. HCT-CI score could aid clinicians to identify the worst-to-perform patients within this population. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND Epithelioid sarcoma (ES) and unclassified sarcoma with epithelioid features (USEF) are clinically and therapeutically unresolved. We compared ES and USEF patients' clinical behavior, treatment, outcome, and molecular marker expression. Furthermore, preclinical ES study models were developed to enable comprehensive benchside investigations. PATIENTS AND METHODS A database of ES and USEF patients (n = 116) treated since 1992 was created. A clinically annotated ES-USEF tissue microarray (TMA) was assayed for tumor-related markers. Newly established human and commercially available ES cell lines were characterized and tested in vivo. RESULTS ES and USEF patients presenting with localized disease exhibited 22% and 25% local recurrence rates, 35% and 19% nodal metastasis rates, and 41% and 53% distant metastasis rates (median follow-up, 54 months and 39 months, respectively). The 5- and 10-year disease-specific survival rates were 88% and 43% and 52% and 42% (ES and USEF, respectively). TMA immunohistochemistry identified integrase interactor (INI)-1 loss, cancer antigen 125, and p53 nuclear expression as significantly more common in ES than USEF cases. Both cell lines preserved ES morphological and biochemical characteristics in vitro and in vivo; loss of INI-1 was shown to occur in both lines. CONCLUSIONS Enhanced knowledge of ES and USEF clinical behavior, marker expression, and molecular determinants, extended via experimental models, will hopefully accelerate development of urgently needed effective targeted therapies for ES and USEF.

Abstract Abstract 4108 Background: The absence of contaminating tumor cells in the graft and the potential for a graft- versus- myeloma (GVM) effect make allogeneic hematopoietic stem cell transplantation (allo-HCT) a useful treatment option for patients with multiple myeloma (MM). Reduced-intensity conditioning (RIC) allo-HCT has led to a more acceptable TRM rate of approximately 10–15%, while preserving the GVM effect. We have previously studied the feasibility of a lower dose of melphalan (100 mg/m2) for allo-HCT for acute myeloid leukemia (AML) [Estey et al. Blood 2007]. Methods: We conducted a randomized phase II trial of two RIC regimens, fludarabine + melphalan 140 mg/m2 (FM140) versus fludarabine + melphalan 100 mg/m2 (FM100) before allo-HCT from related or unrelated donors. The basic hypothesis was that a lower dose of melphalan would result in less toxicity and less GVHD without compromising the engraftment and disease control. Twenty-three patients received 4 weekly doses rituximab 375 mg/m2 as part of their preparative regimen to further reduce the risk of chronic GVHD (Kebriaei et al. BMT 2006). Patients were randomized fairly between the two treatment arms using adaptive dynamic allocation to balance on chemosensitivity and donor type (related vs. unrelated). GVHD prophylaxis consisted of tacrolimus and methotrexate. Results: Fifty allo-HCT patients were randomized between April 2002 and April 2011, 27 to FM140 and 23 to FM100. All patients had a prior auto-HCT and 80% patients had at least one relapse before allo-HCT. Patient characteristics were well matched between the 2 cohorts (Table). The FM100 had more related donors (91% vs. 65%, p=0.01). There were no significant differences between FM140 and FM100 in time to neutrophil engraftment (median 12 days; p=0.21), acute grade II-IV GVHD (22% vs. 21%; p=1.0), chronic GVHD (29% vs. 48%; p=0.24), or CR + VGPR (48 vs. 43%; p=1.0). One-year TRM was 15% in FM140 group, and 13% in the FM100 group (p=1.0). Median PFS for FM140 and FM100 were 8.3 and 11.7 months, respectively (p=0.12).The median OS for FM140 and FM100 were 1.6 and 2.9 years, respectively (p=0.38). The cumulative incidence of disease progression in FM140 and FM100 was 70% and 43%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM 140 (44%) and FM100 (26%). Eight patients (FM140 5, FM100 3) received donor lymphocyte infusions after allo-HCT, and only 6 patients (FM140 4, FM100 2) received maintenance therapy after allo-HCT. Multivariate Cox models showed patients with high-risk or standard-risk cytogenetic abnormalities had similar PFS and OS (p=0.10 and 0.64), and patients with chemoresistant (/=PR) disease at allo-HCT had similar PFS and OS (p=0.56 and 0.73). Conclusions: This single center, prospective, randomized trial illustrates that the reduction in melphalan dose had no adverse impact on engraftment, response rate, PFS or OS. RIC allo-HCT is safe and can overcome adverse impact of HR cytogenetics and chemoresistant disease in a subset of heavily pretreated patients. Disease relapse remains a problem. The use of post-transplant maintenance therapy, pre-emptive DLI and vaccines will be explored in future trials. Disclosures: No relevant conflicts of interest to declare.