Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.

Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group.

Microcalcifications in 1657 Patients with Pure Ductal Carcinoma in Situ of the Breast: Correlation with Clinical, Histopathologic, Biologic Features, and Local Recurrence.

PURPOSE: This study was designed to determine the relationship of microcalcification morphology and distribution with clinical, histopathologic, biologic features, and local recurrence (LR) in patients with pure ductal carcinoma in situ (DCIS) of the breast. METHODS: All patients with pure DCIS who underwent preoperative mammography at our institution from 1996 through 2009 were identified. Mammographic findings were classified according to the ACR BI-RADS lexicon. Associations between mammographic findings and clinical, histopathologic, biologic characteristics, and LR were analyzed. Statistical inference used multiple logistic regression and Cox proportional hazards regression adjusted for age and confounding due to bias from nonrandomized selection of radiation therapy. RESULTS: We identified 1657 patients with microcalcifications visualized on mammography. The mean age at diagnosis was 55 years (SD, 11). The mean follow-up was 7 years (range 1-16). Ipsilateral LR was 4 % in segmentectomy (987) and 1.5 % in mastectomy (670) patients. Increased LR risk was seen in patients with dense breast tissue (p < 0.05) and larger DCIS size (p < 0.01). Radiation therapy was associated with a 2.8-fold decrease in the LR risk. Fine linear (branching) microcalcifications were associated with 5.2-fold increase in LR. Extremely dense breast tissue was associated with positive/close margins (p = 0.04) and multicentricity (p < 0.01). Younger women were more likely to have extremely dense breast tissue (p < 0.0001), multicentric disease (p < 0.0004), and undergo mastectomy (p < 0.0001). CONCLUSIONS: Dense breast tissue, large DCIS size, and fine linear (branching) microcalcifications were associated with increased LR, yet overall LR rates remained low. Extremely dense breast tissue was a risk factor for multicentricity and positive margins in DCIS.

Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms.

Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN-U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters.

Correlation between sonographic findings and clinicopathologic and biologic features of pure ductal carcinoma in situ in 691 patients.

OBJECTIVE: The objective of our study was to compare the sonographic features of pure ductal carcinoma in situ (DCIS) lesions with the initial clinical presentation and histopathologic findings. MATERIALS AND METHODS: The images and records of 691 patients with pure DCIS who underwent preoperative mammography and whole-breast sonography as part of staging workup in a single institution from January 1, 1996, through July 31, 2009, were reviewed. The BI-RADS sonography lexicon was used when reviewing the sonographic studies. Histopathologic features recorded included estrogen receptor (ER) status, nuclear grade, and presence or absence of comedonecrosis. Statistical comparisons were made using the Student t test, chi-square test, Fisher exact test, Kruskal-Wallis or Wilcoxon rank sum test, multiple logistic regression analysis, and Pearson correlation coefficient. RESULTS: A total of 304 (44%) tumors were visible on mammography and sonography; 315 (46%), on mammography only; 58 (8%), on sonography only; and 14 (2%), on neither mammography nor sonography. The most common sonographic appearance of DCIS was an irregular hypoechoic mass with indistinct margins and normal posterior features that was indistinguishable from invasive carcinoma. Patients with symptomatic high-nuclear-grade DCIS, dense breasts, and comedonecrosis were younger and had larger tumors on sonography than asymptomatic women with nondense breasts and low-nuclear-grade and noncomedo DCIS. Women with ER-negative DCIS were older and had larger tumors on sonography than women with ER-positive DCIS. ER-negative tumors were more frequently visible on sonography than ER-positive tumors (p=0.007). High-grade DCIS (p<0.0001) and comedo DCIS (p<0.0001) presented more frequently as microcalcifications, architectural distortion, and ductal changes on sonography than low-grade DCIS or noncomedo DCIS. CONCLUSION: Of the 691 pure DCIS lesions, 362 (52%) were visible on sonography and presented most commonly as a mass. Lesion visibility of DCIS on sonography was not related to nuclear grade or the presence of comedonecrosis.

Analysis of free-form radiology dictations for completeness and clarity for pancreatic cancer staging.

PURPOSE: To assess the completeness and clarity of current free-form radiology reports for pancreatic cancer staging by evaluating them against the elements of the RSNA CT oncology primary pancreas mass dictation template. METHODS: This retrospective study was approved by our Institutional Review Board (IRB). 295 free-form computed tomography (CT) reports for baseline staging of pancreatic cancer (PC) generated between August 2008 and December 2010 were evaluated by one of two radiologists with expertise in pancreatic cancer imaging. Reports which indicated that metastatic disease was present were excluded. The completeness and clarity of the reports were analyzed against the elements of the RSNA CT pancreas mass dictation template. Fisher's exact tests were used to analyze differences by year and type of radiologist. RESULTS: Primary lesion location, size, and effect on bile duct (BD) were provided in 93.9% (277/295), 69.8% (206/295), and 67.5% (199/295) of reports, respectively. Standard terms to describe vascular involvement were used in 47.5% (140/295) of reports. In 20.3% (60/295), the resectability status could not be defined based on the report alone. In 36.9% (109/295) of reports, review of CT images was necessary to understand vascular involvement. Radiologists expert in pancreatic oncology had a higher proportion of reports using standardized terminology and reports in which vascular involvement was understood without revisiting the images. CONCLUSIONS: Free-form reports were more likely to use ambiguous terminology and/or require review of the actual images for understanding resectability status. The use of a standardized reporting template may improve the usefulness of pancreatic cancer staging reports.

Multidetector CT detection of peritoneal metastases: evaluation of sensitivity between standard 2.5 mm axial imaging and maximum-intensity-projection (MIP) reconstructions.

OBJECTIVE: Our purpose was to evaluate the sensitivity of multidetector CT for the detection of peritoneal metastases between standard 2.5 mm axial imaging and maximum-intensity-projection (MIP) reconstructions. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study and waived the need to obtain patient consent. We retrospectively identified 36 patients with pancreatic adenocarcinoma and peritoneal metastatic disease who underwent a pancreatic protocol CT examination of the abdomen and pelvis between January 2012 and January 2014. Three independent radiologists reviewed a randomized combination of standard axial (2.5 mm reconstructed thickness, 2.5 mm interval) and axial MIP reconstructions (6, 3 mm interval) over two sessions. Each reader recorded metastasis location in PACS. Subsequent consensus review by two radiologists determined the final number and size of metastases. RESULTS: The reviewers found 328 peritoneal implants in 36 patients. After accounting for the size, location, and number of lesions as well as multiple readers, a generalized estimating equations model showed that the statistical combination of MIP with standard technique significantly increased the odds of correctly identifying a lesion (OR 2.16; 95% CI 1.86-2.51; p value < 0.0001) compared to standard technique alone. MIP reconstruction as a standalone technique was less sensitive compared to standard technique alone (OR 0.81; 95% CI 0.65-0.99; p value = 0.0468). When compared to standard axial imaging, evaluation via MIP reconstructions resulted in the identification of an additional 50 (15%), 45 (14%), and 55 (17%) lesions by Readers 1-3, respectively. CONCLUSION: The axial 6 mm MIP series is complimentary in the CT evaluation of peritoneal metastases. MIP reconstruction evaluation identified a significant number of additional lesions, but is not adequate as a standalone technique for peritoneal cavity assessment.

Impact of initial PET/CT staging in terms of clinical stage, management plan, and prognosis in 592 patients with non-small-cell lung cancer.

PURPOSE: Our objective was to determine the impact of initial (18)F-FDG PET/CT (PET/CT) staging on clinical stage and the management plan and the prognostic value of PET/CT in patients with non-small-cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the records of 592 patients with NSCLC who were referred to The University of Texas MD Anderson Cancer Center during 2002/2011 and had both PET/CT and conventional CT for initial staging. Clinical stages and management plans were compared between PET/CT and CT. The impact of PET/CT on management plans was considered medium/high when PET/CT changed the planned treatment modality or treatment intent. PET/CT and CT stages were compared with all-cause mortality and survival rates. We also assessed potential prognostic factors for progression-free survival (PFS) and overall survival (OS). RESULTS: PET/CT changed the stage in 170 patients (28.7 %; 16.4 % upstaged, 12.3 % downstaged). PET/CT had a medium/high impact on the management plan in 220 patients (37.2 %). PFS and OS were significantly worse in patients with upstaged disease than in patients with no change in stage (median PFS 29.0 vs. 53.8 months, P < 0.001; median OS:64.7 vs. 115.9 months, P = 0.006). PFS and OS were significantly worse in patients with medium/high impact of PET/CT than in patients with no/low impact of PET/CT (median PFS 24.7 vs. 60.6 months, P < 0.001; median OS 64.7 vs. 115.9 months, P < 0.001). In multivariate analysis, a medium/high impact of PET/CT was an independent predictor of worse PFS (hazard ratio, HR, 1.73; 95 % CI 1.30 - 2.29; P = 0.0002) and OS (HR 1.84; 95 % CI 1.26 - 2.69; P = 0.002). CONCLUSION: Initial PET/CT staging not only impacts stage and management plan but also has prognostic value.

Strain elastography of abnormal axillary nodes in breast cancer patients does not improve diagnostic accuracy compared with conventional ultrasound alone.

OBJECTIVE: The purpose of this study was to determine the diagnostic value of strain elastography (SE) alone and in combination with gray-scale ultrasound in the diagnosis of benign versus metastatic disease for abnormal axillary lymph nodes in breast cancer patients. SUBJECTS AND METHODS: Patients with breast cancer and axillary lymph nodes suspicious for metastatic disease on conventional ultrasound who underwent SE of the suspicious node before ultrasound-guided fine-needle aspiration biopsy (FNAB) were included in this study. On conventional ultrasound, the long- and short-axis diameters, long-axis-to-short-axis ratio, cortical echogenicity, thickness, and evenness were documented. The nodal vascularity was assessed on power Doppler imaging. Elastograms were evaluated for the percentage of black (hard) areas in the lymph node, and the SE-ultrasound size ratio was calculated. Two readers assessed the images independently and then in consensus in cases of disagreement. ROC AUCs were calculated for conventional ultrasound, SE, and both methods combined. Interreader reliability was assessed using kappa statistics. RESULTS: A total of 101 patients with 104 nodes were examined; 35 nodes were benign, and 69 had metastases. SE alone showed a significantly lower AUC (62%) than did conventional ultrasound (92%) (p<0.001). There was no difference between the AUC of conventional ultrasound and the AUC of the combination of conventional ultrasound and SE (93%) (p=0.16). Interreader reliability was moderate for all variables (κ≥0.60) except the SE-ultrasound size ratio (κ=0.35). CONCLUSION: Added SE does not improve the diagnostic ability of conventional ultrasound when evaluating abnormal axillary lymph nodes.

Immunohistochemical expression of hormone receptors in melanoma of pregnant women, nonpregnant women, and men.

The survival advantage of women over men with cutaneous melanoma and the reports of accelerated progression of melanoma during pregnancy have led to studies of the effect of hormones and hormone receptors on the development and progression of melanoma. However, the results are inconclusive. We therefore evaluated the expression of estrogen receptor α, estrogen receptor ß, and androgen receptor in melanomas of stage- and age-matched pregnant women, nonpregnant women, and men by immunohistochemical analysis of formalin-fixed, paraffin-embedded archival tissues. In addition, we also assessed the mitotic rate using the antiphosphohistone H3 antibody by immunohistochemistry. Our data showed a trend of more frequent expression of estrogen receptor ß in the melanomas of pregnant patients than in the melanomas of male patients, without a significant difference observed between pregnant and nonpregnant women. However, no association between the expression of estrogen receptor ß and survival was observed. The small cohort may have limited the statistical power of the study, and large-scale studies are needed to elucidate the potential role of estrogen receptor ß as a prognostic marker of melanoma.

Radiation dose reduction for CT lung cancer screening using ASIR and MBIR: a phantom study.

The purpose of this study was to reduce the radiation dosage associated with computed tomography (CT) lung cancer screening while maintaining overall diagnostic image quality and definition of ground-glass opacities (GGOs). A lung screening phantom and a multipurpose chest phantom were used to quantitatively assess the performance of two iterative image reconstruction algorithms (adaptive statistical iterative reconstruction (ASIR) and model-based iterative reconstruction (MBIR)) used in conjunction with reduced tube currents relative to a standard clinical lung cancer screening protocol (51 effective mAs (3.9 mGy) and filtered back-projection (FBP) reconstruction). To further assess the algorithms' performances, qualitative image analysis was conducted (in the form of a reader study) using the multipurpose chest phantom, which was implanted with GGOs of two densities. Our quantitative image analysis indicated that tube current, and thus radiation dose, could be reduced by 40% or 80% from ASIR or MBIR, respectively, compared with conventional FBP, while maintaining similar image noise magnitude and contrast-to-noise ratio. The qualitative portion of our study, which assessed reader preference, yielded similar results, indicating that dose could be reduced by 60% (to 20 effective mAs (1.6 mGy)) with either ASIR or MBIR, while maintaining GGO definition. Additionally, the readers' preferences (as indicated by their ratings) regarding overall image quality were equal or better (for a given dose) when using ASIR or MBIR, compared with FBP. In conclusion, combining ASIR or MBIR with reduced tube current may allow for lower doses while maintaining overall diagnostic image quality, as well as GGO definition, during CT lung cancer screening.

Clinicopathologic, mammographic, and sonographic features in 1,187 patients with pure ductal carcinoma in situ of the breast by estrogen receptor status.

The clinicopathologic, mammographic, and sonographic findings in patients with pure ductal carcinoma in situ (DCIS) were assessed by estrogen receptor (ER) expression. After institutional review board approval, patients with pure DCIS evaluated from January 1996 to July 2009 with known ER status and available imaging were identified. Images were reviewed as per the ACR BI-RADS(®) lexicon (4th edition). Clinical, pathologic, and imaging characteristics were analyzed by ER status using t test, Chi square test, and Fisher's exact test. Of 1,219 patients with pure DCIS and known ER status identified, 1,187 with complete data were included. Mammography was performed in all 1,187 patients and sonography in 519 (44 %). There were 972 (82 %) patients with ER-positive and 215 (18 %) with ER-negative disease. ER-negative DCIS was more likely to be high grade (93 vs 44 %, p < 0.0001), associated with comedonecrosis (64 vs 29 %, p < 0.0001), and multifocal (23 vs 15 %, p = 0.009). On sonography, ER-negative DCIS was more likely to be visible (61 vs 46 %, p = 0.004), larger (mean size, 2.3 vs 1.6 cm, p = 0.006), and show posterior shadowing (53 vs 28 %, p = 0.006). Mastectomy was more frequently performed for ER-negative DCIS (47 vs 37 %, p = 0.008). Palpable DCIS was visible on sonography in 55 % of cases and mammography in 81 %. Compared with ER-positive palpable DCIS, ER-negative palpable DCIS was larger and more likely to be visible on sonography. Compared with ER-positive noncalcified DCIS, ER-negative noncalcified DCIS was less likely to be visible on mammography. ER-positive and ER-negative pure DCIS have different clinicopathologic and imaging characteristics. ER-negative DCIS is associated with worse prognostic factors than ER-positive DCIS. On sonography, ER-negative DCIS is more frequently visible than ER-positive DCIS, tends to be larger, and more frequently demonstrates posterior shadowing.

Palliative venting gastrostomy in patients with malignant bowel obstruction and ascites.

BACKGROUND: Fluoroscopic-guided placement of a percutaneous decompression gastrostomy tube (PDGT) is used to palliate patients with malignant bowel obstruction (MBO). We report our clinical experience in cases of MBO and ascites that were known to be technically difficult and at increased risk for complications after PDGT placement. METHODS: Between October 2005 and April 2010, a total of 89 consecutive oncology patients with MBO and ascites underwent at least one attempt at PDGT placement. We retrospectively reviewed the electronic medical record to collect demographic details, procedure information, and morbidity and mortality data. Kaplan-Meier curves were used to calculate median survival after PDGT. RESULTS: Ninety-three new gastrostomy encounters occurred in 89 patients. The primary and secondary technical success rates were 72 % (67 of 93) and 77.4 % (72 of 93), respectively. Inadequate gastric distention was the reason for failure in 84.6 % (22 of 26) of the cases in which the initial PDGT attempt was unsuccessful. For ascites management, 13 patients underwent paracentesis and 78 patients underwent placement of an intraperitoneal catheter. The overall complication rate in successful placements was 13.9 %, with a major complication rate of 9.7 %. After PDGT, the median overall survival rate was 28.5 days (95 % confidence interval 20-42). CONCLUSIONS: PDGT is feasible in the majority of patients with MBO and ascites, although there is an inherent risk of major complications. An intraperitoneal catheter can be used to manage ascites to facilitate PDGT.

Primary salivary gland-type lung cancer: imaging and clinical predictors of outcome.

OBJECTIVE: The objective of our study was to assess whether CT features and FDG up-take of primary salivary gland-type tumors of the lung are associated with tumor type, disease stage, or survival. MATERIALS AND METHODS: CT (n = 30) and PET (n = 15) data of 30 consecutive patients with primary salivary gland-type tumors of the lung were retrospectively evaluated for tumor size, location, and homogeneity and the presence of lymphadenopathy, pleural effusions, and metastases. Maximum FDG uptake and volumetric FDG uptake of the tumors were recorded. The Wilcoxon rank sum and Fisher exact tests and univariate Cox regression were used for statistical calculations. RESULTS: Compared with mucoepidermoid carcinomas, adenoid cystic carcinomas (57%) were larger (mean, 3.5 vs 2.2 cm, respectively; p = 0.03), more frequently involved the central airways (94% vs 63%; p = 0.002), and had a higher median FDG uptake (p = 0.0264). Higher FDG uptake of the primary tumor was associated with nodal tumor involvement (p = 0.05). The median overall survival times for patients with adenoid cystic carcinoma and mucoepidermoid carcinoma were 7.7 and 4.0 years, respectively. Imaging features that significantly affected overall survival included the presence of mediastinal or hilar lymphadenopathy (hazard ratio [HR], 4.33; 95% CI, 1.15-16.26; p = 0.03), suspected metastatic disease (HR, 5.10; 95% CI, 1.27-20.47; p = 0.02), and primary tumor heterogeneity (HR, 3.46; 95% CI, 1.04-11.55; p = 0.04). CONCLUSION: Higher FDG uptake is associated with nodal disease in patients with primary salivary gland-type tumors of the lung but is not predictive of survival, whereas CT features suggestive of advanced disease correlate with worse outcome.

Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model.

Solitary fibrous tumor represents a spectrum of mesenchymal tumors, encompassing tumors previously termed hemangiopericytoma, which are classified as having intermediate biological potential (rarely metastasizing) in the 2002 World Health Organization classification scheme. Few series have reported on clinicopathological predictors with outcome data and formal statistical analysis in a large series of primary tumors as a single unified entity. Institutional pathology records were reviewed to identify primary solitary fibrous tumor cases, and histological sections and clinical records reviewed for canonical prognostic indicators, including patient age, tumor size, mitotic index, tumor cellularity, nuclear pleomorphism, and tumor necrosis. Patients (n=103) with resected primary solitary fibrous tumor were identified (excluding meningeal tumors). The most common sites of occurrence were abdomen and pleura; these tumors were larger than those occurring in the extremities, head and neck or trunk, but did not demonstrate significant outcome differences. Overall 5- and 10-year metastasis-free rates were 74 and 55%, respectively, while 5- and 10-year disease-specific survival rates were 89 and 73%. Patient age, tumor size, and mitotic index predicted both time to metastasis and disease-specific mortality, while necrosis predicted metastasis only. A risk stratification model based on age, size, and mitotic index clearly delineated patients at high risk for poor outcomes. While small tumors with low mitotic rates are highly unlikely to metastasize, large tumors ≥ 15 cm, which occur in patients ≥ 55 years, with mitotic figures ≥ 4/10 high-power fields require close follow-up and have a high risk of both metastasis and death.

Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial.

BACKGROUND: Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial. METHODS: The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days -2 and -1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178. FINDINGS: Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group. INTERPRETATION: These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma. FUNDING: This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672).

Native and engineered tropism of vectors derived from a rare species D adenovirus serotype 43.

Unique molecular properties of species D adenoviruses (Ads)-the most diverse yet underexplored group of Ads-have been used to develop improved gene vectors. The low seroprevalence in humans of adenovirus serotype 43 (Ad43), an otherwise unstudied species D Ad, identified this rare serotype as an attractive new human gene therapy vector platform. Thus, in this study we wished to assess biological properties of Ad43 essential to its vectorization. We found that (1) Ad43 virions do not bind blood coagulation factor X and cause low random transduction upon vascular delivery; (2) they clear host tissues more quickly than do traditionally used Ad5 vectors; (3) Ad43 uses CD46 as primary receptor; (4) Ad43 can use integrins as alternative primary receptors. As the first step toward vectorization of Ad43, we demonstrated that the primary receptor specificity of the Ad43 fiber can be altered to achieve infection via Her2, an established oncotarget. Whereas this modification required use of the Ad5 fiber shaft, the presence of this domain in chimeric virions did not make them susceptible for neutralization by anti-Ad5 antibodies.

MRI may be used as a prognostic indicator in patients with extra-abdominal desmoid tumours.

OBJECTIVE: To determine the association of MRI features of extra-abdominal desmoid tumours (DTs) with prognosis. METHODS: MRIs for 90 patients with DT were retrospectively reviewed for imaging features associated with biological behaviour. The primary end point was progression (for lesions managed with chemotherapy, radiation therapy and observation) or recurrence (following surgery). Time to event was studied using univariate and multivariable Cox proportional hazards regression models when accounting for demographic, clinicopathological and imaging variables. Kaplan-Meier plots were used to estimate event-free rate (EFR). RESULTS: Univariate analysis revealed a significant relationship between EFR and treatment, location and compartment of origin [subcutaneous (SC), superficial fascial, intramuscular (IM) and deep fascial/intermuscular]. None of the imaging features commonly associated with biological behaviour of DTs (e.g., shape, enhancement, T2 signal etc.) or surgical margins (in surgical cases) was associated with EFR. Multivariate analysis showed that treatment modality and compartment of origin were independent predictors of EFR. Superficial and deep fascial lesions had a significantly worse EFR as a group [hazard ratio: 3.9; 95% confidence interval (CI): 1.83-8.32; p = 0.0004] than did the SC and IM lesions as a group. 5-year EFR for the fascial lesions was 18% (95% CI: 6-36%), compared with 57% (95% CI: 25-79%) for the SC and IM groups. CONCLUSION: Intramuscular or SC DTs may be associated with improved prognosis. If validated on multireader and prospective studies, these results can provide for rapid risk stratification at the time of initial MRI. ADVANCES IN KNOWLEDGE: This work has shown that imaging features commonly associated with biological activity of desmoid tumours (e.g. shape, T2 signal and enhancement) do not appear to be associated with prognosis in patients undergoing a variety of treatment modalities. The compartment of origin of the lesion, which can be determined on pre-operative MRI, was shown to be associated with prognosis and can allow for risk stratification in patients with DTs.

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole.

PURPOSE: This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS: Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS: The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION: These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Prognostic Factors in Patients Treated with 223Ra: The Role of Skeletal Tumor Burden on Baseline 18F-Fluoride PET/CT in Predicting Overall Survival.

UNLABELLED: The purpose of this study was to evaluate outcome after (223)Ra dichloride therapy ((223)Ra) and to determine whether skeletal tumor burden on whole-body (18)F-fluoride PET/CT can be used as a predictive biomarker of survival in patients treated with (223)Ra. METHODS: Forty-two patients with hormone-refractory prostate cancer underwent (223)Ra and a baseline fluoride PET/CT scan. Fluoride PET/CT parameters were generated, including maximum standardized uptake value (SUVmax) of the hottest lesion (hSUVmax), average SUV of disease (Mean10), and skeletal tumor burden indices of total fluoride skeletal metastatic lesion uptake (TLF10) and total volume of fluoride avid bone metastases (FTV10). Overall survival (OS) was the primary endpoint. Secondary endpoints were progression-free survival and skeletal-related event (SRE). RESULTS: Skeletal tumor burden indices (TLF10 and FTV10) derived from fluoride PET/CT at baseline were highly correlated and significant independent predictors of OS (P = 0.0212; hazard ratio = 5.990; 95% confidence interval = 1.306-27.475). A TLF10 cutoff value of 8,000 discriminated survivors from nonsurvivors after (223)Ra (with TLF10 values < 8,000, the median OS was not estimated, whereas with TLF10 > 8,000, the median OS was 6.67 mo). Visual analysis, Mean10, and hSUVmax were not predictors of OS or progression-free survival. Mean10 was found to be a significant univariate predictor of the odds of having an SRE (P = 0.0445; odds ratio = 1.30; 95% confidence interval = 1.006-1.681), with a Mean10 greater than 19 increasing the risk of SRE. CONCLUSION: Skeletal tumor burden on baseline fluoride PET/CT is a predictive biomarker of OS and the risk of an SRE in patients treated with (223)Ra.

Histologic variability in solitary fibrous tumors reflects angiogenic and growth factor signaling pathway alterations.

This study aimed to evaluate expression of receptor tyrosine kinases, their ligands, and mutational status in solitary fibrous tumors, with correlation to histopathologic variants, tumor stage, and aggressive behavior. Immunohistochemical staining for PDGFα; PDGFß; PDGFR-α; PDGFR-ß; IGF1R; EGFR; VEGF; IGF2; c-Met; c-kit; c-erbB2; PTEN; and phosphorylated (p)AKT, pS6, and p4EBP1 was analyzed in 114 cases of solitary fibrous tumor using tissue microarray. Mutational analysis was performed using Sequenom MassARRAY-based platform. Multiple growth factors were overexpressed in most tumors, and increased numbers of overexpressed factors correlated with activation of the AKT pathway as measured by increased expression of p4EBP1(P = .0005). Compared to hypocellular tumors, localized hypercellular tumors were associated with high vascular endothelial growth factor (32% versus 8%; P = .008) and PDGFß (41% versus 13%; P = .008). Metastatic tumors more frequently overexpressed PDGFR-α compared to localized tumors (75% versus 31%; P < .001). None of the factors examined had prognostic significance in primary tumors. Single-nucleotide polymorphisms involving MET were identified in 4 patients; these do not appear to drive tumor behavior and were not reflected in c-Met expression levels. Simultaneous overexpression of multiple growth factors is common in solitary fibrous tumors; variability in expression may contribute to tumor phenotype and aggressive behavior.