Greatest Percentage Involved Core Length and Risk of Clinically Significant Prostate-Specific Antigen Failure After Radical Prostatectomy.

BACKGROUND: Radical prostatectomy (RP) can cure men with unfavorable intermediate- or high-risk prostate cancer (PC). However, some will experience short prostate-specific antigen (PSA) doubling time (PSADT) failure that requires additional treatment with increased toxicity. The present study investigated whether the greatest percentage of involved biopsy core length (GPC) can preoperatively identify men at risk of short PSADT failure. PATIENTS AND METHODS: A total of 503 men with biopsy-proven PC underwent RP at an academic institution from January 2005 to December 2008. Men with incomplete pathologic information, those who had received neoadjuvant or adjuvant hormonal therapy or chemotherapy, and those who had undergone adjuvant radiation therapy were excluded. The median follow-up period was 4.89 years (interquartile range, 1.97-5.68 years). A competing risk regression was used to assess whether an increasing GPC value was associated with an increased PSADT at < 10-month failure risk, adjusting for age, percentage of positive biopsy results, and risk group. RESULTS: Of the 402 men, 34 (8.46%) developed PSA failure, 17 (50.0%) of whom had a PSADT of < 10 months. An increasing GPC value was significantly associated with an increased PSADT of < 10-month failure risk (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01-1.06; P = .015). Men with a GPC > 30% (median) versus ≤ 30% and unfavorable intermediate- or high-risk PC (P = .011), but not low or favorable intermediate-risk PC (P = .57), had a significantly greater incidence of PSADT < 10-month failure estimates (30% vs. 0% at 5 years). CONCLUSION: Men planning to undergo RP for unfavorable intermediate- or high-risk PC with a GPC of > 30% should be considered for randomized trials evaluating the effect on survival of the neoadjuvant use of treatment that extends survival in those with castrate-resistant metastatic PC.

[18F]-Fluoromisonidazole positron emission tomography/computed tomography visualization of tumor hypoxia in patients with chordoma of the mobile and sacrococcygeal spine.

PURPOSE: To investigate [18F]-fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) detection of targetable hypoxic subvolumes (HSVs) in chordoma of the mobile or sacrococcygeal spine. METHODS AND MATERIALS: A prospective, pilot study of 20 patients with primary or locally recurrent chordoma of the mobile or sacrococcygeal spine treated with proton or combined proton/photon radiation therapy (RT) with or without surgery was completed. The FMISO-PET/CT was performed before RT and after 19.8-34.2 GyRBE (relative biologic effectiveness). Gross tumor volumes were delineated and HSVs defined including voxels with standardized uptake values ≥1.4 times the muscle mean. Clinical characteristics and treatments received were compared between patients with and without HSVs. RESULTS: The FMISO-PET/CT detected HSVs in 12 of 20 patients (60%). Baseline and interval HSV spatial concordance varied (0%-94%). Eight HSVs were sufficiently large (≥5 cm(3)) to potentially allow an intensity modulated proton therapy boost. Patients with HSVs had significantly larger gross tumor volumes (median 410.0 cm(3) vs 63.4 cm(3); P=.02) and were significantly more likely to have stage T2 tumors (5 of 12 vs 0 of 8; P=.04). After a median follow-up of 1.8 years (range, 0.2-4.4 years), a local recurrence has yet to be observed. Three patients developed metastatic disease, 2 with HSVs. CONCLUSIONS: Detection of targetable HSVs by FMISO-PET/CT within patients undergoing RT with or without surgery for treatment of chordoma of the mobile and sacrococcygeal spine is feasible. The study's inability to attribute interval HSV changes to treatment, rapidly changing hypoxic physiology, or imaging inconsistencies is a limitation. Further study of double-baseline FMISO-PET/CT and hypoxia-directed RT dose escalation, particularly in patients at high risk for local recurrence, is warranted.

Greatest percentage of involved core length and the risk of death from prostate cancer in men with highest Gleason score ≥ 7.

INTRODUCTION/BACKGROUND: Men with highest GS ≥ 7 and a differing, lower GS core (ComboGS) have decreased PC-specific mortality (PCSM) risk after RT or RT and androgen deprivation therapy (ADT). Whether the greatest percentage of involved core length (GPC) modulates this risk is unknown. PATIENTS AND METHODS: Men with GS ≥ 7 PC (n = 333) consecutively treated between December 1989 and July 2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%) comprised the study cohort. The GPC was calculated using biopsy core and tumor lengths. We used competing risks regression to assess whether increasing GPC was associated with increased PCSM risk in men with or without ComboGS adjusting for risk group, age, and treatment. RESULTS: After a median follow-up of 5.36 years (interquartile range, 3.22-7.61 years), 92 (28%) men died, 28 (30%) of PC. Increasing GPC was significantly associated with increased risk of PCSM (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Men with GPC ≥ 50% versus < 50% had significantly greater PCSM estimates when ComboGS was present (P < .001) versus absent (P = .55). Of the 127 men with ComboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; neither in men with GS 7 and favorable intermediate-risk PC. CONCLUSION: Men treated with RT for ComboGS, GPC < 50%, GS 7, and favorable intermediate-risk PC have a very low risk of early PCSM. The RTOG 0815 trial will establish whether ADT is necessary to optimize curability in these men.

MRI surveillance following treatment of extremity soft tissue sarcoma.

BACKGROUND AND OBJECTIVES: Local recurrence (LR) following limb-sparing surgery and radiation therapy (RT) for extremity soft tissue sarcoma (STS) is rare. The current study investigates the utility of surveillance nuclear magnetic resonance imaging (MRI) for detection of asymptomatic LRs. METHODS: The study cohort consisted of 168 adult patients with extremity STS treated with limb-sparing surgery and RT with curative intent between October 2001 and January 2011. Follow-up surveillance MRIs and history and physical examinations were performed per the NCCN guidelines with additional MRIs as clinically indicated. The method of LR detection and MRI number and indication were determined. RESULTS: After a median follow-up of 4.7 years (range: 0.6-10.5) 11 (6.5%; 11/168) patients developed LRs. Five hundred two MRIs were obtained, 429 (85.5%; 429/502) for surveillance and 73 (14.5%; 73/502) as clinically indicated. One hundred fourteen patients underwent ≥1 surveillance MRI. The median surveillance MRI interval was 6.4 months (range 1.4-68.9). Surveillance MRI detected an asymptomatic LR in 1 (0.9%; 1/114) patient with a complex reconstruction. CONCLUSIONS: Surveillance MRI infrequently detects asymptomatic LRs following limb-sparing surgery and RT for extremity STS and should be limited to patients whose primary tumor sites are not easily assessed by history and physical examination.

Genetic manipulation of AML1-ETO-induced expansion of hematopoietic precursors in a Drosophila model.

Among mutations in human Runx1/AML1 transcription factors, the t(8;21)(q22;q22) genomic translocation that creates an AML1-ETO fusion protein is implicated in etiology of the acute myeloid leukemia. To identify genes and components associated with this oncogene we used Drosophila as a genetic model. Expression of AML1-ETO caused an expansion of hematopoietic precursors in Drosophila, which expressed high levels of reactive oxygen species (ROS). Mutations in functional domains of the fusion protein suppress the proliferative phenotype. In a genetic screen, we found that inactivation of EcRB1 or activation of Foxo and superoxide dismutase-2 (SOD2) suppress the AML1-ETO-induced phenotype by reducing ROS expression in the precursor cells. Our studies indicate that ROS is a signaling factor promoting maintenance of normal as well as the aberrant myeloid precursors and suggests the importance of antioxidant enzymes and their regulators as targets for further study in the context of leukemia.

CBFbeta is critical for AML1-ETO and TEL-AML1 activity.

AML1-ETO and TEL-AML1 are chimeric proteins resulting from the t(8;21)(q22;q22) in acute myeloid leukemia, and the t(12;21)(p13;q22) in pre-B-cell leukemia, respectively. The Runt domain of AML1 in both proteins mediates DNA binding and heterodimerization with the core binding factor beta (CBFbeta) subunit. To determine whether CBFbeta is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFbeta but not DNA binding. We show that CBFbeta contributes to AML1-ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and is indispensable for its cooperativity with the activated receptor tyrosine kinase TEL-PDGFbetaR in generating acute myeloid leukemia in mice. Similarly, CBFbeta is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFbeta interaction as a therapeutic target in core binding factor leukemias.

Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity.

AML1/ETO results from the t(8;21) associated with 12%-15% of acute myeloid leukemia. The AML1/ETO MYND domain mediates interactions with the corepressors SMRT and N-CoR and contributes to AML1/ETO's ability to repress proliferation and differentiation of primary bone marrow cells as well as to enhance their self renewal in vitro. We solved the solution structure of the MYND domain and show it to be structurally homologous to the PHD and RING finger families of proteins. We also determined the solution structure of an MYND-SMRT peptide complex. We demonstrated that a single amino acid substitution that disrupts the interaction between the MYND domain and the SMRT peptide attenuated AML1/ETO's effects on proliferation, differentiation, and gene expression.

The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity.

AML1/ETO is the chimeric protein resulting from the t(8;21) in acute myeloid leukemia. The Nervy homology 2 (NHR2) domain in ETO mediates oligomerization and AML1/ETO's interactions with ETO, MTGR1, and MTG16, and with the corepressor molecules mSin3A and HDAC1 and HDAC3. We solved the NHR2 domain structure and found it to be an alpha-helical tetramer. We show that oligomerization contributes to AML1/ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and affects AML1/ETO's activity on several endogenous genes. Oligomerization is also required for AML1/ETO's interactions with ETO, MTGR1, and MTG16, but not with other corepressor molecules.

Increase in plasma and surface CD163 levels in patients undergoing coronary artery bypass graft surgery.

Although haptoglobin polymorphism has been shown to be a genetic risk factor in coronary artery disease, its mechanisms of action are incompletely defined. Recently, a macrophage scavenger receptor for the uptake of haptoglobin-hemoglobin (Hp-Hb) complexes was cloned and designated CD163. Macrophage expression of CD163 is increased by glucocorticoids, IL-10 and IL-6. To better understand the in vivo response of CD163 to an inflammatory stimulus and glucocorticoid treatment, we studied 18 patients who underwent elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). We report a rapid increase in plasma levels of soluble CD163 by 1 h post-declamping the aorta during CABG surgery with CPB. Furthermore, we demonstrate significant increases in monocyte CD163 on post-operative day 1; 14-fold for patients pre-treated with methylprednisolone and 3-fold for those who did not receive exogenous glucocorticoids. These findings show CD163 to be rapidly mobilized in response to systemic inflammatory stimuli and to be affected significantly by glucocorticoids in vivo. The proposed role of CD163 as a Hp-Hb scavenger and anti-inflammatory molecule, in conjunction with the results of this study, make CD163 an intriguing target for potential manipulation of the acute response to inflammation.

Mutagenesis of the Runt domain defines two energetic hot spots for heterodimerization with the core binding factor beta subunit.

Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways and in human disease. Mutations in CBF genes are found in leukemias, bone disorders, and gastric cancers. CBFs consist of a DNA-binding CBF alpha subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBF beta subunit. CBF alpha binds DNA in a sequence-specific manner, whereas CBF beta enhances DNA binding by CBF alpha. Both DNA binding and heterodimerization with CBF beta are mediated by a single domain in the CBF alpha subunits known as the "Runt domain." We analyzed the energetic contribution of amino acids in the Runx1 Runt domain to heterodimerization with CBF beta. We identified two energetic "hot spots" that were also found in a similar analysis of CBF beta (Tang, Y.-Y., Shi, J., Zhang, L., Davis, A., Bravo, J., Warren, A. J., Speck, N. A., and Bushweller, J. H. (2000) J. Biol. Chem. 275, 39579-39588). The importance of the hot spot residues for Runx1 function was demonstrated in in vivo transient transfection assays. These data refine the structural analyses and further our understanding of the Runx1-CBF beta interface.