IDH1 and 2 (IDH1/2) are mutated in 10-15% of intrahepatic cholangiocarcinoma (CCA). The reversible IDH1 inhibitor ivosidenib is approved in 2L IDH1-mutant CCA. Cisplatin and gemcitabine (CISGEM) is the standard 1L chemotherapy backbone for advanced CCA. Addition of PD1/PDL1 inhibitors have demonstrated modest improvement in OS (median 12.8 months), highlighting ongoing unmet need. LY3410738 is an oral, potent, selective, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. Here, we present the translational in vivo findings and data from the ongoing phase 1 study of LY3410738 as monotherapy and with CISGEM in advanced IDH1/2m CCA (NCT04521686). In the phase 1 study, dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced relapsed/refractory (R/R) IDH1/2m CCA and other solid tumors. Dose expansion evaluated LY3410738 in combination with CISGEM in treatment naïve advanced IDH1/2m CCA patients. Objectives included determining the RP2D, safety, PK/PD, and antitumor activity. In an IDH1m CCA PDX model, single agent LY3410738 (10-30 mpk, QD) demonstrated >60% tumor growth inhibition. In a combination PDX study, LY3410738 (30 mpk, QD) plus CISGEM (3/60 mpk, Q7Dx3, 3/40mpk, Q7Dx3) treatment for 6 weeks followed by 15 weeks of LY3410738 maintenance led to 85% tumor growth inhibition, while CISGEM alone achieved only 47% tumor growth inhibition (p < 0.001). In the phase 1 dose escalation cohorts, as of November 01, 2022, 45 patients with R/R CCA received LY3410738 monotherapy (25 - 600 mg QD or 150 - 300 mg BID) (1). Median number of prior lines of therapy was 2 (range, 1-7). The ORR was 4.5% with 2 PR and 23 SD. mPFS was 3.5 months (95% CI, 1.9-5.1). 6 months PFS rate was 32.5% (95% CI 18.8-47.0). In the dose expansion cohort, 13 patients with treatment naïve advanced CCA received LY3410738 (300 mg BID or 400 mg QD) in combination with CISGEM. The median age was 64 years (range, 51-77). Median time on treatment was 5.95 months (range, 2.3-9.1). No DLTs were observed. TEAE ≥30% regardless of attribution were anemia (54%), platelet count decreased (54%), nausea (46%), decreased appetite (39%), neutrophil count decreased (39%), and constipation (31%). Most frequent grade ≥3 TEAE ≥25% were neutrophil count decreased (39%), platelet count decreased (39%), and anemia (31%). 7 (54%) patients reported LY3410738 related AEs of which nausea and neutrophil count decreased were grade 3. The ORR was 46% with 6 PR/uPR (pending confirmation and ongoing) and 6 SD. mPFS was not reached, and 6 months PFS rate was 83.3% (95% CI, 27.3-97.5). The PK/PD profiles were consistent with LY3410738 monotherapy (1). In this phase 1 study, LY3410738 in combination with CISGEM demonstrated a favorable safety profile and preliminary efficacy in treatment naïve locally advanced or metastatic IDH1/2m CCA. RP2D evaluation is ongoing. Reference: 1. Rodon J. et al. To be presented at AACR 2023, Apr 14-19.

The primary goal of this study was to characterize patient reported quality of life (QOL) and late toxicity in patients receiving post-prostatectomy IMRT. A consecutive cohort of 199 men (mean age of 63) with prostate cancer after radical prostatectomy received IMRT between 2007 and 2015 using predefined planning guidelines. Patients were prospectively evaluated using the Expanded Prostate Cancer Index Composite (EPIC-26) instrument and RTOG/CTC toxicity grades at baseline and follow up. Treatment was delivered to the prostate bed (median 68 Gy) +/- pelvic lymphatics (65%, median 50.4 Gy) with daily image guidance. 132 (66%) men received androgen deprivation therapy (ADT) for a median of 4 months. Patients were seen at 2 mo, then q6-12 mo up to 84 months. Wilcoxon signed-rank tests compared changes in QOL between baseline and each time point. Generalized estimating equation (GEE) models and Cox regression were used for multivariate analysis (MVA) to identify factors impacting each QOL domain and freedom from ≥ grade 2 (FFG2) gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. Dosimetric data analyzed included the V70, 65, and 40 Gy for bladder and rectum and mean penile bulb dose. Median time from radical prostatectomy to RT was 19 mo. The median V70/65/40 Gy to the bladder and rectum were 18/45/73% and 6/22/54%, respectively. Median follow-up was 33 months with 27% of patients providing 5-year outcomes. Overall urinary (U), bowel (B), sexual(S), and urinary irritation/obstruction (UI/UO) domains declined at 2 months. These domains and urinary continence (UC) also showed a decline at 18 mo (P<0.05) which was less than the minimally important difference. FFG2 GU and GI toxicity were 82% and 89%, respectively at 4 years. Factors impacting QOL and toxicity on MVA are shown in table 1. Only BMI was significant on univariate analysis for GI toxicity.Abstract SU_24_2232; Table 1Multivariate analysisQOL DomainCovariatesCoefficient [95% CI]P valueUCBaseline score Age Bladder V70 Gy.65 [.56,.74] -.37 [-.70,-.04] -.37 {-.58,-.17]<.001 .03 <.001UI/UOBaseline score Age Bladder V70 Gy Never smoker.41 [.30,.53] -.23 [-.43,-.03] -.15 [-.27,-.03] 4.8 [.36,9.1]<.001 .02 .02 .03UBaseline score Age BMI Bladder V70 Gy.64 [.54,.74] -.34 [-.56,-.12] -.30 [-.57,-.03] -.25 [-.39,-.11]<.001 .004 .03 <.001BBaseline score.58 [.48,.68]<.001SBaseline score Pelvic nodal RT.61 [.51,.70] -5.8 [-11.1,-.60]<.001 .01ToxicityCovariatesHazard ratio [95% CI]P valueGIN/AN/AN/AGUAge ADT Diabetes Baseline UI/UO QOL1.06 [1.01,1.12] 2.55 [1.10,5.87] 2.45 [1.04,5.77] .98 [.97,.99].02 .03 .04 <.001 Open table in a new tab Long term QOL and late toxicity are favorable following post prostatectomy IMRT. Certain clinical and dosimetric factors may help guide decision making in consideration of preserving QOL.

Prostacyclin treatment of pulmonary arterial hypertension (PAH) was cumbersome and limited to continuous intravenous (IV) or subcutaneous (SQ) infusion for years. Limited data exists regarding transition from injectable to inhaled prostanoid ever since its availability.

Objectives: To define the frequency of cardiovascular disease (CVD) risk factors in women with type II endometrial cancer and to evaluate the effect of these factors on cancer treatment.

Objectives: To elucidate the differences between women who survive type 2 endometrial cancer for greater than 5 years compared to those surviving less than 2 years to aid in understanding clinical and pathologic risk factors for a poor prognosis at time of initial treatment.

Objectives: To explore the relationship between diabetes (DM) and metformin on uterine risk factors in type 2 endometrial cancers.

Objectives: Ovarian, fallopian tube, and primary peritoneal cancer (OVCA) patients who receive initial intraperitoneal/intravenous (IP/IV) chemotherapy have greater toxicity than those who receive IV treatment. We investigated whether IP/IV patients also experienced increased toxicity at recurrence compared with those who received IV therapy alone. Methods: We identified OVCA patients (2005–2015) using our institution's Ovarian Cancer Database and pharmacy records. Eligible patients had complete chemotherapy records for initial treatment and subsequent recurrences. We compared chemotherapy dosages, toxicity, and outcome for IP/IV and IV patients using appropriate statistical tests. Results: A convenience sample of 67 patients followed for a median of 33.7 months (standard deviation, 29.5) had sufficient chemotherapy data: IV paclitaxel and carboplatin every 21 days (n = 41) and IP/IV chemotherapy (n = 26; 11 IV paclitaxel, IP carboplatin, IP paclitaxel; 11 IV paclitaxel, IP carboplatin; 4 IV paclitaxel, IP cisplatin, IP paclitaxel). IP/IV patients had significantly more dose delays (50% vs 22%, P = .017), at least grade 3 neutropenia (62% vs 24%, P = .024), thrombocytopenia (19% vs 2%, P = .029), or metabolic disturbances (27% vs 2%, P = .002) compared with IV patients. At recurrence, both patient groups received a mean of 6 chemotherapy cycles (range, 1–21). Dose delay at recurrence was more common in patients who received initial IP/IV treatment (7% vs 38%, P = .003); chemotherapy toxicities were similar for second-line chemotherapy. Both groups received a mean of 3 subsequent chemotherapy regimens (range, 2–7). Conclusions: OVCA patients treated with IP/IV chemotherapy are more likely to experience initial chemotherapy toxicity; however, they are able to receive a similar number of subsequent chemotherapy regimens and do not experience increased toxicity or dose delay with second-line chemotherapy.

Objectives: To determine risk factors for early (PFS < 6 months) recurrence in optimally debulked stage III and IV ovarian, fallopian tube and primary peritoneal cancer patients (OVCA).

Urinary incontinence is a common complication following prostatectomy for prostate cancer. There are limited data available on dosimetric parameters that may predict for poor continence recovery in men who receive post-operative intensity modulated radiation therapy (IMRT). The aim of this study was to analyze dosimetric or clinical factors that may correlate to patient-reported outcomes. Ninety-four men with non-metastatic prostate cancer who underwent prostatectomy followed by adjuvant (12%) or salvage (88%) IMRT were included in this study. The median age was 61, and median time from surgery to IMRT was 23.3 months. Androgen deprivation therapy (ADT) was given in 55%. The median dose to the prostate bed was 68 Gy; 56% of men also received a median dose of 50.4 Gy to the pelvic lymph nodes. Clinical characteristics and patient-reported outcomes using the modified expanded prostate cancer index composite (EPIC) questionnaire were collected at baseline (n = 87) and post-treatment at 6 wk (n = 81), 6 mo (n = 78), 12 mo (n = 74), 18 mo (n = 56), 24 mo (n = 53), and 36 mo (n = 41), and 48 mo (n = 27). Dose-volume metrics of relevant structures, including the bladder, genitourinary diaphragm (GUD), vesicourethral junction (VUJ), and penile bulb (PB) were retrospectively contoured and collected using a prospectively defined approach. The distance between the VUJ and GUD (VUJ-GUD) was also measured. The primary endpoint was urinary incontinence as measured by the global score derived from the EPIC questionnaire. Generalized estimating equation (GEE) models were used to test the association of clinical and dosimetric variables with urinary incontinence. The median EPIC urinary incontinence global scores for each time point were: 66.5 at baseline, 72.8 at 6 wk, 72.8 at 6 mo, 72.8 at 12 mo, 66.5 at 18 mo, 75 at 24 mo, 72.8 at 36 mo, and 79 at 48 mo (all p>0.05 compared to baseline by Wilcoxon test). In GEE models adjusted for by baseline continence, bladder V70Gy and penile bulb V70 Gy were associated with urinary incontinence (both p<0.05), while age, race, RT dose, pelvic nodal RT, ADT, time to RT, diabetes, BMI, VUJ-GUD, and lower dose metrics to bladder and penile bulb were not (all p>0.05). In a model which included body mass index (BMI), VUJ-GUD, time from surgery, age, diabetes, and bladder V70Gy, only the bladder V70Gy (p = 0.02) was associated with outcome. The median bladder V70Gy was 21.86 cc. Volumetrically, the median V70Gy was 11%. In this cohort of men, the bladder V70Gy was significantly associated with urinary incontinence after adjuvant or salvage IMRT. This planning metric may play an important role towards preserving continence after post-prostatectomy RT.

PurposeAs outcomes after lung transplantation have improved, renal function is now becoming an important contributor to morbidity and mortality after transplantation. Calcineurin inhibitors are a major cause of worsening renal function in lung transplantation and several studies have suggested the addition of sirolimus or everolimus improves renal function in transplantation. We evaluated the effect of sirolimus in a post hoc analysis of renal function in patients enrolled in a multicenter randomized, open label trial.MethodsData were collected from the AIRSAC study comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus (TAC)-based regimen. Renal function using the Chronic Kidney Disease Epidemiology Collaboration equation was compared at multiple time points post-transplant. Confounding variables were accounted for using a generalized estimating equation.Results180 patients were randomized in the study and included in the analysis. Baseline demographics and the incidence of diabetes and hypertension were similar between the AZA and SIR arms. Hypertension and TAC levels were associated with decreased renal function in both arms (P< 0.05). TAC levels were lower in the SIR arm (6 ng/ml) compared to the AZA arm (8 ng/ml)(P<0.05). There was a significant decline in renal function over three years in both arms, becoming significantly worse in the SIR arm by three years post-transplant (P = 0.03) (Figure 1).Conclusion PurposeAs outcomes after lung transplantation have improved, renal function is now becoming an important contributor to morbidity and mortality after transplantation. Calcineurin inhibitors are a major cause of worsening renal function in lung transplantation and several studies have suggested the addition of sirolimus or everolimus improves renal function in transplantation. We evaluated the effect of sirolimus in a post hoc analysis of renal function in patients enrolled in a multicenter randomized, open label trial. As outcomes after lung transplantation have improved, renal function is now becoming an important contributor to morbidity and mortality after transplantation. Calcineurin inhibitors are a major cause of worsening renal function in lung transplantation and several studies have suggested the addition of sirolimus or everolimus improves renal function in transplantation. We evaluated the effect of sirolimus in a post hoc analysis of renal function in patients enrolled in a multicenter randomized, open label trial. MethodsData were collected from the AIRSAC study comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus (TAC)-based regimen. Renal function using the Chronic Kidney Disease Epidemiology Collaboration equation was compared at multiple time points post-transplant. Confounding variables were accounted for using a generalized estimating equation. Data were collected from the AIRSAC study comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus (TAC)-based regimen. Renal function using the Chronic Kidney Disease Epidemiology Collaboration equation was compared at multiple time points post-transplant. Confounding variables were accounted for using a generalized estimating equation. Results180 patients were randomized in the study and included in the analysis. Baseline demographics and the incidence of diabetes and hypertension were similar between the AZA and SIR arms. Hypertension and TAC levels were associated with decreased renal function in both arms (P< 0.05). TAC levels were lower in the SIR arm (6 ng/ml) compared to the AZA arm (8 ng/ml)(P<0.05). There was a significant decline in renal function over three years in both arms, becoming significantly worse in the SIR arm by three years post-transplant (P = 0.03) (Figure 1). 180 patients were randomized in the study and included in the analysis. Baseline demographics and the incidence of diabetes and hypertension were similar between the AZA and SIR arms. Hypertension and TAC levels were associated with decreased renal function in both arms (P< 0.05). TAC levels were lower in the SIR arm (6 ng/ml) compared to the AZA arm (8 ng/ml)(P<0.05). There was a significant decline in renal function over three years in both arms, becoming significantly worse in the SIR arm by three years post-transplant (P = 0.03) (Figure 1). Conclusion

The legal concept of first person authorization (FPA) is based on the principle that a decision by a person with decision-making capacity should be respected even after he or she dies. Although the transplant community largely supports this concept, its implementation has not been universal. We conducted a web-based survey of all 58 Organ Procurement Organization (OPO)executive directors in the United States to assess OPOs' procurement policies and practices in the context of family objections. All 58 respondents(100%) responded to our survey. All OPOs except one have an online donor registration website. Most OPOs(89%) (51 of 57 respondents) estimated that the frequency of family objecting to organ donation in cases of registered donors was <10%. No OPOs reported the frequency to be higher than 25%. Only 50% (27 of 54) of the OPOs have a written policy on handling family objections. Approximately 80% of the OPOs reported honoring FPA. However, in the past 5 years, 20 OPOs (35%) have not yet participated in organ procurement from a registered deceased donor over family objection. Further research to identify the barriers and possible solutions to implementing FPA is warranted.

Purpose/Objective(s)Although whole pelvic post-prostatectomy radiation therapy (PPRT) is associated with improved biochemical control in select high-risk men, its use may be tempered by the concern for toxicity. Limited data exist regarding the nature of how it may adversely affect quality of life compared to prostate bed alone RT in the era of intensity modulated radiation therapy (IMRT).Materials/MethodsBetween 2006 and 2012, 120 consecutive men received PPRT. Two men with local recurrences treated with RT after becoming castrate-resistant to salvage ADT were excluded from analysis. Of the remaining 118 patients, salvage RT was administered to 103 (87%) men and adjuvant RT to 15 (13%). Median age was 62. The median dose of IMRT was 68 Gy (range, 41.4-72 Gy). 69 men (58%) received pelvic nodal RT to a median dose of 50.4 Gy. 66 men (56%) also received hormonal therapy for a median 4 months. Quality of life (QOL) data and physician assigned toxicity (CTC v4) for gastrointestinal (GI) and genitourinary (GU) domains were prospectively collected using the EPIC instrument. Wilcoxon signed-rank tests were used to assess the changes in QOL measures from baseline at 2-, 6-, 12-, 18-, 24-, 36-, and 48-month follow-up. Generalized estimating equation (GEE) models were used to identify risk factors with p<0.15 and a multivariate approach adjusting for the baseline was produced based on the GEE. Freedom from (FF) toxicity beyond 3 months was estimated by the Kaplan Meier method and statistical comparisons were tested using the log-rank test.ResultsGlobal urinary irritation/obstruction, bowel, and sexual domain scores were all significantly worse than baseline at 2-month follow-up visit (all p≤0.01 by Wilcoxon test) but were no different than baseline at 6-month and subsequent visits through 4 years of follow-up. No significant change in global urinary continence score was observed at any time point. FF grade 1+ or 2+ GI toxicity were 66% and 90%, and FF grade 1+ or 2+ GU toxicity were 57% and 89%, respectively, through 4 years of follow-up. There was no association between receipt of pelvic nodal PPRT and global urinary irritation/obstruction or continence scores, adjusted for by baseline, though there was a trend for decreased global bowel function (P = 0.09) and a significant decrease in global sexual function (P = 0.01). On the multivariate analysis, there was no significant association between receipt of pelvic nodal PPRT and decreased global bowel or sexual function. There was no association with pelvic nodal PPRT and FF grade 1+ (p = 0.64) or 2+ (p = 0.24) GI toxicity, or grade 1+ (p = 0.39) and grade 2+ (p = 0.51) GU toxicity, respectively.ConclusionsPPRT is not associated with significant declines in patient-reported urinary, bowel, or sexual QOL indices 4 years after completion. Receipt of pelvic nodal PPRT does not appear to be associated with inferior QOL or toxicity outcomes compared to prostate bed alone RT. Purpose/Objective(s)Although whole pelvic post-prostatectomy radiation therapy (PPRT) is associated with improved biochemical control in select high-risk men, its use may be tempered by the concern for toxicity. Limited data exist regarding the nature of how it may adversely affect quality of life compared to prostate bed alone RT in the era of intensity modulated radiation therapy (IMRT). Although whole pelvic post-prostatectomy radiation therapy (PPRT) is associated with improved biochemical control in select high-risk men, its use may be tempered by the concern for toxicity. Limited data exist regarding the nature of how it may adversely affect quality of life compared to prostate bed alone RT in the era of intensity modulated radiation therapy (IMRT). Materials/MethodsBetween 2006 and 2012, 120 consecutive men received PPRT. Two men with local recurrences treated with RT after becoming castrate-resistant to salvage ADT were excluded from analysis. Of the remaining 118 patients, salvage RT was administered to 103 (87%) men and adjuvant RT to 15 (13%). Median age was 62. The median dose of IMRT was 68 Gy (range, 41.4-72 Gy). 69 men (58%) received pelvic nodal RT to a median dose of 50.4 Gy. 66 men (56%) also received hormonal therapy for a median 4 months. Quality of life (QOL) data and physician assigned toxicity (CTC v4) for gastrointestinal (GI) and genitourinary (GU) domains were prospectively collected using the EPIC instrument. Wilcoxon signed-rank tests were used to assess the changes in QOL measures from baseline at 2-, 6-, 12-, 18-, 24-, 36-, and 48-month follow-up. Generalized estimating equation (GEE) models were used to identify risk factors with p<0.15 and a multivariate approach adjusting for the baseline was produced based on the GEE. Freedom from (FF) toxicity beyond 3 months was estimated by the Kaplan Meier method and statistical comparisons were tested using the log-rank test. Between 2006 and 2012, 120 consecutive men received PPRT. Two men with local recurrences treated with RT after becoming castrate-resistant to salvage ADT were excluded from analysis. Of the remaining 118 patients, salvage RT was administered to 103 (87%) men and adjuvant RT to 15 (13%). Median age was 62. The median dose of IMRT was 68 Gy (range, 41.4-72 Gy). 69 men (58%) received pelvic nodal RT to a median dose of 50.4 Gy. 66 men (56%) also received hormonal therapy for a median 4 months. Quality of life (QOL) data and physician assigned toxicity (CTC v4) for gastrointestinal (GI) and genitourinary (GU) domains were prospectively collected using the EPIC instrument. Wilcoxon signed-rank tests were used to assess the changes in QOL measures from baseline at 2-, 6-, 12-, 18-, 24-, 36-, and 48-month follow-up. Generalized estimating equation (GEE) models were used to identify risk factors with p<0.15 and a multivariate approach adjusting for the baseline was produced based on the GEE. Freedom from (FF) toxicity beyond 3 months was estimated by the Kaplan Meier method and statistical comparisons were tested using the log-rank test. ResultsGlobal urinary irritation/obstruction, bowel, and sexual domain scores were all significantly worse than baseline at 2-month follow-up visit (all p≤0.01 by Wilcoxon test) but were no different than baseline at 6-month and subsequent visits through 4 years of follow-up. No significant change in global urinary continence score was observed at any time point. FF grade 1+ or 2+ GI toxicity were 66% and 90%, and FF grade 1+ or 2+ GU toxicity were 57% and 89%, respectively, through 4 years of follow-up. There was no association between receipt of pelvic nodal PPRT and global urinary irritation/obstruction or continence scores, adjusted for by baseline, though there was a trend for decreased global bowel function (P = 0.09) and a significant decrease in global sexual function (P = 0.01). On the multivariate analysis, there was no significant association between receipt of pelvic nodal PPRT and decreased global bowel or sexual function. There was no association with pelvic nodal PPRT and FF grade 1+ (p = 0.64) or 2+ (p = 0.24) GI toxicity, or grade 1+ (p = 0.39) and grade 2+ (p = 0.51) GU toxicity, respectively. Global urinary irritation/obstruction, bowel, and sexual domain scores were all significantly worse than baseline at 2-month follow-up visit (all p≤0.01 by Wilcoxon test) but were no different than baseline at 6-month and subsequent visits through 4 years of follow-up. No significant change in global urinary continence score was observed at any time point. FF grade 1+ or 2+ GI toxicity were 66% and 90%, and FF grade 1+ or 2+ GU toxicity were 57% and 89%, respectively, through 4 years of follow-up. There was no association between receipt of pelvic nodal PPRT and global urinary irritation/obstruction or continence scores, adjusted for by baseline, though there was a trend for decreased global bowel function (P = 0.09) and a significant decrease in global sexual function (P = 0.01). On the multivariate analysis, there was no significant association between receipt of pelvic nodal PPRT and decreased global bowel or sexual function. There was no association with pelvic nodal PPRT and FF grade 1+ (p = 0.64) or 2+ (p = 0.24) GI toxicity, or grade 1+ (p = 0.39) and grade 2+ (p = 0.51) GU toxicity, respectively. ConclusionsPPRT is not associated with significant declines in patient-reported urinary, bowel, or sexual QOL indices 4 years after completion. Receipt of pelvic nodal PPRT does not appear to be associated with inferior QOL or toxicity outcomes compared to prostate bed alone RT. PPRT is not associated with significant declines in patient-reported urinary, bowel, or sexual QOL indices 4 years after completion. Receipt of pelvic nodal PPRT does not appear to be associated with inferior QOL or toxicity outcomes compared to prostate bed alone RT.

Objectives To evaluate and compare the ability of DW-MRI and CT to detect sites of peritoneal dissemination in gynecologic malignancies. The reproducibility of DW-MRI and CT interpretation between radiologists was also assessed. Methods Single institution prospective cohort study of women with suspected advanced gynecologic cancer who underwent surgical staging from 2010 to 2013. Participants underwent both DW-MRI and contrast-enhanced CT prior to surgery. Radiologists and surgeons were blinded, respectively, to surgical and DW-MRI results. The area under the receiver operator characteristic curve (AUC) was calculated for each disease site for CT and DW-MRI and compared to surgical findings. Kappa statistics quantified interobserver agreement between both radiologists. Results Twenty seven patients were enrolled. Mean age at surgery was 59years. Ninety percent of participants had stage IIIC/IV disease. For right diaphragm disease, the AUC for DW-MRI was 0.95 compared to 0.81 for CT. For left diaphragm disease, the AUC was 0.89 for DW-MRI compared to 0.74 for CT. The AUC was similar for DW-MRI and CT for omental disease (0.79 versus 0.64); the liver surface (0.61 versus 0.67); bowel mesentery (0.73 versus 0.64); and cul de sac (0.75 versus 0.64). Interobserver agreement for DW-MRI was greater than CT for omental, Morrison's pouch, liver surface, and right diaphragm disease. Conclusions DW-MRI detects right diaphragmatic disease found at surgery with greater accuracy than CT. For other disease sites key to surgical planning, DW-MRI is equivalent to CT. Interobserver agreement was superior for a majority of disease sites evaluated by DW-MRI compared to CT.

Angiogenesis is considered a prognostic factor and therapy target in many tumors but remains controversial in prostate cancer. This study compares the microvessel density of normal prostate and prostate cancer of different grades using an automated approach to determine its clinical utility. Neoplastic and normal prostatic tissues from 60 prostatectomies were examined by routine histological sections (group I); 136 prostatectomies were used to create tissue microarrays (group II). Microvessel density was calculated using CD31 immunostaining. Automated Cellular Image System (ChromaVision, San Juan Capistrano, CA) and Aperio automated systems were used to digitally analyze microvessel density in Groups I and II respectively. Microvessel density was not significantly increased in tumor versus normal prostate in Group I (P = .303). Both the mean vessel count and vessel area were significantly higher in normal tissue than in tumor either by Automated Cellular Image System or Aperio analysis (P < .05). Aperio analysis in group II additionally showed significantly higher values in normal tissue for vessel lumen (P < .001), whereas vessel perimeter, wall thickness, vessel compactness, and shape were not significantly different (P > .05). Aperio comparison of low- versus high-grade prostate cancer demonstrated that only mean vessel count was increased in high-grade tumors (P = .047); no other automated parameter in either group showed significant association with Gleason scores. Irrespective of methodology, microvessel density was not increased in prostate cancer compared to normal prostate. The bias of using vascular hot spots that possibly contributed to previous contradictory results has been mitigated by automated microvessel density quantitation here. Similar microvessel density of low- and high-grade tumors indicate that microvessel density is neither an important nor reliable prognostic marker for prostate cancer.

1084 Background: BRCA1-associated breast cancers have pathologic features and biologic behavior that are distinct from sporadic breast tumors while BRCA2 tumors are indistinguishable. Comparative survival studies have reported conflicting results and recent studies suggest relative resistance to taxane-based chemotherapy in patients with BRCA1 mutations. To determine if there are differences in long-term outcomes for BRCA1, BRCA2 and high-risk non-carriers with stage I, II, and III breast cancer based on adjuvant therapy received, we conducted a retrospective analysis in US and Italian patients. Methods: Patients diagnosed with breast cancer between January 1, 1990 and December 31, 2008 were identified at the University of Chicago Cancer Risk Clinic and the Veneto Institute of Oncology in Padua. There were 80 BRCA1carriers, 78 BRCA2 carriers and 177 high-risk non-carriers ascertained within the same time period. End points were recurrence-free survival (RFS) and overall survival (OS) by type of adjuvant chemotherapy received. Hazard Ratios (HR) and 95% Confidence Intervals (95% CI) were calculated from Cox proportional hazard models. A multivariate analysis was used to adjust for year at diagnosis, stage, grade and Estrogen Receptor (ER) status. Results: The median follow up was 4.98 (0.03-18.9). The RFS-adjusted hazard ratios were not significantly different among mutation carriers and non-carriers (HR among BRCA1 carriers, 0.52; 95% CI, 0.21 to 1.31; HR among BRCA2 carriers, 0.68; 95% CI, 0.31 to 1.48; P=0.326). The OS-adjusted hazard ratios were not significantly different (HR among BRCA1 carriers, 1.24; 95% CI, 0.45 to 3.45; HR among BRCA2 carriers, 0.89; 95% CI, 0.33 to 2.38; P=0.837). Ten year survival was 78% for BRCA1, 83% for BRCA2 and 92% for non-carriers, respectively. The risk of recurrence and death was also not statistically significant among patients treated with different chemotherapy regimens. Conclusions: RFS and OS survival are similar for carriers of a BRCA mutation and non-carriers.

BACKGROUND AND PURPOSE:Clinical and surgical factors predict renal function decline after laparoscopic partial nephrectomy (LPN). Additional histopathologic predictors may be found in the specimen's nonneoplastic tissue but were not studied. This study investigated the significance of histologic findings in addition to other known predictors of renal function after LPN.PATIENTS AND METHODS:Data of 150 patients who underwent LPN was analyzed. Renal function changes (median follow-up 15 months) were correlated with perioperative and histopathologic parameters. Three histopathologic features were evaluated and graded in the nonneoplastic parenchyma: Glomerulosclerosis, arteriosclerosis (AS), and interstitial fibrosis/tubular atrophy. Estimated GFR (eGFR) and percent decline on postoperative day 1 (POD1) and at the last follow-up were measured.RESULTS:Median eGFR percent decline at POD1 and last follow-up was -17 and -10, respectively (P<0.001). New-onset ≥stage III chronic kidney disease developed in only 7% of the patients. Three factors independently predicted POD1 eGFR decline: Artery and vein clamping vs artery only clamping (P=0.002), male sex (P=0.015), and larger tumor (P=0.02). Long-term loss of renal function was associated with POD1 eGFR decline (P=0.002) and the percentage of AS (P=0.01). The study limitations include a retrospective analysis leading to variability in the follow-up length and a small size cohort.CONCLUSIONS:LPN is associated with a favorable renal function outcome in most patients. Pathologic findings in the nonneoplastic tissue, in addition to clinical parameters, can be used to predict which patients are more likely to experience renal function impairment.

Abstract Background: Angiogenesis is critical for breast cancer progression. Within tumors, non-neoplastic cells assist tumor growth by producing growth factors and pro-angiogenic cytokines. Studies have demonstrated that tumor-associated macrophages (TAMs) are recruited to tumors before malignant conversion and are essential for promoting angiogenesis. We sought to study the role that macrophage phenotype—classically activated (M1) and alternatively activated (M2)—plays in the subsequent activation of the angiogenic pathway, with the goal of understanding the mechanisms underlying angiogenesis in the different molecular subtypes of breast cancer.Methods: 128 matching breast tumors, DCIS and normal tissues were obtained from the University of Chicago Breast Cancer SPORE tissue bank under IRB approved protocols. Tissue microarrays were constructed and molecular subtype was assigned based on immunohistochemical (IHC) staining into the following groups: luminal A (ER+, PR+, HER2-), luminal B (ER+, HER2+ or ER+, PR-), HER2-like (ER-, HER2+) and basal-like (ER-, HER2-, EGFR+ and/or CK5/6+). Macrophage phenotype was determined using double staining with CD68/CD163 (M2) and CD68/CD80 (M1). Microvessel density (MVD) was measured by IHC staining using anti-CD34. Staining quantification was performed independently by two pathologists. To control for intra-individual correlation, linear mixed-effects models were used to compare differences in % of M1 and M2 with disease progression. To evaluate the association of MVD with % of M1 and M2, bivariate plots were generated and Pearson's correlation coefficients were calculated. Spearman's correlation coefficients were used for the correlation between macrophage phenotype and tumor stage and grade. The Kaplan-Meier method was used to calculate overall survival.Results: Of the tumors studied, 88% were stage I-II. 17% were grade 1, 39% grade 2 and 44% grade 3. 70 were luminal A, 36 basal-like, 9 HER2-like and 6 luminal B. The ratio of M2:M1 increased with disease progression from normal breast to DCIS to invasive cancer (p<0.001). Increased M2% was associated with high tumor grade, increased MVD and decreased overall survival (all p<0.001). M1% was associated with low tumor grade (<0.001), but was not significantly associated with MVD or overall survival. Both the HER2-like and basal-like subtypes have significantly higher % M2 as compared to the luminal A subtype (p<0.001).Discussion: There are several studies which suggest that activated TAMs are responsible for the secretion of pro-angiogenic cytokines which stimulate neovascularization. To our knowledge, this is the first study that has correlated macrophage phenotype to breast molecular subtype and MVD in human breast tumors. Our findings suggest that the M2 macrophage phenotype is associated with aggressive histopathologic features and poor clinical outcome. Inhibiting the M2 macrophage may prevent the release of pro-angiogenic factors, and might be an effective approach at preventing neovascularization and improving patient outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 107.