Jorge A. Garcia

Myocardial High-Energy Phosphate and Substrate Metabolism in Swine With Moderate Left Ventricular Hypertrophy

BACKGROUNDnAlthough left ventricular hypertrophy (LVH) is frequently associated with impaired coronary vasodilator reserve, it is uncertain whether this leads to myocardial ischemia under physiological conditions. The goal of the present study was to determine whether swine with moderate LVH exhibit metabolic evidence of ischemia when myocardial oxygen requirements are increased.nnnMETHODS AND RESULTSnMyocardial metabolism was evaluated in an open-chest anesthetized preparation at baseline and during dobutamine infusion in 13 adolescent pigs with moderate LVH induced by supravalvular aortic banding and 12 age-matched control pigs. Transmural myocardial blood flow was quantified with radioactive microspheres; the ratio of phosphocreatine to ATP (PCr/ATP) in the anterior LV free wall was measured by 31P-nuclear magnetic resonance; and anterior wall lactate release was quantified from the arterial-coronary venous difference in 14C- or 13C-labeled lactate. In a subset of 5 animals from each group, the metabolic fate of exogenous glucose was determined from the transmyocardial difference in 6-14C-glucose and its metabolites 14C-lactate and 14CO2. Coronary reserve, as assessed by the ratio of blood flow during adenosine infusion to baseline blood flow, was significantly lower in the LVH pigs compared with controls (3.5 +/- 0.4 versus 5.5 +/- 0.4 mL/g.min, P < .05); however, transmural myocardial blood flow was similar in both groups of pigs, both at baseline and with dobutamine stimulation, probably reflecting the higher coronary perfusion pressure in the LVH pigs. At baseline, PCr/ATP tended to be lower in the LVH pigs (P = .09) but decreased similarly with dobutamine infusion in both groups. Isotopically measured anterior wall lactate release did not differ between the groups at baseline, nor did the increase in lactate release differ during dobutamine stimulation. The uptake of glucose, lactate, and free fatty acids did not differ between the groups in the basal state. However, during dobutamine stimulation, glucose uptake was greater in the LVH group (0.84 +/- 0.09 mumol/g.min versus 0.59 +/- 0.08 mumol/g.min, P < .05). In a subset of animals, 14C-glucose was used to assess glucose oxidation. These data showed that the LVH animals had a greater rate of glucose oxidation (0.6 +/- 0.10 versus 0.28 +/- 0.08 mumol/g.min, P < .05) and a greater rate of glucose conversion to lactate (0.20 +/- 0.04 versus 0.09 +/- 0.02 mumol/g.min, P < .05) compared with the control pigs.nnnCONCLUSIONSnThese results suggest that despite their reduced coronary vasodilator reserve and the absence of a greater rise in myocardial blood flow to compensate for a substantially higher LV double product, pigs with this model of moderate LVH do not exhibit a greater susceptibility to myocardial ischemia during dobutamine stress. However, LVH pigs exhibit significantly greater use of exogenous glucose during dobutamine stress, as evidenced by increases in both glucose oxidation and anaerobic glycolysis.

Evaluation and significance of circulating epithelial cells in patients with hormone‐refractory prostate cancer

The urological oncology section is relatively long this month, and this reflects the many high‐quality manuscripts we receive. When you consider our relatively high rejection rate, you will understand just how many papers on this topic are submitted. The high quality of oncology papers is clear in this month’s section. You will also notice that all but one of them are on prostate cancer, and the reason for this is similar to that mentioned above, as this topic is, as might be expected, the most commonly submitted in this section. However, I am only too happy to reassure readers, and those primarily interested in other types of urological cancer, that the imbalance in this month’s section is not a permanent fixture.

Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance.

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.

Clinical and immunomodulatory effects of bevacizumab and low‐dose interleukin‐2 in patients with metastatic renal cell carcinoma: results from a phase II trial

Study Type – Therapy (case series) Level of Evidenceu20034

Association of a 2-weeks-on and 1-week-off schedule of sunitinib with decreased toxicity in metastatic renal cell carcinoma.

406 Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity.nnnMETHODSnThe medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0.nnnRESULTSn21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months).nnnCONCLUSIONSnTreatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.

Change in Psoas Muscle Volume as a Predictor of Outcomes in Patients Treated with Chemotherapy and Radical Cystectomy for Muscle-Invasive Bladder Cancer

Objective: Sarcopenia, or the age-related loss of skeletal muscle mass and function, has been investigated as a potential marker of adverse outcomes among surgical patients. Our aim was to assess for changes in psoas muscle volume (PMV) following administration of neoadjuvant chemotherapy (NAC) in patients with bladder cancer and to examine whether changes in PMV following NAC are predictive of perioperative complications, pathologic response or survival. Methods: During the period of 2009–2013, patients undergoing NAC and radical cystectomy (RC) at our institution with pre and post NAC cross sectional images available were included. Bilateral total psoas muscle volume (PMV) was obtained from pre- and post- NAC images and the proportion of PMV change was calculated by dividing the change PMV by pre-NAC PMV. Analyses for the assessment of factors predicting PMV loss, partial/complete pathologic response (pPR/pCR), complications, readmission, cancer specific (CSS), recurrence-free (RFS) and overall survival (OS) were performed. Results: Total of 60 patients had complete radiological data available. Post-NAC PMV and BMI declines were statistically significant, 4.9% and 0.05%, respectively. NAC dose reduction/delay was a significant predictor of PMV loss (coefficient B 4.6; 95% CI 0.05–9.2; pu200a=u200a0.047). The proportion of PMV decline during NAC was not a predictor of pPR, pCR, complications, readmission, CSS, RFS, or OS. Conclusions: We observed an interval decline in PMV during the period of NAC administration and this decline was more than it could be appreciated with changes in BMI during the same period. PMV decline was associated with the need for dose reduction/dose delay during NAC. In our series, PMV changes occurring during NAC administration were not predictive of pathologic response to chemotherapy, postoperative complications or survival.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3&bgr;-hydroxysteroid dehydrogenase 1 (3&bgr;HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3&bgr;HSD1 to multiple steroidal metabolites, including 3-keto-5&agr;-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5&agr;-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5&agr;-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5&agr;-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5&agr;-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.

A phase II study of linsitinib (OSI-906) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).

197 Background: Novel agents capable of blocking AR ligand independent pathways responsible for the development of CRPC are needed. IGF-1R and its ligands (IGF-1/IGF-2) play a key role in regulating growth, resistance to apoptosis, and invasion in PCa. IGF-1R is overexpressed in PCa and mediates resistance to ADT. OSI-906 is a small molecule potent dual inhibitor of IGF-1R and insulin receptor TK activity. To determine the activity of OSI-906 in men with CRPC a Simon two-staged phase II study was conducted.nnnMETHODSnMen with asymptomatic or mildly symptomatic Met CRPC were eligible. ECOG 0-1, adequate organ function, and no prior chemotherapy for CRPC were required. Pts received OSI-906 at 150mg orally twice daily on a 28-day cycle. Endpoints included PSA response at 12 wks, safety, RECIST-defined response, time to PSA progression, and OS. Correlative studies explored the impact of OSI-906 on AR signaling (androstenedione, DHEA, DHEA-sulfate, p-IGF-1R, p-IR), markers of PD (TGF-b1, IL-6, TNF-a, MCP-1), and CTC and CECs.nnnRESULTSnTo date 18 pts have enrolled and completed 12 wks of therapy. Median age 68 (55-78); Median pre-treatment PSA was 55.23 (range 2.46-277.60); 41% of pts had bone-only disease, 29% soft-tissue only and 29% had both. Although transient PSA declines were noted, 17/18 pts discontinued therapy sec PSA progression. RECIST-defined SD was observed in 8 pts. Pts received a median of 3 cycles of therapy (range 2-6+). Most common G1/2 AEs included AST/ALT changes observed in 41 and 18% of patients respectively, fatigue (59%); prolong QT interval (35%) and nausea/vomiting (35%). No significant change in the number of CTC and CEC counts was observed. An association between pre-treatment PSA and pre-treatment CTC was observed (Spearman r=0.49, p=.04). No correlation between CTC changes and PSA progression was observed .Evaluation of other molecular markers of PD is underway.nnnCONCLUSIONSnTreatment with OSI-906 is safe. No PSA responses or changes in CTC/CECs were noted. Markers of PD might help elucidate potential mechanisms of escape to this alternative pathway in CRPC. OSI-906 plus an AA might provide synergistic activity in this setting.nnnCLINICAL TRIAL INFORMATIONnNCT01533246.

Discrepancy between reported progressive disease per radiology report and treating oncologist tumor measurements in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib.

420 Background: The determination of progressive disease (PD) on sunitinib in mRCC by conventional tumor size criteria is often complex. Frequently, radiology reports cite disease progression that does not meet RECIST criteria or does not adequately describe index lesions. Characterization of the frequency and magnitude of this phenomenon has not been previously reported.nnnMETHODSnThe medical records of a subset of mRCC patients treated at The Cleveland Clinic who had received sunitinib for > 12 months were retrospectively reviewed. All Radiology reports from post-baseline scans were reviewed for the presence of text in the body or conclusion of the report consistent with disease progression (specifically the terms progressive, new and/or interval enlargement/worsening). The date of the report first containing one or more of these terms was recorded, as was the date of RECIST-defined PD determined by the treating Oncologist.nnnRESULTSnTwenty patients were identified in an initial review. Patient characteristics included: 85% male, 100% clear cell histology, 90% prior nephrectomy and 80% with prior systemic therapy. Thirteen patients (65%) had a radiology report citing a progressive disease term prior to treating physician-determined RECIST-defined PD. The median time from first radiology report citing a progressive disease term until RECIST PD per Oncologist measurements was 2.9 months (range, 0 to 12.8 months).nnnCONCLUSIONSnThere is significant discrepancy between the first mention of disease progression by a Radiology report and when a treating Oncologist measures disease progression per RECIST criteria. This discrepancy could impact patient care by influencing drug discontinuation. These data emphasize the importance of multidisciplinary scan review and tumor measurements by both radiologists and treating physicians. Analysis is ongoing in additional patients.

Identifying patients with node-positive prostate cancer who may benefit from adjuvant pelvic radiation following prostatectomy.

195 Background: Three PRTs address the role adjuvant radiotherapy (RT) following radical prostatectomy (RP) in men with locally advanced and/or margin positive prostate cancer (PCa), one of which demonstrated an improvement in overall survival by the addition of early RT. Not addressed in these studies is the role of adjuvant RT in lymph node positive (LN+) PCa.nnnMETHODSnWe reviewed an IRB-approved prospective database at the Cleveland Clinic and identified 84 men with non-metastatic, LN+ PCa treated with RP from 1987-2010. Men receiving neoadjuvant therapy or adjuvant RT were excluded from this analysis. Pelvic failure (PF) was defined as recurrence in the prostate bed or pelvic LN up to the common iliacs. Distant failures (DF) were defined as any LN recurrence beyond the common iliacs, bone, or other solid organ metastases. Kaplan-Meier estimates of pelvic failure (PF), distant failure (DF) and overall survival (OS) were conducted.nnnRESULTSnMedian follow-up was 6 years. The median initial PSA was 10.1 ng/mL, 50% had Gleason 7, 12% had Gleason 8, 31% had Gleason 9 disease. The median number of LNs dissected was 11 (range 1-49) and 36% had >1 LN+. Extracapsular extension was present in 90%, seminal vesicle invasion in 66%, and surgical margins positive in 55%. The 6 week post-operative PSA was undetectable (<0.2 ng/ml) in 58%. Overall, 41% received immediate androgen deprivation therapy (ADT), and 45% received delayed ADT after biochemical or clinical failure, while 23% received salvage RT and 22% received chemotherapy. The 10-year OS was 61%. Clinically documented PF and DF occurred in 14% and 24%, respectively. Gleason score was the factor most predictive of PF, DF, and OS. Comparing Gleason score of ≤7 vs. ≥8, the 5-year PF rate was 3% vs. 24% (p=0.006), the 5-year DF rate was 2% vs. 37% (p<0.0001), and 5-year OS was 97% vs. 74% (p<0.0001), respectively. The number of LN+ was not prognostic.nnnCONCLUSIONSnMen with Gleason score ≥8 LN+ PCa have a high rate of pelvic recurrence, and pelvic radiation may be worthy of prospective investigation.