Publications (25)179.4 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: We report the contrast-enhanced computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography findings in adrenal histoplasmosis and candidiasis. Both demonstrated bilateral hypermetabolic heterogeneous adrenal masses with limited wash-out on delayed CT. Adrenal candidiasis has not been previously reported, nor have the CT wash-out findings in either infection. The adrenal imaging findings are indistinguishable from malignancy, which is more common; but in this setting, physicians should be alert to the differential diagnosis of fungal infections, since it can be equally deadly. Copyright © 2015. Published by Elsevier Inc.
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- [Show abstract] [Hide abstract] ABSTRACT: The ideal surgical management of hereditary pheochromocytomas includes planning for a potential metachronous bilateral presentation and the possibility of lifelong steroid dependence if bilateral adrenalectomy is needed. An intact and viable cortical remnant after bilateral pheochromocytoma resection can eliminate the necessity for steroid dependency, but can increase the risk of pheochromocytoma recurrence. We retrospectively reviewed outcomes of all patients with a diagnosis of hereditary pheochromocytomas treated at our tertiary cancer institution from 1962-2011, with subset analysis of patients undergoing a cortical-sparing procedure in the setting of bilateral adrenalectomy. Of the ninety-six patients who underwent adrenalectomy for hereditary pheochromocytomas, 47 presented with bilateral disease. In 15 of the 49 patients (30%) who originally underwent unilateral adrenalectomy, pheochromocytoma developed in the contralateral gland at a median of 8.2 years (range 1 to 20 years) after the initial diagnosis. There were 4 recurrences in 55 cortical-sparing remnants (7%) and 3 recurrences in the adrenal bed after 101 intended total adrenal resections (3%) (p = 0.24). Total bilateral adrenalectomy was performed in 25 patients and acute adrenal insufficiency developed in 5 (20%) of those patients. An intended cortical-sparing adrenalectomy was performed in 39 patients and acute adrenal insufficiency developed in 1 (3%). Of these patients with adequate follow-up, 21 of 27 (78%) were steroid independent at 3-year follow-up. Sex, median age, adrenal vein preservation, metachronous adrenal resection, and bilateral cortical-sparing procedures did not predict steroid independence at 3 years. Cortical-sparing adrenalectomy avoids long-term corticosteroid dependence in the majority of patients with hereditary pheochromocytoma with minimal risk of acute adrenal insufficiency. Recurrence occurs in approximately 7% of adrenal remnants.
- [Show abstract] [Hide abstract] ABSTRACT: RECIST is used to quantify tumor changes during exposure to anticancer agents. Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Clinical trials dictate a patient's management options based on the category into which his or her response falls. However, the association between response and survival is not well studied in the early trial setting. To study the correlation between response as quantified by RECIST and overall survival (OS, the gold-standard survival outcome), we analyzed 570 participants of 24 phase I trials conducted between October 2004 and May 2009, of whom 468 had quantifiable changes in tumor size. Analyses of Kaplan-Meier estimates of OS by response and null Martingale residuals of Cox models were the primary outcome measures. All analyses are landmark analyses. Kaplan-Meier analyses revealed strong associations between change in tumor size by RECIST and survival (P = 4.5 × 10(-6) to < 1 × 10(-8)). The relationship was found to be near-linear (R(2) = 0.75 to 0.92) and confirmed by the residual analyses. No clear inflection points were found to exist in the relationship between tumor size changes and survival. RECIST quantification of response correlates with survival, validating RECIST's use in phase I trials. However, the lack of apparent boundary values in the relationship between change in tumor size and OS demonstrates the arbitrary nature of the CR/PR/SD/PD categories and questions emphasis placed on this categorization scheme. Describing tumor responses as a continuous variable may be more informative than reporting categoric responses when evaluating novel anticancer therapies.
- [Show abstract] [Hide abstract] ABSTRACT: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). Forty-two patients with advanced cancer (19 male/23 female, median age = 53, median number of prior therapies = 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma.
- [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study was to evaluate poly(L-glutamic acid)-benzyl-DTPA-Gd (PG-Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02 and 0.08 mmol Gd/kg. T(1)-weighted MR images were acquired at 1.5 T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small-molecule contrast agent Magnevist was used as a control. PG-Gd in the monkey showed a bi-exponential disposition. The initial blood concentrations within 2 h of PG-Gd administration were much higher than those for Magnevist. The high blood concentration of PG-Gd was consistent with the MR imaging data, which showed prolonged circulation of PG-Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 h after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration-time curve was observed when the administered single dose was increased from 0.01 to 0.08 mmol/kg. By 2 days after PG-Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 h at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 h and a volume of distribution at steady-state of 85.5 ml/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on the potential systemic toxicity of PG-Gd in both rodents and large animals are warranted before testing this agent in humans.
- [Show abstract] [Hide abstract] ABSTRACT: Posterior retroperitoneoscopic adrenalectomy (PRA) is an excellent surgical option for adrenal gland removal. The operation requires that surgeons learn a new approach with few similarities to anterior adrenalectomy. This study reports a large series of PRAs incorporated into surgical care using a team-model approach. The prospective endocrine surgery database was queried to identify patients who underwent PRA during a recent 4-year period. Demographic, operative, and pathologic data were recorded. The authors' initial experiences with PRA (group 1) are compared with our contemporary experience (group 2). One hundred and eighteen PRAs were successfully performed (100 unilateral and 9 bilateral). Indications were pheochromocytoma in 21 patients, Cushing's syndrome or Cushing's disease in 22 patients, aldosteronoma in 22 patients, virilizing tumor in 3 patients, isolated metastasis in 28 patients, and nonfunctional mass in 19 patients. Forty-eight percent of patients had undergone earlier abdominal surgery. Forty-eight percent were obese (body mass index [calculated as kg/m(2)] ≥30). No significant differences were found in operative time (110 versus 118 minutes, p = 0.30), tumor size (2.59 versus 2.85 cm, p = 0.44), or body mass index (29.63 versus 29.93, p = 0.82) between groups 1 and 2. Both complications (15.9% versus 7.7%, p = 0.29) and conversion rates (9.5% versus 1.9%, p = 0.19) were lower in group 2, although this was not statistically significant. PRA is a technique safely performed for a variety of adrenal lesions, is ideal for patients who have undergone earlier abdominal surgery, and is feasible in obese patients. Proficiency can be obtained during a short period, leading to low conversion and complication rates. This technique should be incorporated into the armamentarium of the endocrine surgeon. A team approach to learning new surgical techniques is effective.
- [Show abstract] [Hide abstract] ABSTRACT: This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function. Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin. Median total bilirubin was 2.8 mg/dL (range, 0.2-5.2 mg/dL). Median Child-Pugh score was 7 (range, 5-10). Thirty treatments were delivered (2-7 per patient). Median age of patients was 57 years (range, 25-69 years). Three patients (1 with colorectal, 1 with hepatocellular, and 1 with ovarian cancer) attained partial responses. Two had failed previous oxaliplatin and cisplatin treatment. Some with elevated bilirubin at baseline had a significant drop in bilirubin with treatment (bilirubin 5.2 → 1 mg/dL, 4.8 → 1.1 mg/dL, and 5.2 → 1.8 mg/dL). The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. One patient died of enzyme-linked, immunoassay-confirmed, heparin-induced thrombocytopenia during the sixth cycle of therapy. At doses tested, this regimen was safe and demonstrated antitumor activity in patients with advanced refractory malignancies involving the liver, including those with hepatic insufficiency. Further study is warranted.
- [Show abstract] [Hide abstract] ABSTRACT: Liver metastases in patients with cancer are associated with poor survival. The authors of this report conducted a phase 1 study of hepatic arterial infusion (HAI) oxaliplatin combination therapy in patients with advanced cancer and liver metastases. Treatment consisted of escalating doses of HAI oxaliplatin 60 mg/m(2) to 175 mg/m(2) and intra-arterial heparin 3000 IU (Day 1); leucovorin 200 mg/m(2) intravenously (iv) and 5-fluorouracil 300 mg/m(2) bolus plus 600 mg/m(2) iv (Days 1 and 2); and bevacizumab 10 mg/kg iv (Day 3). A conventional "3 + 3" design was used. Fifty-seven patients were treated, including 30 women and 27 men. The median age was 57 years, and the patients had received a median of 3 prior therapies (range, 1-7 prior therapies). The most common cancer was colorectal (n = 29). Overall, 204 cycles were administered (median per patient, 2 cycles; range, 1-17 cycles). The maximum tolerated dose (MTD) of HAI oxaliplatin was 140 mg/m(2). Dose-limiting toxicities were grade 4 thrombocytopenia (n = 1) and grade 4 hypokalemia (n = 1) at 150 mg/m(2) (n = 5). Thirty-three patients (58%) had no toxicity greater than grade 1. The most common toxicities were thrombocytopenia (n = 19), fatigue (n = 15), nausea/vomiting (n = 6), constipation (n = 6), and diarrhea (n = 4). Of 55 patients who were evaluable for response (according to Response Evaluation Criteria in Solid Tumors), 4 patients (7%) had a partial response (PR), and 32 patients (58%) had stable disease (SD), including 15 patients (48%) who had SD for >/=4 months. Of 28 patients with colorectal cancer, 3 patients (11%) had a PR, and 9 patients (32%) had SD for >/=4 months. HAI oxaliplatin combined with systemic 5-fluorouracil, leucovorin, and bevacizumab had antitumor activity in patients with advanced cancer and liver metastases, and the current results indicated that this combination warrants further study. Cancer 2010. (c) 2010 American Cancer Society.
- [Show abstract] [Hide abstract] ABSTRACT: Tumor-associated macrophages (TAMs) are diverse population containing multiple subtypes. M2 macrophages promote tumor growth and metastasis, in part by secreting a wide range of proangiogenic factors and growth factors. Selective depletion of M2 macrophages has been evaluated as a novel approach to anti-cancer therapy. In this study, a dual magneto-optical imaging probe, PG-Gd-NIR813 was synthesized and evaluated for non-invasive assessment of TAMs after intravenous injection. PG-Gd-NIR813 injected in nude rats bearing C6 tumors showed high uptake of the polymeric contrast agent in the tumor at 1 and 48 h after injection both in vivo and ex vivo optical imaging. T(1)-weighted MR imaging results showed accumulation of PG-Gd-NIR813 into the tumor necrotic area, which was confirmed by TUNEL staining of resected tumors. The uptake of PG-Gd-NIR813 within tumor necrosis decreased after animals were treated by the macrophage-depleting agent. Immunohistochemical staining demonstrated that PG-Gd-NIR813 colocalized with CD68 (marker for macrophages) and CD169 (marker for activated macrophages), but not with CD163 (residential macrophages). Using combined near-infrared fluorescence imaging and magnetic resonance imaging (MRI), we demonstrated that the accumulation of PG-Gd-NIR813 in tumors was mediated through M2 TAMs. Therefore, poly(L-glutamic acid) based reagents could be potentially used to image response to antitumor therapies targeted at M2 TAMs. Furthermore, poly(L-glutamic acid) is a promising carrier for candidate immunotherapeutics targeting M2 TAMs.
- [Show abstract] [Hide abstract] ABSTRACT: To compare nondestructive in vivo and ex vivo micro-computed tomography (muCT) and ex vivo dual-energy-X-ray-absorptiometry (DXA) in characterizing mineralized cortical and trabecular bone response to prostate cancer involving the skeleton in a mouse model. In vivo microCT was performed before and 10 weeks after implantation of human prostate cancer cells (MDA-PCa-2b) or vehicle into SCID mouse femora. After resection, femora were imaged by nondestructive ex vivo specimen microCT at three voxel sizes (31 micro, 16 micro, 8 micro) and DXA, and then sectioned for histomorphometric analysis of mineralized bone. Bone mineral density (BMD), trabecular parameters (number, TbN; separation, TbSp; thickness, TbTh) and mineralized bone volume/total bone volume (BV/TV) were compared and correlated among imaging methods and histomorphometry. Statistical tests were considered significant if P<0.05. Ten weeks post inoculation, diaphyseal BMD increased in the femur with tumor compared to the opposite femur by all modalities (p<0.005, n = 11). Diaphyseal BMD by in vivo microCT correlated with ex vivo 31 and 16 microm microCT and histomorphometry BV/TV (r = 0.91-0.94, P<0.001, n = 11). DXA BMD correlated less with bone histomorphometry (r = 0.73, P<0.001, n = 11) and DXA did not distinguish trabeculae from cortex. By in vivo and ex vivo microCT, trabecular BMD decreased (P<0.05, n = 11) as opposed to the cortex. Unlike BMD, trabecular morphologic parameters were threshold-dependent and when using "fixed-optimal-thresholds," all except TbTh demonstrated trabecular loss with tumor and correlated with histomorphometry (r = 0.73-0.90, P<0.05, n = 11). Prostate cancer involving the skeleton can elicit a host bone response that differentially affects the cortex compared to trabeculae and that can be quantified noninvasively in vivo and nondestructively ex vivo.
- [Show abstract] [Hide abstract] ABSTRACT: We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement. Patients were treated with HAI cisplatin 100-125 mg/m(2) (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20-35 mg/m(2) IV (day 1) every 28 days. A "3 + 3" study design was used. Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m(2) level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m(2) and systemic doxil 35 mg/m(2) dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for ≥4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for ≥4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD. The MTD was HAI cisplatin 100 mg/m(2) and systemic doxil 35 mg/m(2). This regimen demonstrated antitumor activity, especially in breast cancer.
- [Show abstract] [Hide abstract] ABSTRACT: Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.
- [Show abstract] [Hide abstract] ABSTRACT: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used. Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks.
- [Show abstract] [Hide abstract] ABSTRACT: Imexon is an iminopyrrolidone that induces apoptosis and has synergistic activity with docetaxel in preclinical models. This trial was designed to establish the maximum tolerated dose (MTD) of imexon given with docetaxel in breast, prostate and non-small cell lung cancer (NSCLC). 34 patients received protocol therapy. 26 patients received escalating doses of imexon given intravenously over 60 min on days 1-5 every 21 days. Docetaxel was administered intravenously at a fixed dose of 75 mg/m(2) immediately following imexon on day 1 every 21 days. A 3+3 design was used with eight additional patients treated at MTD. Response was measured using RECIST. Seven dose levels of imexon were evaluated (390 mg/m(2) to 1,700 mg/m(2)). The MTD was imexon 1,300 mg/m(2) IV on days 1-5 in combination with docetaxel. Dose limiting toxicities were grade 3 non-cardiac chest pain and grade 3 diarrhea. Activity was seen in 4 patients [2 partial responses (NSCLC (PR=1), prostate cancer (PR=1)), 2 minor responses (MR=breast, NSCLC)]. Eleven patients had stable disease by RECIST (including the patients with MR; prostate cancer=6, NSCLC=3). Six (one with breast cancer, two with prostate cancer and three with NSCLC) demonstrated stable disease (SD) for > or = 3 months. The MTD of combination therapy is imexon 1,300 mg/m(2) IV on days 1-5 with docetaxel 75 mg/m(2) IV on day 1 of a 21 day treatment cycle. Demonstrated responses warrant further investigation in phase II trials of which a phase II trial in NSCLC is planned.
- [Show abstract] [Hide abstract] ABSTRACT: In a search for more effective combination chemotherapy for the treatment of metastatic melanoma, we conducted a phase I trial of a novel combination of docetaxel, temozolomide, and cisplatin. Patients with inoperable or recurrent metastatic melanoma with a Zubrod performance status of 2 or less and adequate organ function were eligible. The dose of docetaxel was escalated between cohorts of patients, and the doses of temozolomide and cisplatin were fixed. A standard 3 + 3 dose escalation design was used to determine the maximum tolerated dose (MTD). Among 23 patients who were enrolled, 21 were evaluable for toxicity. Eighteen patients (78%) had stage IV-M1c disease. The dose-limiting toxicities were myelosuppression and pulmonary embolism. The MTD was 30 mg/m(2) docetaxel on days 1, 8, and 15 when given with 150 mg/m(2) temozolomide on days 1-5, and 20 mg/m(2) cisplatin on days 1-4, repeating every 4 weeks. Among 19 patients evaluated for response, 6 (32%) had partial responses and 5 (26%) had stable disease. Among 14 chemo-naive patients, 6 (43%) had a partial response and 4 (29%) had stable disease. Nine patients developed brain metastases by the time of the last follow-up evaluation, and the median time to brain metastases for all 19 evaluable patients has not been reached. This combination was well tolerated and appears to be a promising treatment for patient with metastatic melanoma.
- [Show abstract] [Hide abstract] ABSTRACT: To evaluate the contribution to scan-rescan coefficient of variation (CV) of patient-specific arterial input function (AIF) measurement in dynamic contrast-enhanced MRI (DCE-MRI) data, and to determine whether any advantage or disadvantage to using a data-derived arterial input function is related to the anatomical location of the target lesion. Two methods are presented for the calculation of perfusion parameters from DCE-MRI data using a two-compartment model. The first method makes use of a single-model AIF across all study data sets, while the second uses an automated process to derive an AIF specific to each data set. Both methods are applied to the analysis of a 25-subject scan-rescan study of patients with advanced solid tumors located in either the lungs or the liver. The parameters of interest in this study are the volume transfer constant between arterial plasma and extracellular extravascular space (Ktrans) and the blood-normalized initial area under the tumor enhancement curve over the first 90 seconds postinjection (IAUCBN90). The use of a data-derived AIF reduces the visit-to-visit CV in both parameters for liver lesions by approximately 70% while the improvement is less than 20% for lung lesions. The use of a data-derived AIF in the analysis of DCE-MRI data provides a substantial reduction in scan-rescan CV in the measurement of vascular parameters such as Ktrans and IAUCBN90. These results show a much larger advantage in the liver than in the lungs. However, this difference is largely driven by a small number of outliers, and may be spurious.
- [Show abstract] [Hide abstract] ABSTRACT: Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors. Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow. In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed. Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.
- [Show abstract] [Hide abstract] ABSTRACT: Adrenal cortical carcinoma (ACC) is a rare disease in which recurrence after surgery is common. Mitotane is the primary systemic treatment for recurrent ACC; data are limited regarding the impact of mitotane on recurrent ACC. We reviewed the records of all patients who underwent surgery for ACC evaluated at our institution from 1991 to 2006. The median disease-free survival for all 186 patients was 12 months and the median overall survival (OS) was 37 months. Higher stage at presentation (P = .002) and tumor cortisol production (P = .007) were associated with a worse OS. Mitotane was given to 67 evaluable patients with recurrent ACC. A response to mitotane was observed in 13 (19%) of the 67 patients. For patients with stable or responding disease to mitotane, the median OS from date of recurrence was 18 months, compared with 9 months (P = .01) for those who progressed. Patients with recurrent ACC who have stable or responding disease to mitotane have a more favorable prognosis than those who progress. Mitotane should be considered in most patients with recurrent ACC, including as preoperative therapy for those with recurrent disease considered for surgical resection.
- [Show abstract] [Hide abstract] ABSTRACT: AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined. Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001). In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
- • Department of Radiology
- • Department of Surgical Oncology
University of HoustonHouston, Texas, United States