Showing papers by "Marek Ancukiewicz published in 2014"

Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma

Abstract: Purpose: Mutations in the IDH1 and IDH2 ( IDH1 / 2 ) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1 / 2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1 / 2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. Experimental Design: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1 / 2 mutational status, tumor burden, and a number of clinical variables. Results: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1 / 2 -mutant (median, 478 ng/mL) versus IDH1 / 2 –wild-type (median, 118 ng/mL) tumors ( P P IDH1 / 2 -mutant cases ( P IDH1 / 2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. Conclusions: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884–90. ©2014 AACR .

A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma.

Abstract: Purpose To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients Methods and Materials Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine The primary objective was to demonstrate a rate of toxicity grade ≥3 of Results The phase 2 dose was established at 5 daily doses of 5 GyE Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion There were no grade 4 or 5 toxicities, and only 2 of 35 patients (41%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1) Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy Thirty of 37 (81%) had positive nodes Locoregional failure occurred in 6 of 37 resected patients (162%), and distant recurrence occurred in 35 of 48 patients (729%) With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P Conclusions This study met the primary endpoint by showing a rate of 41% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation Treatment was associated with favorable local control In exploratory analyses, KRAS G12D status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival

Long-term Cosmetic Outcomes and Toxicities of Proton Beam Therapy Compared With Photon-Based 3-Dimensional Conformal Accelerated Partial-Breast Irradiation: A Phase 1 Trial

Abstract: Purpose To present long-term outcomes of a prospective feasibility trial using either protons or 3-dimensional conformal photon-based (accelerated partial-breast irradiation [APBI]) techniques. Methods and Materials From October 2003 to April 2006, 98 evaluable patients with stage I breast cancer were treated with APBI (32 Gy in 8 fractions given twice daily) on a prospective clinical trial: 19 with proton beam therapy (PBT) and 79 with photons or mixed photons/electrons. Median follow-up was 82.5 months (range, 2-104 months). Toxicity and patient satisfaction evaluations were performed at each visit. Results At 7 years, the physician rating of overall cosmesis was good or excellent for 62% of PBT patients, compared with 94% for photon patients ( P =.03). Skin toxicities were more common for the PBT group: telangiectasia, 69% and 16% ( P =.0013); pigmentation changes, 54% and 22% ( P =.02); and other late skin toxicities, 62% and 18% ( P =.029) for PBT and photons, respectively. There were no significant differences between the groups in the incidences of breast pain, edema, fibrosis, fat necrosis, skin desquamation, and rib pain or fracture. Patient-reported cosmetic outcomes at 7 years were good or excellent for 92% and 96% of PBT and photon patients, respectively ( P =.95). Overall patient satisfaction was 93% for the entire cohort. The 7-year local failure rate for all patients was 6%, with 3 local recurrences in the PBT group (7-year rate, 11%) and 2 in photon-treated patients (4%) ( P =.22). Conclusions Local failure rates of 3-dimensional APBI and PBT were similar in this study. However, PBT, as delivered in this study, led to higher rates of long-term telangiectasia, skin color changes, and skin toxicities. We recommend the use of multiple fields and treatment of all fields per treatment session or the use of scanning techniques to minimize skin toxicity.

Underutilization of radiation therapy in patients with glioblastoma: predictive factors and outcomes.

Abstract: BACKGROUND Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients. METHODS The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all-cause mortality. RESULTS Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR = 1.048 per year increase, 95% CI = 1.046-1.051, P < .001), lower annual income (OR = 0.93 per $10,000 increase, 95% CI = 0.90-0.96, P < .001), African American race (reference = white, OR = 1.19, 95% CI = 1.03-1.37, P = .02), Hispanic race (OR = 1.34, 95% CI = 1.19-1.50, P < .001), Asian American race (OR = 1.24, 95% CI = 1.04-1.48, P < .001), unmarried status (OR = 1.71, 95% CI = 1.60-1.83, P < .001), and subtotal resection/biopsy (OR = 1.82, 95% CI = 1.69-1.96, P < .001). The use of radiation was significantly associated with improved overall survival (2-year survival: 14.6% versus 4.2%, P < .001; adjusted HR = 2.09, 95% CI = 2.02-2.16, P < .001). When the population was restricted to patients < 50 years old, these findings remained largely unchanged. CONCLUSIONS Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research. Cancer 2014;120:238–243. © 2013 American Cancer Society.

Seeds and Soil: Unraveling the Role of Local Tumor Stroma in Distant Metastasis

Abstract: Distant metastasis is the chief cause of cancer mortality. This is particularly true for breast cancer, for which the last decades have brought notable advances in locoregional (surgical, radiation) and systemic (hormonal, chemotherapies) treatment approaches. However, metastatic progression remains a poorly understood process. Therefore, it has been difficult to predict the presence of occult micrometastases in patients and the molecular and cellular mechanisms critical for their formation and progression. As a result, devising novel anti-metastatic therapies has been and remains a great challenge in oncology. Certain gene signatures (eg, MammaPrint, Oncotype DX) have shown statistically significant association with distant disease recurrence and are in clinical use as prognostic markers. These signatures appear to be driven predominately by genes reflecting the level of proliferation and hormone receptors in those tumors. But in addition to intrinsic properties of the cancer cells, a key role has been proposed for the tumor microenvironment in cancer cell survival and progression to metastasis. The contribution of the microenvironment may enhance an otherwise very inefficient process (1,2) and includes angiogenesis and the multi-faceted participation of activated fibroblasts and immune cells. Our understanding of this process is largely based on evidence from mouse models. However, the murine models have several limitations and may not fully reproduce the metastatic cascade in patients. Most metastasis studies have utilized experimental models in which cancer cells are injected as a bolus into the circulation upstream of the metastatic site. The limitation of such an approach is that it overlooks critical events taking place in the primary tumor and systemically prior to metastatic cell colonization. Models featuring spontaneous metastasis from a primary tumor are markedly better; however, these models generally do not metastasize to the same site(s) as the human disease they aim to model. Furthermore, such models are rare, and their metastatic cascade phenomena may represent only a small subset of possible human cases. Both implanted cancer cell models and genetically engineered mouse models—the current gold standard for understanding cancer biology—have these limitations. Finally, although most new agents are first tested in the metastatic setting, more recently there has been considerable interest in evaluating novel therapeutic agents in the neoadjuvant (preoperative) setting for some aggressive subtypes of breast cancer (eg, triple-negative and human epidermal growth factor receptor 2 [HER2]-positive). This approach offers the potential for accelerated Food and Drug Administration approval if the agent demonstrates a substantial increase in the rate of pathological complete response of the primary cancer (3). However, therapeutic effects on the primary cancer may not accurately reflect effects on micrometastatic disease in the setting of a different microenvironment. Preclinical studies often provide little insight in this regard, because most of them are done in primary tumors with no metastasis. This discordance may help explain the observation that drugs that increase pathological complete response rates have failed to decrease rates of metastatic disease. In a report in this issue of the Journal, Rohan et al. examined whether the frequency of microstructural units formed by cancer cells, perivascular macrophages and endothelial cells— termed Tumor MicroEnvironment for Metastasis or TMEM— are associated with the risk of metastatic recurrence (4). The authors identified the cancer cells that comigrate and interact with macrophages at intravasation sites based on the expression of Mena, which is an Ena/VASP protein family member and a

A comparative study of circulating biomarkers of anti-VEGF therapy in phase II trials in advanced hepatocellular carcinoma (HCC) patients (pts).

Abstract: 2543 Background: Sorafenib, a multikinase inhibitor of VEGFR, remains the only approved systemic therapy in HCC. Several other anti-VEGFR agents have either failed or continued in phase III trials....

Increased perfusion due to vascular normalization improves oxygenation and survival in glioblastoma patients treated with cediranib with or without chemoradiation

Abstract: BACKGROUND: (blind field). METHODS: We evaluated MRI markers in 84 GBM patients enrolled in phase 2 trials (NCT00305656, NCT00662506) to investigate the mechanisms of tumor response to anti-VEGF treatment. Forty newly diagnosed GBM (nGBM) patients were treated with the oral pan-VEGFR inhibitor, cediranib, in combination with radiation and temozolomide. Fourteen nGBM patients were treated with radiation and temozolomide alone. Thirty recurrent GBM (rGBM) patients were treated with cediranib alone. All patients underwent serial brain MRI scans at uniform time points. RESULTS: In both the nGBM and rGBM cohorts treated with cediranib, increased tumor perfusion was observed in 20/40 and 7/30 patients, respectively. In contrast, in the nGBM cohort not treated with cediranib increased tumor perfusion was observed in 1/14 patients. Increased tumor perfusion was associated with improved overall survival in nGBM (p = 0.040) and rGBM (p = 0.009) patients. Moreover, increased perfusion was associated with improved tumor oxygenation status in patients the nGBM patients treated with cediranib and chemoradiation. These findings are consistent with a recent report in rGBM patients treated with bevacizumab. CONCLUSIONS: Anti-VEGF therapy confers clinical benefit to GBM patients by normalization of tumor vessels. We hypothesize that the subset of GBM subjects who experience increased perfusion and improved tumor oxygenation status after anti-VEGF therapy will derive optimal benefit from concurrent chemoradiation and innate anti-tumor immune mechanisms. MRI techniques may enable early identification of GBM patients most likely to benefit from this expensive, and potentially toxic, class of anti-cancer drugs. SECONDARY CATEGORY: Imaging.