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1.  Investigation of the diffusion abnormality index as a new imaging biomarker for early assessment of brain tumor response to radiation therapy 
Neuro-Oncology  2013;16(1):131-139.
Background
Diffusion MRI, although having the potential to be a biomarker for early assessment of tumor response to therapy, could be confounded by edema and necrosis in or near the brain tumors. This study aimed to develop and investigate the ability of the diffusion abnormality index (DAI) to be a new imaging biomarker for early assessment of brain metastasis response to radiation therapy (RT).
Methods
Patients with either radiosensitive or radioresistant brain metastases that were treated by whole brain RT alone or combined with bortezomib as a radiation sensitizer had diffusion-weighted (DW) MRI pre-RT and 2 weeks (2W) after starting RT. A patient-specific diffusion abnormality probability function (DAProF) was created to account for abnormal low and high apparent diffusion coefficients differently, reflecting respective high cellularity and edema/necrosis. The DAI of a lesion was then calculated by the integral of DAProF-weighted tumor apparent diffusion coefficient histogram. The changes in DAI from pre-RT to 2W were evaluated for differentiating the responsive, stable, and progressive tumors and compared with the changes in gross tumor volume and conventional diffusion metrics during the same time interval.
Results
In lesions treated with whole brain RT, the DAI performed the best among all metrics in predicting the posttreatment response of brain metastases to RT. In lesions treated with whole brain RT + bortezomib, although DAI was the best predictor, the performance of all metrics worsened compared with the first group.
Conclusions
The ability of DAI for early assessment of brain metastasis response to RT depends upon treatment regimes.
doi:10.1093/neuonc/not153
PMCID: PMC3870818  PMID: 24327584
cancer; diffusion abnormality index; DW-MRI; imaging biomarker
2.  Neoadjuvant Stereotactic Body Radiation Therapy (SBRT), Capecitabine, and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma 
Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically given its anatomical location and its frequent association with primary sclerosing cholangitis (PSC). Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node negative patients has been advanced by select liver transplant centers for treatment of patients with unresectable disease. This approach has most commonly used external beam radiotherapy combined with biliary brachytherapy and 5-FU based chemotherapy. Our center has recently embarked on a protocol utilizing stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node negative patients until liver transplantation. We therefore retrospectively determined tolerability and pathologic response in this pilot study. Over a three year period 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50–60 Gy, 3–5 fractions over two weeks). Following one week of rest, capecitabine was initiated at 1330 mg/m2/day and continued until liver transplantation. During neoadjuvant therapy, there were a total of 35 adverse events with cholangitis and palmar/plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplant and 6 patients received a liver transplant. Explant pathology of hilar tumors showed at least a partial treatment response in five patients with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic and low proliferative indices were measured on histological examination. Eleven transplant-related complications occurred, and one-year survival after transplant was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.
doi:10.1002/lt.23757
PMCID: PMC4185427  PMID: 24115315
Malignancy/liver transplantation; sclerosing cholangitis; bile duct cancer; biliary neoplasms; external beam radiotherapy
3.  HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s †, ‡ 
Purpose
STAT3 plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 is failure in clinic. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo.
Experimental Design
The expression of HAb18G/CD147, pSTAT3 and CD44s were determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 was assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot, immunofluorescence staining, immunoprecipitation, and in vivo tumor formationusing loss or gain-of-function strategies.
Results
Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. CyPA, a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147 dependent mechanisms. HAb18G/CD147 was associated and co-localized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high co-expression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer.
Conclusions
We identified HAb18G/CD147 as a novel upstream activator of STAT3 via interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.
doi:10.1158/1078-0432.CCR-13-0621
PMCID: PMC3873783  PMID: 24132924
Pancreatic cancer; HAb18G/CD147; CD44; STAT3; tumor development
4.  The Long Non-Coding RNA PCAT-1 Promotes Prostate Cancer Cell Proliferation through cMyc12 
Neoplasia (New York, N.Y.)  2014;16(11):900-908.
Long non-coding RNAs (lncRNAs) represent an emerging layer of cancer biology, contributing to tumor proliferation, invasion, and metastasis. Here, we describe a role for the oncogenic lncRNA PCAT-1 in prostate cancer proliferation through cMyc. We find that PCAT-1–mediated proliferation is dependent on cMyc protein stabilization, and using expression profiling, we observed that cMyc is required for a subset of PCAT-1–induced expression changes. The PCAT-1–cMyc relationship is mediated through the post-transcriptional activity of the MYC 3′ untranslated region, and we characterize a role for PCAT-1 in the disruption of MYC-targeting microRNAs. To further elucidate a role for post-transcriptional regulation, we demonstrate that targeting PCAT-1 with miR-3667-3p, which does not target MYC, is able to reverse the stabilization of cMyc by PCAT-1. This work establishes a basis for the oncogenic role of PCAT-1 in cancer cell proliferation and is the first study to implicate lncRNAs in the regulation of cMyc in prostate cancer.
doi:10.1016/j.neo.2014.09.001
PMCID: PMC4240923  PMID: 25425964
PCAT-1; lncRNA; cell proliferation; 3’UTR; cMyc
5.  A Pilot Study of Diffusion-Weighted MRI in Patients Undergoing Neoadjuvant Chemoradiation for Pancreatic Cancer 
Translational Oncology  2014;7(5):644-649.
PURPOSE: In the current study we examined the ability of diffusion MRI (dMRI) to predict pathologic response in pancreatic cancer patients receiving neoadjuvant chemoradiation. METHODS: We performed a prospective pilot study of dMRI in patients with resectable pancreatic cancer. Patients underwent dMRI prior to neoadjuvant chemoradiation. Surgical specimens were graded according to the percent tumor cell destruction. Apparent diffusion coefficient (ADC) maps were used to generate whole-tumor derived ADC histogram distributions and mean ADC values. The primary objective of the study was to correlate ADC parameters with pathologic and CT response. RESULTS: Ten of the 12 patients enrolled on the study completed chemoradiation and had surgery. Three were found to be unresectable at the time of surgery and no specimen was obtained. Out of the 7 patients who underwent pancreaticoduodenectomy, 3 had a grade III histopathologic response (> 90% tumor cell destruction), 2 had a grade IIB response (51% to 90% tumor cell destruction), 1 had a grade IIA response (11% to 50% tumor cell destruction), and 1 had a grade I response (> 90% viable tumor). Median survival for patients with a grade III response, grade I-II response, and unresectable disease were 25.6, 18.7, and 6.1 months, respectively. There was a significant correlation between pre-treatment mean tumor ADC values and the amount of tumor cell destruction after chemoradiation with a Pearson correlation coefficient of 0.94 (P = .001). Mean pre-treatment ADC was 161 × 10− 5 mm2/s (n = 3) in responding patients (> 90% tumor cell destruction) compared to 125 × 10− 5 mm2/s (n = 4) in non-responding patients (> 10% viable tumor). CT imaging showed no significant change in tumor size in responders or non-responders. CONCLUSIONS: dMRI may be useful to predict response to chemoradiation in pancreatic cancer. In our study, tumors with a low ADC mean value at baseline responded poorly to standard chemoradiation and would be candidates for intensified therapy.
doi:10.1016/j.tranon.2014.07.005
PMCID: PMC4225651  PMID: 25389460
6.  A Multi-Institutional Phase II Study of Neoadjuvant Gemcitabine and Oxaliplatin with Radiation Therapy in Patients with Pancreatic Cancer 
Cancer  2013;119(15):2692-2700.
Background
The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin and radiation (RT) in localized pancreatic cancer.
Methods
Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, PS≤2, and adequate organ function. Treatment consisted of two, 28 day cycles of gemcitabine (1g/m2 over 30 minutes days 1, 8, 15) and oxaliplatin (85mg/m2 days 1, 15) with RT during cycle 1 (30Gy in 2Gy fractions). Patients were evaluated for surgery following cycle 2. Resected patients received 2 cycles of adjuvant chemotherapy.
Results
Sixty-eight evaluable patients were treated at 4 centers. By central radiology review, 23 patients were resectable, 39 borderline resectable, and 6 unresectable. Sixty-six patients (97%) completed cycle 1/RT and 61 patients (90%) cycle 2. Adverse events ≥ grade 3 during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients were resected (63%) with R0 resection in 36 (84%). Median overall survival for all patients was 18.2 months (95%CI 13–26.9), those resected 27.1 months (95%CI 21.2–47.1) and those not resected 10.9 months (95%CI 6.1–12.6). A decrease in CA19-9 following neoadjuvant therapy was associated with R0 resection (p=0.02) which resulted in a median survival of 34.6 months (95% CI 20.3–47.1). Fourteen patients (21%) are alive and disease-free at a median follow-up time of 31.4 months (range, 24–47.6).
Conclusion
Preoperative therapy with full dose gemcitabine, oxaliplatin and RT was feasible and resulted in a high percentage of R0 resections. Results are particularly encouraging given a majority of patients with borderline resectable disease.
doi:10.1002/cncr.28117
PMCID: PMC4174603  PMID: 23720019
pancreatic cancer; neoadjuvant; gemcitabine; oxaliplatin
7.  Improving the efficacy of chemoradiation with targeted agents 
Cancer discovery  2014;4(3):280-291.
Chemoradiation is the standard therapy for the majority of inoperable, locally advanced cancers. While there is a need to improve chemoradiation efficacy, normal tissue toxicity limits our ability to give additional chemotherapy or higher doses of radiation. Thus, there is excitement about the addition of molecularly targeted agents, which tend to be less toxic than chemotherapy, to chemoradiation regimens. Unfortunately, initial empiric attempts have not been successful. This review will focus on the evidence that supports rational combinations of targeted agents with chemoradiation, with an emphasis on agents that target the DNA damage response and radiation-induced membrane signaling.
doi:10.1158/2159-8290.CD-13-0337
PMCID: PMC3947675  PMID: 24550033
chemoradiation; homologous recombination; targeted agents; sensitization; locally advanced cancer
8.  Phase I Trial of Radiotherapy Concurrent with Twice-Weekly Gemcitabine for Head and Neck Cancer: Translation From Preclinical Investigations Aiming to Improve the Therapeutic Ratio12 
Translational Oncology  2014;7(4):479-483.
BACKGROUND: Once-weekly gemcitabine concurrent with radiotherapy was highly effective in the treatment of head and neck cancer (HNC) but limited by high mucosal toxicity. Pre-clinical investigations suggested that delivering gemcitabine at substantially lower doses twice weekly during radiotherapy improved the therapeutic ratio. We sought to translated these preclinical findings to a phase I trial. METHODS: Twenty-five patients with non-resectable HNC were scheduled to receive gemcitabine twice weekly during the last 2 weeks (total 5 infusions) of hyperfractionated radiotherapy delivering 1.2 Gy twice daily to total 76.8 Gy. Tumor biopsies to measure active intracellular (phosphorylated) gemcitabine were planned after the first drug delivery. Patients were assigned to escalating dose cohorts using the Continuous Reassessment Method. RESULTS: Twenty-one patients evaluable for toxicity were divided into cohorts receiving twice weekly treatment with 10, 20, 33, or 50 mg/m2 gemcitabine. Dose-limiting toxicity was grade 3-4 confluent mucositis/pharyngitis, and the maximally tolerated dose (MTD) was 20 mg/m2. Median survival was 20 months, with no difference between cohorts receiving lower (10, 20 mg/m2) or higher (33, 50 mg/m2) gemcitabine doses. Tumor biopsies after the first drug delivery showed only a minority of tumor cells in the specimens. CONCLUSION: These findings validate preclinical models that show that gemcitabine is radiation sensitizer at doses far below those used for systemic chemotherapy. However, the improvement in the therapeutic ratio predicted from the preclinical study did not translate into a substantial relative increase in the MTD of the drug in the clinical phase I trial.
doi:10.1016/j.tranon.2014.04.016
PMCID: PMC4202797  PMID: 25171890
9.  Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor, MK8776 
Purpose
The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Chk1 inhibitor, MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models.
Experimental Design
We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)- proficient and deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776.
Results
We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer.
Conclusions
Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer.
doi:10.1158/1078-0432.CCR-12-3748
PMCID: PMC3745540  PMID: 23804422
pancreatic cancer; Chk1; radiosensitization; homologous recombination repair; gemcitabine; cell cycle checkpoint
10.  Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair 
Purpose
To identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and thus improve survival, we performed an siRNA library screen in pancreatic cancer cells. We investigated PPP2R1A, a scaffolding subunit of protein phosphatase 2A (PP2A) as a lead radiosensitizing target.
Experimental Design
We determined the effect of PP2A inhibition by genetic (PPP2R1A siRNA) and pharmacological (LB100, a small molecule entering Phase I clinical trials) approaches on radiosensitization of Panc-1 and MiaPaCa-2 pancreatic cancer cells both in vitro and in vivo.
Results
PPP2R1A depletion by siRNA radiosensitized Panc-1 and MiaPaCa-2 cells, with radiation enhancement ratios of 1.4 (P<0.05). Likewise, LB100 produced similar radiosensitization in pancreatic cancer cells, but minimal radiosensitization in normal small intestinal cells. Mechanistically, PPP2R1A siRNA or LB100 caused aberrant CDK1 activation, likely resulting from accumulation of the active forms of PLK1 (pPLK1 T210) and CDC25C (pCDC25C T130). Furthermore, LB100 inhibited radiation-induced Rad51 focus formation and homologous recombination repair (HRR), ultimately leading to persistent radiation-induced DNA damage, as reflected by γH2AX expression. Finally, we identified CDC25C as a key PP2A substrate involved in LB100-mediated radiosensitization as depletion of CDC25C partially reversed LB100-mediated radiosensitization. In a mouse xenograft model of human pancreatic cancer, LB100 produced significant radiosensitization with minimal weight loss.
Conclusions
Collectively, our data demonstrate that PP2A inhibition radiosensitizes pancreatic cancer both in vitro and in vivo via activation of CDC25C/CDK1 and inhibition of HRR, and provide proof-of-concept evidence that PP2A is a promising target for the improvement of local therapy in pancreatic cancer.
doi:10.1158/1078-0432.CCR-13-0788
PMCID: PMC3754450  PMID: 23780887
pancreatic cancer; protein phosphatase 2A; radiosensitization; homologous recombination repair
11.  Predictive Models for Regional Hepatic Function Based upon 99mTc-IDA SPECT and Local Radiation Dose for Physiological Adaptive RT 
Purpose
High dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed prior to and during the course of RT using 99mTc-labeled immindodiacetic acid (IDA) SPECT could predict regional liver function reserve after RT.
Methods and Materials
Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans prior to RT, during, and one month after completion of RT. Indocyanine green (ICG) tests (a measure of overall liver function) were performed within 1 day of each scan. 3D volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After co-registration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and post-RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, Dose, Priori and Adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function post-RT.
Results
The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r = −0.80, p<0.0001), for all time points. Linear correlations between local doses and regional HEFs one month post-RT were significant in 12 patients. In the priori model, regional HEF post-RT was predicted by the planned dose and regional HEF assessed prior to RT (R=0.71, p<0.0001). In the adaptive model, regional HEF post-RT was predicted by regional HEF re-assessed during RT and the remaining planned local dose (R=0.83, p<0.0001).
Conclusions
99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage.
doi:10.1016/j.ijrobp.2013.04.007
PMCID: PMC3710542  PMID: 23688813
99mTc-IDA SPECT; Hepatic extraction fraction; intrahepatic cancer; radiation-induced liver disease; radiation toxicity
12.  Low Dose Rate Radiosensitization of Hepatocellular Carcinoma In Vitro and in Patients1 
Translational Oncology  2014;7(4):472-478.
Transarterial radioembolization (TARE) with 90Y microspheres delivers low dose rate radiation (LDR) to intrahepatic tumors. In the current study, we examined clonogenic survival, DNA damage, and cell cycle distribution in hepatocellular carcinoma (HCC) cell lines treated with LDR in combination with varying doses and schedules of 5-fluorouracil (5-FU), gemcitabine, and sorafenib. Radiosensitization was seen with 1 to 3 μM 5-FU (enhancement ratio 2.2–13.9) and 30 to 100 nM gemcitabine (enhancement ratio 1.9–2.9) administered 24 hours before LDR (0.26 Gy/h to 4.2 Gy). Sorafenib radiosensitized only at high concentrations (3–10 μM) when administered after LDR. For a given radiation dose, greater enhancement was seen with LDR compared to standard dose rate therapy. Summarizing our clinical experience with low dose rate radiosensitization, 13 patients (5 with HCC, 8 with liver metastases) were treated a total of 16 times with TARE and concurrent gemcitabine. Six partial responses and one complete response were observed with a median time to local failure of 7.1 months for all patients and 9.9 months for patients with HCC. In summary, HCC is sensitized to LDR with clinically achievable concentrations of gemcitabine and 5-FU in vitro. Encouraging responses were seen in a small cohort of patients treated with TARE and concurrent gemcitabine. Future studies are needed to validate the safety and efficacy of this approach.
doi:10.1016/j.tranon.2014.05.006
PMCID: PMC4202782  PMID: 24956939
hepatocellular carcinoma; yttrium-90 microspheres; transarterial radioembolization; radiosensitization
13.  Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy 
The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8–9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.
doi:10.1093/jnci/djt055
PMCID: PMC3733308  PMID: 23503600
14.  Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study 
Purpose
Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine.
Methods and Materials
Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint.
Results
Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P = .001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P = .001) and PFS (HR 3.04, P = .001), and it was a stronger predictor of death than either local progression (HR 1.46, P = .42) or distant progression (HR 3.31, P = .004).
Conclusions
In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.
doi:10.1016/j.ijrobp.2012.11.020
PMCID: PMC3646633  PMID: 23265573
15.  Physiological Imaging-Defined Response-Driven Subvolumes of a Tumor1 
Summary
Dose painting of the physiological imaging-defined subvolumes of the tumors by intensity-modulated radiotherapy is hypothesized to lead to a better outcome than distributing a uniform dose within a target volume defined by anatomic imaging. We developed a general method to delineate the subvolumes of a tumor based upon multiple physiological imaging and tested their complementary roles for assessment of therapy response.
Purpose
To develop an image analysis framework to delineate the physiological imaging-defined subvolumes of a tumor in relating to treatment response and outcome.
Materials and Methods
Our proposed approach delineates the subvolumes of a tumor based upon its heterogeneous distributions of physiological imaging parameters. The method assigns each voxel a probabilistic membership function belonging to the physiological parameter classes defined in a sample of tumors, and then calculates the related subvolumes in each tumor. We applied our approach to regional cerebral blood volume (rCBV) and Gd-DTPA transfer constant (Ktrans) images of patients who had brain metastases and were treated by whole brain radiotherapy (WBRT). Forty-five lesions were included in the analysis. Changes in the rCBV (or Ktrans)-defined subvolumes of the tumors from pre RT to 2 weeks (2W) after the start of WBRT were evaluated for differentiation of responsive, stable and progressive tumors using Mann-Whitney U test. Performance of the newly developed metrics for predicting tumor response to WBRT was evaluated by Receiver Operating Characteristic (ROC) analysis.
Results
The percentage decrease in the high-CBV defined subvolumes of the tumors from pre-RT to 2W was significantly greater in the group of responsive tumors than the group of stable and progressive ones (p<0.007). The change in the high-CBV defined subvolumes of the tumors from pre-RT to 2W was a predictor for post-RT response significantly better than change in the gross tumor volume observed during the same time interval (p=0.012), suggesting the physiological change occurs prior to the volumetric change. Also, Ktrans did not add significant discriminatory information for assessing response with respect to rCBV.
Conclusion
The physiological imaging-defined subvolumes of the tumors delineated by our method could be a candidate for boost target, for which further development and evaluation is warranted.
doi:10.1016/j.ijrobp.2012.10.036
PMCID: PMC3638951  PMID: 23257692
16.  Genetic Variations in TGFβ1, tPA and ACE and Radiation-induced Thoracic Toxicities in Patients with Non-Small Cell Lung Cancer 
Objective
We hypothesized that radiation induced thoracic toxicity (RITT) of the lung, esophagus and pericardium share a similar mechanism, and aimed to examine whether genetic variation of transforming growth factor-beta1 (TGFβ1), tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE), are associated with RITT in patients with non-small cell lung cancer (NSCLC).
Material and methods
Patients with stage I-III NSCLC were enrolled and received radiotherapy (RT). Blood samples were obtained pre-RT and at 4–5 weeks during RT and plasma TGF-β1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood pre-RT were analyzed for the following frequent genetic variations: TGFβ1 509C/T, tPA −7351 C/T, and ACE I/D. RITT score was defined as the sum of radiation induced toxicity grades in esophagus, lung and pericardium.
Results
76 NSCLC patients receiving definitive RT were enrolled. Patients with TGFß1 509CC had higher mean grade of esophagitis (1.4±0.2 vs. 0.8±0.2, p=0.019) and RITT score (2.6±0.3 vs. 1.6±0.3, p=0.009) than T allele carriers. Although no significant relationship was observed between RITT and the tPA or ACE variants individually, patients with any high risk alleles (tPA CC or ACE D or TGFß1 509CC) had significantly higher grade of developing combined RITT (p<0.001). Patients with TGFß1 509CC had greater increase of plasma TGF ß1 levels at 4-5 weeks during-RT than T allele carriers (CC 1.2±0.2 vs. T 0.7±0.1, p=0.047).
Conclusion
This exploratory study demonstrated that sensitivity of radiation toxicity may be determined by genomic factors associated with TGFβ1 and genes involved in TGFβ1 pathway.
doi:10.1097/JTO.0b013e318274592e
PMCID: PMC3646090  PMID: 23334061
single nucleotide polymorphism; toxicity; radiotherapy; non-small cell lung cancer
17.  Efficacy of an EGFR-Specific Peptide against EGFR-Dependent Cancer Cell Lines and Tumor Xenografts12 
Neoplasia (New York, N.Y.)  2014;16(2):105-114.
We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al. (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem 288, 26879–26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.
PMCID: PMC3978391  PMID: 24709418
18.  KRAS Protein Stability Is Regulated through SMURF2: UBCH5 Complex-Mediated β-TrCP1 Degradation12 
Neoplasia (New York, N.Y.)  2014;16(2):115-128.
Attempts to target mutant KRAS have been unsuccessful. Here, we report the identification of Smad ubiquitination regulatory factor 2 (SMURF2) and UBCH5 as a critical E3:E2 complex maintaining KRAS protein stability. Loss of SMURF2 either by small interfering RNA/short hairpin RNA (siRNA/shRNA) or by overexpression of a catalytically inactive mutant causes KRAS degradation, whereas overexpression of wild-type SMURF2 enhances KRAS stability. Importantly, mutant KRAS is more susceptible to SMURF2 loss where protein half-life decreases from >12 hours in control siRNA-treated cells to <3 hours on Smurf2 silencing, whereas only marginal differences were noted for wild-type protein. This loss of mutant KRAS could be rescued by overexpressing a siRNA-resistant wild-type SMURF2. Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS-family E3, β-transducing repeat containing protein 1 (β-TrCP1). Conversely, β-TrCP1 is accumulated on SMURF2 loss, leading to increased KRAS degradation. Therefore, as expected, β-TrCP1 knockdown following Smurf2 siRNA treatment rescues mutant KRAS loss. Further, we identify two conserved proline (P) residues in UBCH5 critical for SMURF2 interaction; mutant of either of these P to alanine also destabilizes KRAS. As a proof of principle, we demonstrate that Smurf2 silencing reduces the clonogenic survival in vitro and prolongs tumor latency in vivo in cancer cells including mutant KRAS-driven tumors. Taken together, we show that SMURF2:UBCH5 complex is critical in maintaining KRAS protein stability and propose that targeting such complex may be a unique strategy to degrade mutant KRAS to kill cancer cells.
PMCID: PMC3978392  PMID: 24709419
19.  The Quality-of-Life Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer 
Purpose
Existing studies that examine the effect of neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer on patient quality of life (QOL) are limited. Our goals were to prospectively explore acute changes in patient-reported QOL endpoints during and after treatment and to establish a distribution of scores that could be used for comparison as new treatment modalities emerge.
Methods and Materials
Fifty patients with locally advanced rectal cancer were prospectively enrolled at 2 institutions. Validated cancer-specific European Organization for Research and Treatment of Cancer (EORTC QLQ-CR30) and colorectal cancer-specific (EORTC QLQ-CR38 and EORTC QLQ-CR 29) QOL questionnaires were administered to patients 1 month before they began CRT, at week 4 of CRT, and 1 month after they had finished CRT. The questionnaires included multiple symptom scales, functional domains, and a composite global QOL score. Additionally, a toxicity scale was completed by providers 1 month before the beginning of CRT, weekly during treatment, and 1 month after the end of CRT.
Results
Global QOL showed a statistically significant and borderline clinically significant decrease during CRT (−9.50, P=.0024) but returned to baseline 1 month after the end of treatment (−0.33, P=.9205). Symptoms during treatment were mostly gastrointestinal (nausea/ vomiting +9.94, P<.0001; and diarrhea +16.67, P=.0022), urinary (dysuria +13.33, P<.0001; and frequency +11.82, P=.0006) or fatigue (+16.22, P<.0001). These symptoms returned to baseline after therapy. However, sexual enjoyment (P=.0236) and sexual function (P=.0047) remained persistently diminished after therapy.
Conclusions
Rectal cancer patients undergoing neoadjuvant CRT may experience a reduction in global QOL along with significant gastrointestinal and genitourinary symptoms during treatment. Moreover, provider-rated toxicity scales may not fully capture this decrease in patient-reported QOL. Although most symptoms are transient, impairment in sexual function may persist after the completion of therapy and merits further investigation.
doi:10.1016/j.ijrobp.2012.09.006
PMCID: PMC3578309  PMID: 23058059
20.  Prediction of Liver Function by Using Magnetic Resonance-based Portal Venous Perfusion Imaging 
Purpose
To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning.
Methods and Materials
Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model.
Results
There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT.
Conclusions
This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.
doi:10.1016/j.ijrobp.2012.02.037
PMCID: PMC3629546  PMID: 22520476
21.  A phase I/II trial of intensity-modulated radiation (IMRT) dose escalation with concurrent fixed- dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer 
Purpose
Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by IMRT with FDR-G, freedom from local progression (FFLP) and overall survival (OS).
Methods and Materials
Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status (PS) of 0–2, ANC of ≥1500/mm3, platelets ≥100,000/mm3, creatinine <2 mg/dl, bilirubin <3 mg/dl and ALT/AST ≤2.5 x ULN. FDR-G (1000 mg/m2/100-minutes I.V.) was given on days −22 and −15, 1, 8, 22, and 29. IMRT started day 1. Dose levels were escalated from 50 to 60 Gy in 25 fractions. DLT was defined as gastrointestinal toxicity ≥Grade (G)3, neutropenic fever, or deterioration in PS to ≥3 between day 1 and 126. Dose level was assigned using TITE-CRM with the target DLT rate set to 0.25.
Results
Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% CI: 32–79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6–22.2) and 30% (95% CI 17–45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months.
Conclusions
High dose radiotherapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.
doi:10.1016/j.ijrobp.2012.02.051
PMCID: PMC3421048  PMID: 22543215
pancreatic cancer; chemoradiotherapy; IMRT; gemcitabine; local control
22.  Impact of Perfusion Map Analysis on Early Survival Prediction Accuracy in Glioma Patients1 
Translational Oncology  2013;6(6):766-774.
Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high-grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas.
PMCID: PMC3890712  PMID: 24466380
23.  Targeted Radiosensitization of ETS Fusion-Positive Prostate Cancer through PARP1 Inhibition12 
Neoplasia (New York, N.Y.)  2013;15(10):1207-1217.
ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1) in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07) fold (mean ± SEM) and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03) relative to ERG-negative cells (P < .05). Neutral and alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers.
PMCID: PMC3819636  PMID: 24204199
24.  Dosimetric Analysis of Radiation-Induced Gastric Bleeding 
Purpose
Radiation-induced gastric bleeding has been poorly understood. In this study, we describe dosimetric predictors for gastric bleeding after fractionated radiotherapy and compare several predictive models.
Materials & Methods
The records of 139 sequential patients treated with 3-dimensional conformal radiotherapy (3D-CRT) for intrahepatic malignancies between January 1999 and April 2002 were reviewed. Median follow-up was 7.4 months. Logistic regression and Lyman normal tissue complication probability (NTCP) models for the occurrence of ≥ grade 3 gastric bleed were fit to the data. The principle of maximum likelihood was used to estimate parameters for all models.
Results
Sixteen of 116 evaluable patients (14%) developed gastric bleeds, at a median time of 4.0 months (mean 6.5 months, range 2.1–28.3 months) following completion of RT. The median and mean of the maximum doses to the stomach were 61 and 63 Gy (range 46 Gy–86 Gy), respectively, after bio-correction to equivalent 2 Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis was most predictive of gastric bleed (AUROC=0.92). Best fit Lyman NTCP model parameters were n =0.10, and m =0.21, with TD50(normal) =56 Gy and TD50(cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD50 value for the cirrhosis patients points out their greater sensitivity.
Conclusion
This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding, and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.
doi:10.1016/j.ijrobp.2012.02.029
PMCID: PMC3423508  PMID: 22541965
NTCP; Gastric Bleed; Hepatic Irradiation; Complications
25.  Concurrent whole brain radiotherapy and bortezomib for brain metastasis 
Background
Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.
Methods
A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.
Results
Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).
Conclusions
Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.
doi:10.1186/1748-717X-8-204
PMCID: PMC3765365  PMID: 23965287
Radiation; Brain; Melanoma; Bortezomib; Phase I; TITE-CRM; Diffusion tensor imaging; MRI

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