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author:("Dueland, vein")
1.  Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks 
Organ toxicity in cancer therapy is likely caused by an underlying disposition for given pathophysiological mechanisms in the individual patient. Mechanistic data on treatment toxicity at the patient level are scarce; hence, probabilistic and translational linkages among different layers of data information, all the way from cellular targets of the therapeutic exposure to tissues and ultimately the patient’s organ systems, are required. Throughout all of these layers, untoward treatment effects may be viewed as perturbations that propagate within a hierarchically structured network from one functional level to the next, at each level causing disturbances that reach a critical threshold, which ultimately are manifested as clinical adverse reactions. Advances in bioinformatics permit compilation of information across the various levels of data organization, presumably enabling integrated systems biology-based prediction of treatment safety. In view of the complexity of biological responses to cancer therapy, this communication reports on a “top-down” strategy, starting with the systematic assessment of adverse effects within a defined therapeutic context and proceeding to transcriptomic and proteomic analysis of relevant patient tissue samples and computational exploration of the resulting data, with the ultimate aim of utilizing information from functional connectivity networks in evaluation of patient safety in multimodal cancer therapy.
doi:10.3390/ijms151222835
PMCID: PMC4284741  PMID: 25501337
cancer treatment; radiotherapy; chemotherapy; targeted therapy; treatment toxicity; clinical study; biomarkers; proteomics; transcriptomics; systems analysis
2.  Biomarkers of Histone Deacetylase Inhibitor Activity in a Phase 1 Combined-Modality Study with Radiotherapy 
PLoS ONE  2014;9(2):e89750.
Background
Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy.
Patients and Methods
Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat.
Results
This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed.
Conclusion
Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting.
doi:10.1371/journal.pone.0089750
PMCID: PMC3934935  PMID: 24587009
3.  Patterns of Recurrence After Liver Transplantation for Nonresectable Liver Metastases from Colorectal Cancer 
Annals of Surgical Oncology  2013;21(4):1323-1329.
Background
Surgical resection is the only curative modality for colorectal liver metastases (CLM), and the pattern of recurrences after resection affects survival. In a prospective study of liver transplantation (Lt) for nonresectable CLM we have shown a 5-year overall survival rate of 60 %, but 19 of 21 experienced recurrence. This study reports the pattern of recurrences after Lt for CLM and the effect on survival.
Methods
Characterization of metastatic lesions in a prospective study for Lt for nonresectable CLM was performed (n = 21). The study included reexamination of chest computed tomographic scans taken before Lt.
Results
At the time of first recurrence, 16 were a single site, and three were multiple sites. Thirteen of the single sites were pulmonary recurrences. The pulmonary recurrences appeared early and were slow growing, and several were accessible to surgical treatment. When chest computed tomographic scans were reexamined, seven patients had pulmonary nodules at the time of Lt without an effect on survival. There was no first single-site hepatic recurrence. Six of the seven patients who developed metastases to the transplanted liver died from metastatic disease.
Conclusions
The pulmonary recurrences after Lt for CLM were of an indolent character, even those that were present at the time of Lt. This contrasts with the finding of metastases to the transplanted liver, which was prognostically adverse. The lack of single hepatic first-site recurrences and hepatic metastases only as part of disseminated disease is different from the pattern of recurrence after liver resection. This suggests two distinct mechanisms for hepatic recurrences after resection for CLM.
doi:10.1245/s10434-013-3449-9
PMCID: PMC3942624  PMID: 24370906
4.  Tumor Phosphatidylinositol-3-Kinase Signaling and Development of Metastatic Disease in Locally Advanced Rectal Cancer 
PLoS ONE  2012;7(11):e50806.
Background
Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.
Patients and Methods
Point mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.
Results
Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.
Conclusion
High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.
doi:10.1371/journal.pone.0050806
PMCID: PMC3511283  PMID: 23226389
5.  Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy 
Background
In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.
Findings
Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.
Conclusions
When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.
Trial registration
ClinicalTrials.gov: NCT00455351
doi:10.1186/1748-717X-6-33
PMCID: PMC3086833  PMID: 21473790
6.  hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes 
Cancer Immunology, Immunotherapy  2011;60(6):809-818.
Immunotherapy targeting the hTERT subunit of telomerase has been shown to induce robust immune responses in cancer patients after vaccination with single hTERT peptides. Vaccination with dendritic cells (DCs) transfected with hTERT mRNA has the potential to induce strong immune responses to multiple hTERT epitopes and is therefore an attractive approach to more potent immunotherapy. Blood samples from such patients provide an opportunity for identification of new, in vivo processed T-cell epitopes that may be clinically relevant. A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she obtained stable disease on gemcitabine treatment. Due to severe neutropenia, the chemotherapy was terminated. The patient has subsequently been treated with autologous DCs loaded with hTERT mRNA for 3 years. Immunomonitoring was performed at regular intervals following start of vaccination and clinical outcome measured by CT and PET/CT evaluation. The patient developed an immune response against several hTERT-derived Th and CTL epitopes. She presently shows no evidence of active disease based on PET/CT scans. No serious adverse events were experienced and the patient continues to receive regular booster injections. We here provide evidence for the induction of hTERT-specific immune responses following vaccination of a pancreas cancer patient with DCs loaded with hTERT mRNA. These responses are associated with complete remission. A thorough analysis of this patient immune response has provided a unique opportunity to identify novel epitopes, associated with clinical effects. These will be included in future hTERT vaccines.
doi:10.1007/s00262-011-0991-9
PMCID: PMC3098983  PMID: 21365467
Telomerase (hTERT); Epitope identification; Dendritic cell vaccination; Pancreas cancer
7.  Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2009;27(25):4116-4123.
Purpose
Two phase I studies were conducted of ABR-217620 alone or in combination with docetaxel. This is a recombinant fusion protein consisting of a mutated variant of the superantigen staphylococcal enterotoxin E (SEA/E-120) linked to fragment antigen binding moiety of a monoclonal antibody recognizing the tumor-associated antigen 5T4.
Patients and Methods
Patients with non–small-cell lung cancer (NSCLC), pancreatic cancer (PC), and renal cell cancer (RCC) received 5 daily boluses of ABR-217620 (3-month cycles) in escalating doses to determine the maximum-tolerated dose (MTD; ABR-217620 dose escalation monotherapy [MONO] study). Doses were selected based on individual patient anti–SEA/E-120 titers pretreatment. Patients with NSCLC received 4 daily, escalating doses of ABR-217620 followed by docetaxel in 21-day cycles (ABR-217620 dose escalation combination with docetaxel [COMBO] study).
Results
Thirty-nine patients were enrolled in the MONO study and 13 were enrolled in the COMBO study. The monotherapy MTD was 26 μg/kg (NSCLC and PC) and 15 μg/kg (RCC). Dose-limiting toxicities (DLTs) in the MONO study were fever, hypotension, acute liver toxicity, and vascular leak syndrome. In the COMBO study, the MTD was 22 μg/kg (neutropenic sepsis). Adverse events included grade 1 to 2 fever, hypotension, nausea, and chills. Treatment caused a systemic increase of inflammatory cytokines and selective expansion of SEA/E-120 reactive T-cells. Tumor biopsies demonstrated T-cell infiltration after therapy. Fourteen patients (36%) had stable disease (SD) on day 56 of the MONO study. Two patients (15%) in the COMBO study had partial responses, one in a patient with progressive disease on prior docetaxel, and five patients (38%) had SD on day 56.
Conclusion
ABR-217620 was well tolerated with evidence of immunological activity and antitumor activity.
doi:10.1200/JCO.2008.20.2515
PMCID: PMC2734423  PMID: 19636016

Results 1-7 (7)