Publications by authors named "Donn C Young"

35 Publications

Antigen-directed cancer surgery for primary colorectal cancer: 15-year survival analysis.

Ann Surg Oncol 2012 Jan 6;19(1):131-8. Epub 2011 Jul 6.

Division of Surgical Oncology, Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH, USA,

Background: Tumor-associated glycoprotein-72 (TAG-72) is a mucin-like high-molecular-weight glycosylated protein complex overexpressed by many adenocarcinomas. Antigen-directed cancer surgery using radiolabeled anti-TAG-72 murine monoclonal antibodies (muMAbs) has been previously investigated for colorectal cancer. Survival analysis of primary colorectal cancer patients with a minimum of 15-year follow-up after antigen-directed cancer surgery was performed to assess the impact of complete surgical resection of all detectable radiolabeled anti-TAG-72 muMAb.

Methods: Survival analysis was performed on 92 patients (study group) with primary colorectal cancer (July 1990 to August 1995) treated with antigen-directed cancer surgery using (125)I-labeled anti-TAG-72 muMAb. The study group was subdivided into those with no detectable TAG-72 antigen-bearing tissues (TAG-72 negative, N=33) and those with persistent detectable TAG-72 antigen-bearing tissues (TAG-72 positive, N=59) at completion of surgery. Comparisons were made with a control group (546 patients) from the same time period.

Results: Study group and control group were demographically similar, as were TAG-72-negative subgroup and TAG-72-positive subgroup. TAG-72-negative subgroup had significantly improved median survival (8.8 versus 2.5 years; P=0.005) and time-dependent survival (45.4% versus 22.0% at 10 years; P=0.002 and 39.4% versus 20.3% at 15 years; P=0.003) compared with TAG-72-positive subgroup. TAG-72 positivity was as an independent predictor of long-term mortality risk, when controlled for pathologic stage of disease.

Conclusions: Absence of detectable TAG-72 antigen within the surgical field at completion of antigen-directed cancer surgery for primary colorectal cancer is of significant prognostic value, conferring a long-term survival advantage to those in whom complete surgical removal of all tissues with detectable radiolabeled anti-TAG-72 muMAb was accomplished.
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http://dx.doi.org/10.1245/s10434-011-1880-3DOI Listing
January 2012

Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN).

Cancer Chemother Pharmacol 2011 Mar 19;67(3):579-86. Epub 2010 May 19.

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine and The Ohio State University Medical Center, Columbus, OH, USA.

Purpose: This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel.

Patients And Methods: Twenty-eight patients with head and neck cancer were enrolled. Patients were orally given erlotinib (50 mg) daily plus 35 mg/m² of docetaxel intravenously weekly × 3 every 4 weeks. Dose escalation of erlotinib was in 50-mg increments until toxicity. Pharmacokinetics were studied with LC-MS/MS, standard, and population pharmacokinetic methods.

Results: Ninety-five courses were successfully given (median 3, range 1-6). The most frequent side effects were diarrhea, fatigue, skin rash, anemia, and hypoalbuminemia. Dose de-escalation for both erlotinib and docetaxel was due to skin rash, neutropenia and/or severe infection with docetaxel to 25 mg/m² and erlotinib to starting dose of 50 mg and re-escalation of docetaxel to 35 mg/m². Responses were observed in 4/26 evaluable patients (100 mg erlotinib). In 24 patients, the mean Cmax and AUC erlotinib values increased with dose and following cumulative dosing (days 7 and 8 vs. day 1, p < 0.05). The CL/F (~7 L/h), V/F (~140 L), and t1/2 (~20 h) for erlotinib were similar to the reported. The mean AUC ratio of metabolite OSI-420 to erlotinib following repetitive dosing at 100 mg (+ or - docetaxel) showed a ~50% increase (p < 0.02), possibly suggesting self-enzyme induction. Population pharmacokinetic studies showed no significant covariate affecting erlotinib pharmacokinetics.

Conclusions: The combination of erlotinib and docetaxel was associated with significant toxicity, which limited the amount of administered erlotinib. Dosing for phase II trials was docetaxel 35 mg/m² and erlotinib 50 mg. The reason for excessive toxicity is not clear, but not due to change in pharmacokinetics.
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http://dx.doi.org/10.1007/s00280-010-1332-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828747PMC
March 2011

Perioperative (18)F-fluorodeoxyglucose-guided imaging using the becquerel as a quantitative measure for optimizing surgical resection in patients with advanced malignancy.

Am J Surg 2009 Dec;198(6):834-40

Department of Radiology, The Ohio State University, Columbus, OH, USA.

Background: (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) scanning is a widely accepted preoperative tumor imaging modality. Herein, we evaluate the becquerel (Bq) as a potential novel quantitative PET measure for application of surgical specimen imaging.

Methods: Retrospectively, PET-avid lesions that could be followed from preoperative imaging, confidently identified in the operating room, imaged ex vivo, and correlated with histopathology were included in this study. Bq counts from both in vivo (preoperative) and ex vivo (surgical specimen) PET/CT images were measured and correlated with histopathology.

Results: Fifty-five PET-avid lesions in 37 patients were included. Forty-six of 55 PET-avid lesions identified were found to contain malignancy on histopathology. Mean Bq counts for the PET-avid lesions were significantly higher that the adjacent PET-nonavid areas (background) within both in vivo and ex vivo imaging (P < .001 and P < .001, respectively). When analyzing all 55 lesions, we found significant increases in Bq levels. PET-avid lesions from in vivo to ex vivo images (P < .001) without significant increases in Bq levels in PET-nonavid lesions from in vivo to ex vivo images (P = .06). When comparing Bq levels between the 2 groups (malignant and benign), we found significantly higher Bq counts in the malignant group on in vivo imaging (P = .02) as well as significantly lower Bq counts in FDG-nonavid areas on ex vivo imaging (P = .04) within the malignant group. Significant differences in PET-avid to PET-nonavid Becquerels ratios within both in vivo and ex vivo images (P = .004, P = .002 respectively) were found, with ex vivo ratio being significantly higher (P < .001).

Conclusions: (18)F-FDG PET/CT imaging using Bqs is the potential to discern malignant lesions from benign tissues within both in vivo and ex vivo scans.
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http://dx.doi.org/10.1016/j.amjsurg.2009.08.014DOI Listing
December 2009

A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignancies.

Mol Cancer Ther 2009 Nov 3;8(11):2983-91. Epub 2009 Nov 3.

Division of Hematology and Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Our preclinical work showed a dramatic synergy between interleukin-12 (IL-12) and trastuzumab for stimulation of natural killer cell cytokine secretion. We aimed to determine the safety profile of IL-12 when given in combination with trastuzumab and paclitaxel to patients with metastatic HER2-overexpressing cancers. Paclitaxel was given i.v. at 175 mg/m(2) every 3 weeks. Trastuzumab was given on day 1 each week (4 mg/kg initially and 2 mg/kg thereafter) in combination with injections of IL-12 on days 2 and 5 starting in cycle 2. This trial accrued 21 patients with metastatic HER2-positive tumors (breast, 7; colon, 6; esophagus, 4; stomach, 2; pancreas, 1; thyroid, 1). The IL-12 component was dose-escalated in cohorts of three patients. The dose-limiting toxicity was grade 3 fatigue at the 300 ng/kg dose level in two patients. The recommended phase II dose was 200 ng/kg administered s.c. There was one complete response in a patient with breast cancer, partial responses in 4 patients (breast, 2; esophageal, 2), and stabilization of disease lasting 3 months or greater (SD) in 6 other patients. All but one response occurred in patients with HER2 3+ disease. Two SD patients completed 1 year of therapy. Ten patients had progressive disease. There was increased activation of extracellular signal-regulated kinase in peripheral blood mononuclear cells and increased levels of IFN-gamma and several chemokines in patients with clinical benefit (complete response, partial response, or SD), but not in patients with progressive disease. IL-12 in combination with trastuzumab and paclitaxel therefore exhibits an acceptable toxicity profile and has activity in patients with HER2-overexpressing cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-09-0820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996611PMC
November 2009

A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2010 May 23;66(1):151-8. Epub 2009 Sep 23.

The Ohio State University, B401, Starling Loving Hall, 320 W 10th av, Columbus, OH 43210, USA.

Purpose: A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.

Patients And Methods: Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6-2 mg/m(2)) on days 2 and 9 and IV paclitaxel at 100 mg/m(2) on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.

Results: Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0-9), received 318 doses (median 5, range 1-34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70-80% at the MTD of 1.8 mg/m(2) of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.

Conclusion: Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m(2).
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http://dx.doi.org/10.1007/s00280-009-1145-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540804PMC
May 2010

Comparison of intraoperative frozen section analysis for sentinel lymph node biopsy during breast cancer surgery for invasive lobular carcinoma and invasive ductal carcinoma.

World J Surg Oncol 2009 Mar 24;7:34. Epub 2009 Mar 24.

Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.

Background: Sentinel lymph node (SLN) biopsy is the standard of care for the surgical assessment of the axilla during breast cancer surgery. However, the diagnostic accuracy of intraoperative frozen section analysis for confirming metastatic involvement of SLNs in cases of invasive lobular carcinoma (ILC) versus that of invasive ductal carcinoma (IDC) has generated controversy secondary to a frequently low-grade cytologic appearance and an often discohesive pattern displayed by metastatic lymph nodes in ILC. In the current report, we present a comparison of intraoperative frozen section analysis for confirming the presence of metastatic disease within SLNs during breast cancer surgery for ILC and IDC.

Methods: We evaluated the results of 131 consecutive cases of ILC from 1997 to 2008 and 133 cases of IDC (selected by a random sequence generator program) from amongst 1163 consecutive cases of IDC from the same time period. All cases had at least one SLN that had both intraoperative frozen section analysis and confirmatory permanent section analysis performed.

Results: No statistically significant difference was found in the sensitivity (67% vs. 75%, P = 0.385), specificity (100% vs. 100%), accuracy (86% vs. 92%, P = 0.172), false negative rate (33% vs. 25%, P = 0.385), negative predictive value (81% vs. 89%, P = 0.158), and positive predictive value (100% vs. 100%) for frozen section analysis for confirming the presence of metastatic disease within SLNs during breast cancer surgery for ILC and IDC.

Conclusion: Since there was no statistically significant difference in sensitivity, specificity, accuracy, false negative rate, negative predictive value, and positive predictive value between frozen section analysis of SLNs for patients with ILC and IDC, the clinical accuracy of confirming metastatic involvement of SLNs on frozen section analysis for ILC should not be considered inferior to the clinical accuracy for IDC. Therefore, frozen section analysis of all SLNs during breast cancer surgery in patients with ILC should remain the standard of care in order to reduce the risk of the need of a later, separate axillary lymph node dissection.
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http://dx.doi.org/10.1186/1477-7819-7-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667517PMC
March 2009

Validation of an LC-MS based approach for profiling histones in chronic lymphocytic leukemia.

Proteomics 2009 Mar;9(5):1197-206

Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.

The in vitro evaluation of histones and their PTMs has drawn substantial interest in the development of epigenetic therapies. The differential expression of histone isoforms may serve as a potential marker in the classification of diseases affected by chromatin abnormalities. In this study, protein profiling by LC and MS was used to explore differences in histone composition in primary chronic lymphocytic leukemia (CLL) cells. Extensive method validations were performed to determine the experimental variances that would impact histone relative abundance. The resulting data demonstrated that the proposed methodology was suitable for the analysis of histone profiles. In 4 normal individuals and 40 CLL patients, a significant decrease in the relative abundance of histone H2A variants (H2AFL and H2AFA/M*) was observed in primary CLL cells as compared to normal B cells. Protein identities were determined using high mass accuracy MS and shotgun proteomics.
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http://dx.doi.org/10.1002/pmic.200800333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108439PMC
March 2009

Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial.

Cancer 2008 Dec;113(12):3450-8

Department of Psychology, Ohio State University, Columbus, OH 43210-1222, USA.

Background: The question of whether stress poses a risk for cancer progression has been difficult to answer. A randomized clinical trial tested the hypothesis that cancer patients coping with their recent diagnosis but receiving a psychologic intervention would have improved survival compared with patients who were only assessed.

Methods: A total of 227 patients who were surgically treated for regional breast cancer participated. Before beginning adjuvant cancer therapies, patients were assessed with psychologic and behavioral measures and had a health evaluation, and a 60-mL blood sample was drawn. Patients were randomized to Psychologic Intervention plus assessment or Assessment only study arms. The intervention was psychologist led; conducted in small groups; and included strategies to reduce stress, improve mood, alter health behaviors, and maintain adherence to cancer treatment and care. Earlier articles demonstrated that, compared with the Assessment arm, the Intervention arm improved across all of the latter secondary outcomes. Immunity was also enhanced.

Results: After a median of 11 years of follow-up, disease recurrence was reported to occur in 62 of 212 (29%) women and death was reported for 54 of 227 (24%) women. Using Cox proportional hazards analysis, multivariate comparison of survival was conducted. As predicted, patients in the Intervention arm were found to have a reduced risk of breast cancer recurrence (hazards ratio [HR] of 0.55; P = .034) and death from breast cancer (HR of 0.44; P = .016) compared with patients in the Assessment only arm. Follow-up analyses also demonstrated that Intervention patients had a reduced risk of death from all causes (HR of 0.51; P = .028).

Conclusions: Psychologic interventions as delivered and studied here can improve survival.
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http://dx.doi.org/10.1002/cncr.23969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661422PMC
December 2008

A prospective pilot clinical trial evaluating the utility of a dynamic near-infrared imaging device for characterizing suspicious breast lesions.

Breast Cancer Res 2007 ;9(6):R88

Biomedical Engineering Department, The Ohio State University, Columbus, OH 43210, USA.

Introduction: Characterizing and differentiating between malignant tumors, benign tumors, and normal breast tissue is increasingly important in the patient presenting with breast problems. Near-infrared diffuse optical imaging and spectroscopy is capable of measuring multiple physiologic parameters of biological tissue systems and may have clinical applications for assessing the development and progression of neoplastic processes, including breast cancer. The currently available application of near-infrared imaging technology for the breast, however, is compromised by low spatial resolution, tissue heterogeneity, and interpatient variation.

Materials And Methods: We tested a dynamic near-infrared imaging schema for the characterization of suspicious breast lesions identified on diagnostic clinical ultrasound. A portable handheld near-infrared tissue imaging device (P-Scan; ViOptix Inc., Fremont, CA, USA) was utilized. An external mechanical compression force was applied to breast tissue. The tissue oxygen saturation and hemoglobin concentration were recorded simultaneously by the handheld near-infrared imaging device. Twelve categories of dynamic tissue parameters were derived based on real-time measurements of the tissue hemoglobin concentration and the oxygen saturation.

Results: Fifty suspicious breast lesions were evaluated in 48 patients. Statistical analyses were carried out on 36 out of 50 datasets that satisfied our inclusion criteria. Suspicious breast lesions identified on diagnostic clinical ultrasound had lower oxygenation and higher hemoglobin concentration than the surrounding normal breast tissue. Furthermore, histopathologic-proven malignant breast tumors had a lower differential hemoglobin contrast (that is, the difference of hemoglobin concentration variability between the suspicious breast lesion and the normal breast parenchyma located remotely elsewhere within the ipsilateral breast) as compared with histopathologic-proven benign breast lesions.

Conclusion: The proposed dynamic near-infrared imaging schema has the potential to differentiate benign processes from those of malignant breast tumors. Further development and refinement of the dynamic imaging device and additional subsequent clinical testing are necessary for optimizing the accuracy of detection.
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http://dx.doi.org/10.1186/bcr1837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246191PMC
March 2008

Ultraviolet radiation-induced corneal degeneration in 129 mice.

Toxicol Pathol 2007 Oct;35(6):819-26

Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA.

Ultraviolet radiation (UVR) is a risk factor for the development of ocular disease in humans, including acute photokeratitis, chronic corneal spheroidal degeneration, and cataract formation. This report describes the ocular lesions seen in 21 mice chronically exposed to UVR as part of a skin carcinogenicity study. All globes were affected to varying degrees. The primary lesion, not previously reported in UVR-exposed mice, was marked loss of keratocytes relative to age-matched controls. Secondary lesions included corneal stromal thinning, keratoconus, corneal vascularization and fibrosis, keratitis, globe rupture, and phthisis bulbi. In addition, more than 90% of UVR-exposed and unexposed lenses had evidence of cataract formation; this is the first report of the occurrence of spontaneous cataracts in 129 mice. In a subsequent study, apoptotic cells were identified histologically and by cleaved caspase 3 immunoreactivity in the corneal epithelium and, less commonly, in the corneal stroma after acute UVR exposure. Based on this finding, we propose that the loss of keratocytes observed in the chronic study was due to UVR-induced apoptosis.
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http://dx.doi.org/10.1080/01926230701584197DOI Listing
October 2007

Good science requires sound biostatistical principles.

Am J Surg 2007 Jul;194(1):136-7; author reply 137-9

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http://dx.doi.org/10.1016/j.amjsurg.2006.06.039DOI Listing
July 2007

Multimodal intensification regimens for advanced, resectable, previously untreated squamous cell cancer of the oral cavity, oropharynx, or hypopharynx: a 12-year experience.

Arch Otolaryngol Head Neck Surg 2007 Apr;133(4):320-6

Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center-Arthur G. James Cancer Hospital, Columbus, Ohio, USA.

Objective: To determine the feasibility of, compliance with, and long-term survival with intensification treatment regimens for patients with advanced, resectable, previously untreated head and neck squamous cell carcinoma.

Design: Prospective phase 2 clinical trial (3 similar, consecutively evolved trials).

Setting: Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University.

Patients: One hundred twenty-three patients (median age, 60 years; range, 30-78 years) with previously untreated, resectable, advanced squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx.

Interventions: Perioperative cisplatin chemoradiotherapy, surgical resection with intraoperative radiotherapy, and postoperative paclitaxel and cisplatin chemoradiotherapy.

Main Outcome Measures: The feasibility, compliance, and long-term survival associated with the 3 intensification regimens.

Results: Compliance with all 3 intensification regimens averaged 61% (75/123). Patient-directed noncompliance occurred in 16 patients (13%). The average locoregional (112/123, 91%) and systemic (106/123, 86%) disease control rates were excellent. Overall long-term disease-specific survival was 73%. Median time at risk was 62.5 months (range, 1 day to 100.4 months).

Conclusions: The intensification regimens result in excellent disease control rates and long-term survival in this particular patient population. Future evolution of these regimens will include some modifications to further decrease toxic effects followed by phase 2 multi-institutional trials to determine whether the single-institutional experience can be duplicated. The results of these studies will determine whether phase 3 trials can be proposed.
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http://dx.doi.org/10.1001/archotol.133.4.320DOI Listing
April 2007

Re-emphasizing the concept of adequacy of intraoperative assessment of the axillary sentinel lymph nodes for identifying nodal positivity during breast cancer surgery.

World J Surg Oncol 2007 Feb 9;5:18. Epub 2007 Feb 9.

Section of Surgical Oncology of the Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

Background: Although sentinel lymph node (SLN) biopsy is a standard of care for the evaluation of the axillary lymph nodes during breast cancer surgery, a substantial degree of variation exists among individual surgeons as to what represents an adequate assessment. The aim of the current study was to assess when metastatic disease was first identified within consecutively harvested SLN candidates for invasive breast cancers demonstrating a positive SLN.

Methods: We retrospectively analyzed a series of 400 breast cancers from a recently published prospective randomized clinical trial. A combined radiocolloid and blue dye technique was used. All potential SLN candidates, containing counts of at least 10% of the hottest SLN and/or containing blue dye, were harvested and were consecutively numbered in the order of the decreasing level of counts (with the hottest SLN representing SLN #1).

Results: Among 371 invasive breast cancers, a SLN was identified within 353 cases (95%). Mean number of SLNs identified was 2.5 (range, 1 to 9), with a single SLN identified in 104 (29%) cases, two identified in 110 (31%), three identified in 73 (21%), four identified in 35 (10%), five identified in 16 (5%), and six or more identified in 15 (4%). A positive SLN was found in 104 (29%) cases. SLN #1 was the first positive SLN in 86 (83%). SLN #2 was the first positive SLN in 15 (14%). SLN #3, SLN #4, and SLN #5 were the first positive SLN in one case (1%) each. A positive SLN was found in 18% (19/104) of cases when a single SLN was identified, as compared to in 34% (85/249) when two or more SLNs were identified (P = 0.003).

Conclusion: The accurate and optimal assessment of the axilla during breast cancer surgery requires persistence and diligence for attempting to identify all potential SLN candidates in order to avoid failing to recognize a positive SLN. The scenario in which only a single negative SLN candidate is intraoperatively identified is one that should raise some concern to the operating surgeon.
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http://dx.doi.org/10.1186/1477-7819-5-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797807PMC
February 2007

Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers.

Clin Cancer Res 2007 Jan;13(1):246-52

Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio, USA.

Purpose: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a steroid nuclear receptor that is activated by natural compounds such as specific fatty acids and synthetic drugs such as thiazolidinedione antidiabetic agents. Expressed in normal and malignant mammary epithelial cells, activation of PPARgamma is associated with antiproliferative effects on human breast cancer cells in preclinical studies. The purpose of this study was to test the hypothesis that PPARgamma ligand therapy might inhibit tumor growth and progression in human breast cancer.

Experimental Design: We conducted a pilot trial of short-term (2-6 weeks) treatment with the thiazolidinedione rosiglitazone in 38 women with early-stage (T(is)-T(2), N(0-1), M(0)) breast cancer, administered between the time of diagnostic biopsy and definitive surgery.

Results: Short-term treatment with rosiglitazone (8 mg/d) did not elicit significant effects on breast tumor cell proliferation using Ki67 expression as a measure of cell proliferation and surrogate marker of tumor growth and progression. In pretreatment tumors notable for nuclear expression of PPARgamma by immunohistochemistry, down-regulation of nuclear PPARgamma expression occurred following rosiglitazone administration (P = 0.005). No PPARG mutations were identified, and the incidence of P12A and H446H polymorphisms did not differ relative to U.S. controls (P = 0.5). Treatment with rosiglitazone resulted in increased serum adiponectin (P < 0.001), decreased insulin levels (P = 0.005), and increased insulin sensitivity (P = 0.004). Rosiglitazone was well tolerated without serious adverse events.

Conclusion: Our data indicate that short-term rosiglitazone therapy in early-stage breast cancer patients leads to local and systemic effects on PPARgamma signaling that may be relevant to breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-1947DOI Listing
January 2007

Poor prognosis for biomarkers.

Authors:
Donn C Young

Ann Surg Oncol 2007 Jan 7;14(1):270. Epub 2006 Oct 7.

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http://dx.doi.org/10.1245/s10434-006-9162-1DOI Listing
January 2007

Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia.

Blood 2007 Jan 26;109(2):399-404. Epub 2006 Sep 26.

Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.

Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200x10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.
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http://dx.doi.org/10.1182/blood-2006-05-020735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785084PMC
January 2007

Prospective randomized clinical trial comparing intradermal, intraparenchymal, and subareolar injection routes for sentinel lymph node mapping and biopsy in breast cancer.

Ann Surg Oncol 2006 Nov 7;13(11):1412-21. Epub 2006 Sep 7.

Section of Surgical Oncology, Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

Background: Multiple injection routes, including intradermal (ID), intraparenchymal (IP), and subareolar (SA), are used for 99mTc-sulfur colloid administration for sentinel lymph node (SLN) mapping and biopsy in breast cancer. The aim of this study was to compare localization by ID, IP, and SA injection routes based on preoperative lymphoscintigraphy and intraoperative identification.

Methods: Four hundred prospectively randomized breast cancers underwent SLN mapping and biopsy.

Results: Preoperative lymphoscintigraphy demonstrated localization to the axilla in 126/133 (95%) ID, 82/132 (62%) IP, and 96/133 (72%) SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.081 IP vs. SA), with a mean duration of preoperative lymphoscintigraphy of 139 +/- 18 minutes. Mean time to first localization when localization was demonstrated on preoperative lymphoscintigraphy was 8 +/- 14 minutes for ID, 53 +/- 49 for IP, and 22 +/- 29 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.003 IP vs. SA). Intraoperative identification of a SLN at the time of SLN biopsy was successful in 133/133 (100%) ID, 121/134 (90%) IP, and 126/133 (95%) SA (P < 0.001 ID vs IP; P = 0.014 ID vs. SA; P = 0.168 IP vs. SA), with a mean time from injection of 99mTc-sulfur colloid to start of SLN biopsy of 288 +/- 71 minutes. Mean intraoperative time to harvest the first SLN was 9 +/- 4 minutes for ID, 13 +/- 6 for IP, and 12 +/- 6 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.410 IP vs. SA).

Conclusions: The ID injection route demonstrated a significantly greater frequency of localization, decreased time to first localization on preoperative lymphoscintigraphy, and decreased time to harvest the first SLN. This represents the first prospective randomized clinical trial to confirm superiority of the ID route for administration of 99mTc-sulfur colloid during SLN mapping and biopsy in breast cancer.
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http://dx.doi.org/10.1245/s10434-006-9022-zDOI Listing
November 2006

Long-term results of a multimodal intensification regimen for previously untreated advanced resectable squamous cell cancer of the oral cavity, oropharynx, or hypopharynx.

Laryngoscope 2006 Apr;116(4):607-12

Department of Otolaryngology-Head and Neck Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Background: Long-term disease control of an intensified treatment regimen for previously untreated stage III and IV resectable oral cavity, oropharyngeal, or hypopharyngeal squamous cell carcinoma was analyzed.

Methods: Forty-three patients with previously untreated, advanced stage, resectable squamous carcinomas of the oral cavity, oropharynx, or hypopharynx were enrolled in a prospective phase II institutional clinical trial at a tertiary care National Cancer Institute-designated comprehensive cancer center. It includes preoperative accelerated hyperfractionated radiotherapy with concurrent cisplatin followed immediately by surgery and intraoperative radiotherapy, and completed with early postoperative weekly paclitaxel, two additional cisplatin cycles, and concurrent once-daily radiotherapy beginning on day 28 after surgery.

Results: Forty-three patients enrolled in the study. Protocol compliance was 53%. The range of time at risk was 10.4 to 56.23 months (median, 45 months). The locoregional (93%) and systemic (91%) disease control rates were excellent. Overall long-term survival was 79%.

Conclusions: An intensive treatment regimen that improves compliance and long-term disease control is clearly feasible for this patient population.
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http://dx.doi.org/10.1097/01.mlg.0000208340.42071.f9DOI Listing
April 2006

Phase I study of the sequential combination of interleukin-12 and interferon alfa-2b in advanced cancer: evidence for modulation of interferon signaling pathways by interleukin-12.

J Clin Oncol 2005 Dec;23(34):8835-44

Division of Hematology, The Ohio State University, Columbus, USA.

Purpose: To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs).

Patients And Methods: Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-alpha-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs.

Results: No IL-12-or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021).

Conclusion: The combination of rhIL-12 and IFN-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.
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http://dx.doi.org/10.1200/JCO.2005.02.1691DOI Listing
December 2005

Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone.

J Nutr 2005 May;135(5):983-8

Department of Surgery, Division of Surgical Oncology, The Ohio State University, Columbus, OH 43210, USA.

Overexpression of human epidermal growth factor receptor 2 (HER-2/neu) characterizes a molecular subtype of breast cancer associated with poor clinical outcome. Preventive strategies for HER-2/neu-positive breast cancer, which is often estrogen and progesterone receptor negative, remain undefined. Activators of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor also expressed in breast cancer, hold potential as cancer prevention agents. PPARgamma ligands include specific fatty acids and synthetic compounds, such as the thiazolidinediones, which appear to inhibit cell proliferation and tumorigenesis. We hypothesized that a thiazolidinedione, rosiglitazone, may serve as a chemopreventive agent for HER-2/neu-associated mammary carcinogenesis, but that efficacy may be influenced by dietary fat content. We studied the effects of diets enriched with corn or fish oil (25% of energy) with and without rosiglitazone (12 g/kg) in a 2 x 2 factorial design on mammary tumorigenesis in murine mammary tumor virus (MMTV)-HER-2/neu transgenic mice. Despite in vitro evidence of antiproliferative effects in an MMTV-HER-2/neu tumor cell line, rosiglitazone did not affect mammary carcinogenesis in vivo. Interestingly, fish oil-based diets markedly suppressed breast tumor incidence (57% of mice vs. 87% of corn oil-fed mice, P = 0.0001) as well as tumor multiplicity (P = 0.001) and mammary gland dysplasia (P = 0.001). These findings demonstrate a potent preventive effect of (n-3) PUFA on HER-2/neu-mediated mammary carcinogenesis, without interaction with a synthetic PPARgamma activator. Further studies focusing on the mechanisms by which (n-3) fatty acids suppress HER-2/neu signaling pathways involved in the pathogenesis of breast cancer are warranted.
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http://dx.doi.org/10.1093/jn/135.5.983DOI Listing
May 2005

TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia.

J Clin Oncol 2005 Jun 4;23(17):3877-85. Epub 2005 Apr 4.

Division of Human Cancer Genetics, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA.

Purpose: Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease for which natural history can be predicted based on the presence or absence of immunoglobulin (Ig) variable heavy chain (V(H)) gene mutations. Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V(H) mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells.

Materials And Methods: TWIST2 promoter methylation was identified by restriction landmark genome scanning. Southern blot (SB), bisulfite sequencing, and combined bisulfite restriction analysis (COBRA), and quantitative SB-COBRA was performed to study methylation of the TWIST2 promoter. Reverse transcription polymerase chain reaction assays were used to study TWIST2 expression in CLL cells.

Results: Following identification and confirmation of TWIST2 methylation in CLL patients, we demonstrated that expression of this transcription factor is related to the degree of promoter methylation. Expression of TWIST2 in a CLL cell line in which the promoter is methylated was increased following decitabine treatment. We next studied 53 patients by COBRA and demonstrated that 72% of patient samples with mutated Ig V(H) show TWIST2 methylation, while only 16% of patient samples with unmutated Ig V(H) were methylated (P < .001). In a subset of patients, methylation of TWIST2 correlated with mRNA expression.

Conclusion: TWIST2 is differentially methylated in CLL cells relative to Ig V(H) mutational status and can be quantitatively monitored by SB-COBRA. Based on the known role of TWIST2 in silencing p53 function in other malignancies, future studies should focus on the role of TWIST2 in CLL and related lymphoproliferative diseases.
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http://dx.doi.org/10.1200/JCO.2005.02.196DOI Listing
June 2005

Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance.

Blood 2005 May 21;105(10):4021-7. Epub 2005 Jan 21.

Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, 336 L. M. Parks Hall, Columbus, OH 43210, USA.

Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210(E255K) and Ba/F3p210(T315I). The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210(E255K) and Ba/F3p210(T315I) were 14 +/- 4 and 30 +/- 2 microM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 microM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.
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http://dx.doi.org/10.1182/blood-2004-07-2967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895085PMC
May 2005

Holidays, birthdays, and postponement of cancer death.

JAMA 2004 Dec;292(24):3012-6

Comprehensive Cancer Center and Center for Biostatistics, The Ohio State University, Columbus 43210, USA.

Context: Articles in the medical literature and lay press have supported a belief that individuals, including those dying of cancer, can temporarily postpone their death to survive a major holiday or other significant event, but results and effects have been variable.

Objective: To determine whether, for the patient dying of cancer, a "death takes a holiday" effect showing a reduction in deaths in the week before a significant event was associated with Christmas, the US holiday of Thanksgiving, or the date of the individual's birthday.

Design, Setting, And Subjects: Analysis of death certificate data for all 1,269,474 persons dying in Ohio from 1989-2000, including 309,221 persons dying with cancer noted as the leading cause of death.

Main Outcome Measure: We measured the total number of cancer deaths in the 2 weeks centered on the event of interest and the proportion of these deaths that occurred in the week before the event to determine whether this proportion was significantly different from 0.5 by using an exact binomial test.

Results: The proportion of persons dying of cancer in the week before Christmas, Thanksgiving, and the individual's birthday was not significantly different from the proportion dying in the week after the event (P = .52, .26, and .06, respectively). However, among black individuals there was an increase in cancer deaths in the week before Thanksgiving (P = .01), whereas women showed an increase in cancer deaths in the week before their birthday (P = .05). There was no statistically significant excess of deaths in the postevent week in any subgroup.

Conclusion: We found no evidence, in contrast to previous studies, that cancer patients are able to postpone their deaths to survive significant religious, social, or personal events.
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http://dx.doi.org/10.1001/jama.292.24.3012DOI Listing
December 2004

A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients.

Clin Cancer Res 2004 Aug;10(15):5027-37

Department of Molecular Virology, Immunology, and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.

Purpose: On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab.

Patients And Methods: Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy.

Results: Fifteen patients were treated, including 12 with HER2 2+ or 3+ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3+ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3+ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon (IFN)gamma by natural killer cells only in those patients experiencing a clinical response or stabilization of disease. Elevated serum levels of macrophage inflammatory protein-1alpha, tumor necrosis factor-alpha, and the antiangiogenic factors IFN-gamma inducible protein-10 and monokine induced by gamma were also observed in these patients. Patient genotyping suggested that a specific IFN-gamma gene polymorphism might have been associated with increased IFN-gamma production. The ability of patient peripheral blood cells to conduct antibody-dependent cellular cytotoxicity against tumor targets in vitro did not correlate with clinical response or dose of IL-12.

Conclusions: The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN-gamma and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-0265DOI Listing
August 2004

Smallpox vaccination in the shadow of Jenner.

Authors:
Donn C Young

Lancet 2004 Feb;363(9410):738

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http://dx.doi.org/10.1016/S0140-6736(04)15684-5DOI Listing
February 2004

Effect of static magnetic field exposure of up to 8 Tesla on sequential human vital sign measurements.

J Magn Reson Imaging 2003 Sep;18(3):346-52

Department of Radiology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210, USA.

Purpose: To determine if increasing static magnetic field strength exposures up to 8 Tesla (T) affect vital signs or electrocardiograms (ECGs) in normal human volunteers.

Materials And Methods: We studied 25 normal subjects, consisting of 19 men and six women, ages 24-53 years. The vital signs and ECGs of the subjects were measured 14 times inside and outside the magnetic field. This included the heart rate, respiratory rate, systolic and diastolic blood pressures, finger pulse oxygenation levels, core body temperature via the external auditory canal temperature, and fiber optic core body sublingual temperatures. Inside the magnetic field the vital signs were measured sequentially at field strengths of 8, 6, 4.5, 3, and 1.5 T.

Results: The only statistically significant effect of magnetic field strength was observed with systolic blood pressure. An average increase of 3.6 mm Hg in systolic blood pressure was seen with 8 T exposure. ECG rhythm strip analysis demonstrated no significant changes post-exposure.

Conclusions: Normal subjects exposed to varying magnetic field strengths of up to 8 T demonstrated no clinically significant changes in vital signs. Transient ECG artifacts were noted to increase with the field strength.
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http://dx.doi.org/10.1002/jmri.10367DOI Listing
September 2003

Patterns of recurrence after sentinel lymph node biopsy for breast cancer.

Ann Surg Oncol 2003 May;10(4):376-80

Division of Surgical Oncology, Department of Surgery, Arthur G. James Cancer Hospital, and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.

Background: Sentinel lymph node biopsy (SLNB) is gaining acceptance as an alternative to axillary lymph node dissection. The purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB.

Methods: Two-hundred twenty-two consecutive patients undergoing SLNB from April 6, 1998, to October 27, 1999, and who were >or=24 months out from their procedure were identified from a prospectively maintained database. Retrospective chart review and data analysis were performed to identify variables predictive of recurrence.

Results: The median patient follow-up was 32 months (range, 24-43 months). A total of 159 patients (72%) were sentinel lymph node (SLN) negative and had no further axillary treatment. Five of these patients (3.1%) developed a recurrence (one local and four distant), with no isolated regional (axillary) recurrences. Sixty-three patients (28%) were SLN positive and underwent a subsequent axillary lymph node dissection. Six of these patients (9.5%) developed a recurrence (three local, one regional, and two distant). Pathologic tumor size (P <.001), lymphovascular invasion (P =.018), and a positive SLN (P =.048) were all statistically significantly associated with disease recurrence.

Conclusions: With a minimum follow-up of 24 months, patients with a negative SLN and no subsequent axillary treatment demonstrate a low frequency of disease recurrence. This supports the use of SLNB as the sole axillary staging procedure in SLN-negative patients.
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http://dx.doi.org/10.1245/aso.2003.07.026DOI Listing
May 2003

Pre-emptive analgesia in gynecologic surgical procedures: preoperative wound infiltration with ropivacaine in patients who undergo laparotomy through a midline vertical incision.

Am J Obstet Gynecol 2003 Apr;188(4):901-5

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ohio State University, Columbus, USA.

Objective: We tested the hypothesis that local anesthetic that is injected before a vertical midline abdominal incision would decrease the use of postoperative opioids.

Study Design: Patients who would undergo abdominal surgical procedures with general anesthesia by a planned vertical midline incision were enrolled in the study. Patients were assigned randomly to receive either 0.5% ropivacaine or normal saline solution placebo that was injected in the subcuticular tissue and fascia before the incision of each. All patients received morphine after the operation with a patient-controlled analgesia device. Morphine consumption was measured during the postoperative period at intervals of 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, and 24 to 48 hours. Postoperative pain was assessed at 6, 12, 24, and 48 hours after the conclusion of the procedure with a visual analog scale.

Results: Eighty-four patients were enrolled in the study; 16 patients were excluded; therefore, 68 patients had useable data. The two treatment groups did not differ in age, height, weight, the length of the operation, the length of the incision, the position of the incision, the placement of drains, or the procedure that was performed. There was no significant difference in morphine consumption for any of the four intervals. The visual analog scale was not significantly different between the two groups at 6, 12, or 24 hours after operation. The visual analog scale at 48 hours was lower in the group that received ropivacaine (2.69 vs 4.26, P =.02). Data were analyzed by the Student t test.

Conclusion: Pre-emptive analgesia with 0.5% ropivacaine given before skin incision does not decrease the postoperative analgesic use in patients who undergo laparotomy by a midline vertical skin incision.
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http://dx.doi.org/10.1067/mob.2003.216DOI Listing
April 2003

A chimeric multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumor responses.

J Immunol 2003 Apr;170(8):4242-53

Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH 43210, USA.

Immunotherapeutic approaches to cancer should focus on novel undertakings that modulate immune responses by synergistic enhancement of antitumor immunological parameters. Cancer vaccines should preferably be composed of multiple defined tumor Ag-specific B and T cell epitopes. To develop a multiepitope vaccine, 12 high ranking B cell epitopes were identified from the extracellular domain of the human epidermal growth factor receptor-2 (HER-2) oncoprotein by computer-aided analysis. Four novel HER-2 B cell epitopes were synthesized as chimeras with a promiscuous T cell epitope (aa 288-302) from the measles virus fusion protein (MVF). Two chimeric peptide vaccines, MVF HER-2(316-339) and MVF HER-2(485-503) induced high levels of Abs in outbred rabbits, which inhibited tumor cell growth. In addition, Abs induced by a combination of two vaccines, MVF HER-2(316-339) and MVF HER-2(628-647) down-modulated receptor expression and activated IFN-gamma release better than the individual vaccines. Furthermore, this multiepitope vaccine in combination with IL-12 caused a significant reduction (p = 0.004) in the number of pulmonary metastases induced by challenge with syngeneic tumor cells overexpressing HER-2. Peptide Abs targeting specific sites in the extracellular domain may be used for exploring the oncoprotein's functions. The multiepitope vaccine may have potential application in the treatment of HER-2-associated cancers.
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http://dx.doi.org/10.4049/jimmunol.170.8.4242DOI Listing
April 2003