Takamaru Ashikaga

University of Vermont, Burlington, Vermont, United States

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Publications (76)592.88 Total impact

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    ABSTRACT: Long non-coding RNAs (lncRNAs) are potential biomarkers for breast cancer risk stratification. LncRNA expression has been investigated primarily by RNA sequencing, quantitative reverse transcription PCR or microarray techniques. In this study, six breast cancer-implicated lncRNAs were investigated by chromogenic in situ hybridisation (CISH). Invasive breast carcinoma (IBC), ductal carcinoma in situ (DCIS) and normal adjacent (NA) breast tissues from 52 patients were screened by CISH. Staining was graded by modified Allred scoring. HOTAIR, H19 and KCNQ1OT1 had significantly higher expression levels in IBC and DCIS than NA (p<0.05), and HOTAIR and H19 were expressed more strongly in IBC than in DCIS tissues (p<0.05). HOTAIR and KCNQ101T were expressed in tumour cells; H19 and MEG3 were expressed in stromal microenvironment cells; MALAT1 was expressed in all cells strongly and ZFAS1 was negative or weakly expressed in all specimens. These data corroborate the involvement of three lncRNAs (HOTAIR, H19 and KCNQ1OT1) in breast tumourigenesis and support lncRNA CISH as a potential clinical assay. Importantly, CISH allows identification of the tissue compartment expressing lncRNA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    No preview · Article · Aug 2015 · Journal of clinical pathology
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    ABSTRACT: The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses. Eighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters Cmax , AUC0-24 , t1/2 , CL, and Vd on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287 + TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma. We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m(2) . The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135 mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy. Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle. Pediatr Blood Cancer 2015; 9999:1-8 © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Jul 2015 · Pediatric Blood & Cancer
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    ABSTRACT: Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. Clinicaltrials.gov NCT#01059071.
    Full-text · Article · May 2015 · PLoS ONE
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    ABSTRACT: Patients with metastatic colon cancer (mCRC) are at increased risk for venous thromboembolism (VTE). Limited preclinical data suggests that the oncogene (KRAS) mutational status of the tumor represents a plausible clinical link to systemic hypercoagulability in cancer patients. To determine if a tumor genetic characteristic, KRAS mutational status, is associated with an increased risk of VTE in patients with mCRC. A retrospective cohort study of patients with mCRC and KRAS testing results was conducted at multiple practice sites across New England in the United States. The primary outcome was a VTE event, defined as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), either six months before or at any time after the diagnosis of mCRC. KRAS status (mutated vs. wild type) and other relevant predictors of thrombosis were collected. Of 172 histologically confirmed patients with mCRC, 40 developed a VTE (23.3%). Sixty-five patients (37.8%) had a mutant KRAS status. The incidence of VTE and DVT among patients with mutated KRAS was 32.3 and 23.1%, respectively. The corresponding incidence among patients with wild type KRAS was 17.8 and 9.4%. Odd ratios for the association were 2.21 (95%CI, 1.08-4.53) for VTE and 2.62 (95%CI, 1.12-6.12) for DVT, and remained significant despite adjustment for Khorana score and bevacizumab use. Tumor mutant KRAS status is associated with an increased risk of VTE in patients with mCRC. The tumor genetic profile may represent a novel and important risk factor for thrombosis in patients with cancer. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Thrombosis and Haemostasis
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    ABSTRACT: The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Full-text · Article · Feb 2015 · Cancer Medicine
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    ABSTRACT: This National Institutes of Health (NIH) workshop was cosponsored by the NIH Office of Disease Prevention (ODP), the NIH Pain Consortium, the National Institute on Drug Abuse, and the National Institute of Neurological Disorders and Stroke. A multidisciplinary working group developed the workshop agenda, and an evidence-based practice center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the workshop discussion. During the 1.5-day workshop, invited experts discussed the body of evidence, and attendees had opportunities to provide comments during open discussion periods. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the ODP Web site for 2 weeks for public comment. This article is an abridged version of the panel's report, the full version of which is available at at https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/opioids-chronic-pain/workshop-resources#finalreport.
    No preview · Article · Jan 2015 · Annals of internal medicine
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    Leah J Novinger · Takamaru Ashikaga · David N Krag
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    ABSTRACT: The purpose of this study was to determine the clonal relationship between B cells within a breast cancer and the B cells in the tumor-draining lymph node (TDLN). We also determined the binding capacity of antibodies derived from these sources to autologous cancer and autologous noncancer breast tissue. Antibody clonality of B cells derived from tumor and lymph node was determined by analyzing heavy and light chain immunoglobulin sequences. The number of shared clonal groups observed between tumor and lymph node antibodies was significant for both heavy (p = 0.004) and light chain (p = 0.012) populations. Panning with phage-displayed single-chain variable fragment libraries derived from the tumor and lymph node B cells resulted in multiple antibodies that bound autologous tumor. Sequence analysis of enriched antibodies recovered after the third round of panning the tumor and TDLN libraries against autologous tumor lysates had a genetic relationship. These results indicate that B cells infiltrating a patient's breast cancer and B cells present in the tumor-draining lymph node are clonally and functionally related.
    Preview · Article · Sep 2014 · Cancer Immunology and Immunotherapy

  • No preview · Article · Mar 2014 · Cancer Research

  • No preview · Article · Aug 2013 · Cancer Research

  • No preview · Article · Aug 2013 · Cancer Research
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    ABSTRACT: Surveys are important research tools that permit the accumulation of information from large samples that would otherwise be impractical to collect. Resident surveys have been used frequently to monitor the quality of postgraduate training. Low response rates threaten the utility of this research tool. The purpose of this study was to determine the standard response rate of surveys administered to surgery residents and identify characteristics associated with achieving greater response rates. A search of peer-reviewed literature published between September 2003 and June 2011 was performed with the use of PubMed with Medical Subject Headings: "internship and residency," "surgery," "data collection," and "questionnaires." For inclusion, articles must have described a survey given to active surgery residents within the United States. Surveys were evaluated based on the following criteria: population size, response rate, incentive use, follow-up use, survey format (online vs paper), and institution versus national. Of 433 initial results, 47 met inclusion criteria with a mean response rate of 65.3%. Surveys administered in paper format had a greater response rate compared with those given electronically (mean 78.6% vs 36.4%, respectively, P < .001). Greatest mean response rates were seen for institutional surveys compared with those given nationally (83.1% vs 42% respectively, P < .001). Our review demonstrated that paper surveys administered at the institutional level and during assemblies integrated into residents' schedules demonstrated enhanced response rates. The validity and generalizability of data collected through such surveys will improve as the aspects which dictate response rate are better understood and implemented.
    Full-text · Article · Jul 2013 · Surgery
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    ABSTRACT: BACKGROUND: The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioning and health-related quality of life (HRQoL) has not been well-studied. OBJECTIVE: To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper extremity function, activities, and HRQoL. METHODS: The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparing sentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and arm volume were measured objectively. PROs included symptoms; arm function; limitations in social, recreational, occupational, and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariable linear regression models. RESULTS: In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM. LIMITATIONS: Arm mobility and edema were measured simultaneously only once during the follow-up (6 months). CONCLUSION: Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.
    No preview · Article · Aug 2012 · The journal of supportive oncology
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    ABSTRACT: The purpose of this study is to evaluate the feasibility of ultrafast 3-T MRI in the evaluation of children with acute lower abdominal pain for the detection of appendicitis. Forty-two pediatric patients (30 girls and 12 boys; mean age, 11.5 years; age range, 4-17 years) with acute abdominal pain were prospectively studied. Ultrafast 3-T MRI was performed with a three-plane single-shot turbo spin-echo sequence and an axial T2-weighted turbo spin-echo sequence with fat suppression. All scans were performed without sedation or oral or IV contrast agent. Scan times were less than 8 minutes 45 seconds (median, 5 minutes 40 seconds). Patients underwent CT or ultrasound or both as a comparison study to the MRI examination. The MRI, CT, and ultrasound examinations were interpreted independently by four board-certified radiologists who were blinded to patient information, study interpretations, surgical pathologic findings, and final diagnosis. Twelve of 42 cases of acute appendicitis were detected with 100% sensitivity, 99% specificity, 100% negative predictive value, and 98% positive predictive value, all of which were statistically significant (p < 0.01). The pooled and individual receiver operating characteristic curves for radiologists' interpretation of the diagnosis of acute appendicitis were greater than 0.95 in all cases (p < 0.01) Ultrafast 3-T MRI is a feasible alternative imaging modality for the diagnosis of acute appendicitis in children, particularly in cases where ultrasound is equivocal or nondiagnostic, as an alternative to CT. Ultrafast MRI requires no sedation and no oral or IV contrast agent and has no associated radiation exposure risks.
    Full-text · Article · Jun 2012 · American Journal of Roentgenology
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    ABSTRACT: Patients diagnosed with high-risk neuroblastoma (NB), an extracranial solid tumor in children, have metastases and low survival (30%) despite aggressive multi-modal therapy. Therefore new therapies are urgently needed. We show significant in vitro and in vivo antitumor efficacy of RKS262 in NB. RKS262 showed superior cytotoxicity (IC(50) = 6-25 μM) against six representative NB cell lines compared to its parent analog Nifurtimox (currently in phase 2). Pre-formulated RKS262 (150 mg/kg/daily) pellets administered orally, suppressed tumor growth (60%, p = 0.021) in NB xenograft mice within 28 days. RKS262-treated SMSKCNR cells showed TUNEL-positive DNA nicks and activation of ROS, MAPKs (SAPK/JNK), caspase-3, and p53, along with suppression of the IGF-1R/PI3K/PKC pathway and the Bcl2 family of proteins. RKS262 caused G(2)/M-phase arrest and suppressed cdc-2, cyclin B1, p21, and cyclin D1/D4 expression. N-acetyl-cysteine (NAC; 10 mM) pre-treatment rescued cell viability of RKS262 (23 µM)-treated SMSKCNR cells, and pre-treatment with ascorbic acid (100 μM) and a MAPK inhibitor SB203580 (20 μM) reversed SAPK/JNK, caspase-3 activation, PARP-1 cleavage, and suppression of IGF-1R, PI3K, and PKC phosphorylation. Further, treatment with exogenous BDNF (50 nM) did not suppress SAPK/JNK or ROS activation due to RKS262. Rather, BDNF (50 nM), EGF (100 nM) and IGF-1 (100 nM) co-treatment with RKS262 induced a remarkable S-phase arrest rather than a G(2)/M phase arrest when RKS262 was used alone. In summary, RKS262 shows oral efficacy in NB xenograft animals, and induces apoptosis in vitro in SMSKCNR cells via cell cycle arrest, MAPK and ROS activation, and suppression of IGF-1R/PI3K/PKC and Bcl2 family proteins in a growth factor (BDNF/EGF/IGF-1)-independent fashion.
    Full-text · Article · Jun 2011 · Cancer biology & therapy
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    ABSTRACT: Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (p<10(-5)) were upregulated. Other genes related to apoptosis, oxidative stress, DNA damage, protein folding and nucleosome formation were differentially involved in cells following treatment with nifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.
    No preview · Article · Mar 2011 · International Journal of Oncology
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    ABSTRACT: Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking. We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively. Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.).
    Full-text · Article · Feb 2011 · New England Journal of Medicine

  • No preview · Article · Jan 2011 · Cancer Research
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    ABSTRACT: Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830. 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. US Public Health Service, National Cancer Institute, and Department of Health and Human Services.
    Full-text · Article · Oct 2010 · The Lancet Oncology
  • Marie E Wood · Teresa A Fama · Takamaru Ashikaga · Hyman B Muss
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    ABSTRACT: Pretreatment preferences for adjuvant therapy were examined and compared with actual treatment received. Before definitive surgery, women with node-negative breast cancer were asked to indicate their preference for adjuvant therapy in response to 3 different clinical scenarios. The scenarios provided precise risk, benefit, and side effect information with low-, moderate-, or high-risk risk of death from breast cancer. Contingency table and Spearman rank correlation coefficients were used to examine associations. Kruskal-Wallis rank sum tests were used for group comparisons, with the Friedman rank sum test being used for correlated samples. A total of 75 women enrolled between February 2002 and April 2005; 24% were aged > 65 years. After definitive surgery, 21% of women had ductal carcinoma in situ, and 89% had receptor-positive disease. There was a significant correlation between risk of recurrence and aggressiveness of treatment preferred (P < .001). After surgical staging, the high-risk group received more aggressive treatment compared with the low-risk group (P = .004). In the 51 women with invasive receptor-positive tumors, there was a significant difference (P = .002) in aggressiveness of treatment received based on risk of recurrence. Only 45% of the women received what they had preferred for the level of their risk before surgery. Women were more likely to receive a less aggressive therapy than they preferred initially (P = .0002). This study is among the first to correlate pretreatment preference for therapy with the actual therapy received. Less than half of women received their indicated preference before definitive surgery, with most women receiving less aggressive therapy. Future studies will need to examine this discrepancy.
    No preview · Article · Oct 2010 · Clinical Breast Cancer
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    ABSTRACT: The demonstration of human papillomavirus (HPV) in 99.7% of cervical carcinoma surgical specimens from around the world required investigations by multiple alternative polymerase chain reaction (PCR) assays. A similar approach may therefore be necessary to best characterize HPV prevalence and genotype distribution among cervical cytology samples. In an earlier study, 752 of 799 (94.1%) abnormal and 82 of 300 (27.3%) normal cytology specimens tested HPV positive after PCR using GP5+/6+primers. This study has reinvestigated the "HPV negative" abnormal samples (20 atypical squamous cells of undetermined significance, 5 low-grade squamous intraepithelial lesion, 14 atypical squamous cells, cannot exclude HSIL, 6 high-grade squamous intraepithelial lesion) and an age-matched cohort of "HPV negative" normal (negative for an intraepithelial lesion or malignancy) samples by PCR using PGMY09/11, FAP59/64, and LCR-E7 primers. PGMY09/11-GP5+/6+ nested PCR was performed on samples that were HPV negative by PGMY09/11 PCR. After the first 3 assays, HPV was detected in 41 of 45 (91.1%) abnormal and in 10 of 47 (21.3%) normal samples (P<0.0001). Eighteen HPV genotypes were detected and in some samples the genotype that was identified differed between the tests. The nondetection of common HPV genotypes (eg, HPVs 6, 11, 16, and 18) was notable. High-grade histopathology was found for 2 patients with HPV52-positive cytopathology. Combined with our earlier study, HPV (40 different genotypes) is shown in 99.5% of abnormal samples (99.8% inclusive of the nested PCR data). These findings show that HPV genotype and prevalence estimates are dependent on the method(s) of detection and indicate that suboptimal analytical sensitivity for one or more of the less common high-risk HPV genotypes could lead to impaired clinical sensitivity. HPV may be causal in almost every instance of abnormal cervical cytology; however, passenger HPV that is incidental to an abnormality may also have been detected.
    No preview · Article · Sep 2010 · Diagnostic molecular pathology: the American journal of surgical pathology, part B

Publication Stats

4k Citations
592.88 Total Impact Points

Institutions

  • 1980-2015
    • University of Vermont
      • • Department of Mathematics and Statistics
      • • Department of Surgery
      • • College of Medicine
      • • Vermont Cancer Center
      • • Office of Health Promotion Research
      Burlington, Vermont, United States
  • 2014
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2011
    • National Surgical Adjuvant Breast and Bowel Project
      Pittsburgh, Pennsylvania, United States
  • 2007
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1999-2005
    • University of Vermont Medical Center
      Burlington, Vermont, United States
  • 2000
    • Burlington College
      Burlington, Vermont, United States