Publications by authors named "Mihai Merzianu"

31 Publications

Profiling the Stromal and Vascular Heterogeneity in Patient-derived Xenograft Models of Head and Neck Cancer: Impact on Therapeutic Response.

Cancers (Basel) 2019 Jul 6;11(7). Epub 2019 Jul 6.

Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson's trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC.
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http://dx.doi.org/10.3390/cancers11070951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679003PMC
July 2019

IgG4 expression in cutaneous marginal zone lymphoma with plasmacytic differentiation and localized amyloid deposition: A useful clue to cutaneous origin.

JAAD Case Rep 2018 Oct 3;4(9):883-886. Epub 2018 Oct 3.

Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York.

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http://dx.doi.org/10.1016/j.jdcr.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172439PMC
October 2018

Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study.

Am J Clin Pathol 2018 Oct;150(5):393-405

Pathology and Anatomical Sciences, University at Buffalo-The State University of New York.

Objectives: To assess bone marrow (BM) sampling in academic medical centers.

Methods: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed.

Results: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent.

Conclusions: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.
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http://dx.doi.org/10.1093/ajcp/aqy066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166687PMC
October 2018

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Am J Surg Pathol 2018 10;42(10):1297-1305

Department of Pathology, UT Southwestern Medical Center, Dallas, TX.

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.
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http://dx.doi.org/10.1097/PAS.0000000000001096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133728PMC
October 2018

Lip mass.

J Am Dent Assoc 2018 Jul 3;149(7):650-654. Epub 2018 May 3.

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http://dx.doi.org/10.1016/j.adaj.2018.03.020DOI Listing
July 2018

Cancer stem cell and its niche in malignant progression of oral potentially malignant disorders.

Oral Oncol 2017 12 12;75:140-147. Epub 2017 Nov 12.

Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, USA; Integrated Head and Neck Oncology Research Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Foundation, Bangalore, India; Head and Neck Oncology, Mazumdar Shaw Medical Centre, Bangalore, India; Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program, Roswell Park Cancer Institute, Buffalo, USA. Electronic address:

Objective: The purpose of this study was to determine association between cancer stem cells (CSCs) and their niche with progression of oral potentially malignant disorders.

Materials And Methods: Patients with histologically confirmed oral potentially malignant disorders, stratified into high/low risk lesions based on the degree of dysplasia and oral cancer were included in this study. Immunohistochemical profiling of markers of CSCs (CD44), endothelial cells (CD31) and CSC-vascular niche cross-talk (CXCR4 and SDF1) were carried out. Statistical analysis was performed to correlate the relationship of markers with histopathology grade (ANOVA, and χ test, unpaired t test) using GraphPad InStat v3.06.

Results: The study included 550 samples (349 patients) and analysis showed progressive increase in expression levels of CSC and its niche markers with increase in grade of dysplasia as compared to the normal cohort (p < 0.05). Co-expression analysis revealed that, in comparison to the normal cohort, a larger percentage of patients showed increased expression of CD31 and CD44 (CD31/CD44; p < 0.05) and of CXCR4 and SDF1 (CXCR4/SDF1; p = 0.04), suggesting an association of the CSCs and the vascular niche. Further, distribution of patients with CD44/CXCR4 (p < 0.05) and CD31/SDF1 (p = 0.01) was significantly increased in the high-risk group (18%), suggesting a correlation between CD44/CXCR4 cells, the vascular niche and progression of oral dysplastic lesions.

Conclusion: The increased expression of CSCs, the vascular niche and their cross talk markers are associated with increase in severity of dysplasia suggesting their role in the progression of oral potentially malignant disorders and may hence be used in identifying high-risk OPMD.
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http://dx.doi.org/10.1016/j.oraloncology.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880641PMC
December 2017

Improving margin revision: Characterization of tumor bed margins in early oral tongue cancer.

Oral Oncol 2017 12 1;75:184-188. Epub 2017 Nov 1.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Objectives: To improve margin revision, this study characterizes the number, fragmentation, and orientation of tumor bed margins (TBM) in patients with pT1-2 pN0 squamous cell carcinoma (SCC) of the oral tongue.

Materials And Methods: Pathology reports (n=346) were reviewed. TBM parameters were indexed. In Group 1 patients all margins were obtained from the glossectomy specimen and there were no TBM. In Revision Group/Group 2 (n=103), tumor bed was sampled to revise suboptimal margins identified by examination of the glossectomy specimen. In Group 3 (n=124), TBM were obtained before examination of the glossectomy specimen.

Results And Conclusions: Fewer TBMs were obtained per patient in Group 2 compared to Group 3 (57/103, 55% of patients with <3 vs. 117/124, 94%, ≥3 TBMs, respectively). The new margin surface was more frequently indicated in Group 2 compared to Group 3 (59/103, 57%, vs. 19/124, 15%, p<.001). If glossectomy specimen margins are accepted as the reference standard, then the TBM was 15% sensitive in Group 2 (95% confidence interval [CI], 7-29) and 32% sensitive in Group 3 (95% CI, 15-55). TBM fragmentation (23/103, 22% vs. 42/124, 34%) and frozen vs. permanent discrepancies (8/103, 3% vs. 3/124, 2%) were similar between Groups 2 and 3. The new margin surface was not indicated in 6 of 11 cases with discrepant frozen vs. permanent pathology findings, precluding judgment on final margin status. To facilitate the assessment of final margins, TBM should be represented by one tissue fragment with a marked new margin surface.
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http://dx.doi.org/10.1016/j.oraloncology.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774620PMC
December 2017

Smoking cessation is associated with improved survival in oropharynx cancer treated by chemoradiation.

Laryngoscope 2016 12 27;126(12):2733-2738. Epub 2016 Jun 27.

Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, New York, U.S.A.

Objectives/hypothesis: The effect of smoking and human papillomavirus (HPV) on overall survival (OS) of oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing concurrent chemotherapy (CCRT) remains unclear.

Study Design: Retrospective review.

Methods: Clinical characteristics of OPSCC patients treated between 2008 and 2015 with CCRT were abstracted from medical records. OS curves and multivariate cox proportional hazard ratios (HRs) were examined.

Results: Of 120 evaluable patients, 71% had HPV tumors. Median follow-up duration for the entire cohort was 41.5 months (range = 6-88 months). HPV current smokers experienced significantly worse 5-year OS (73% alive vs. 36% alive, P = .01) and there was a similar trend in HPV current smokers (66% alive vs. 31% alive, P = .28) compared to former/never smokers undergoing CCRT. In a multivariate cox proportional hazard model adjusted for age, gender, and overall tumor stage, HPV current smokers experienced nearly a fourfold increase in overall mortality in comparison to HPV never/former smokers (HR = 3.68, 95% CI = 1.35-10.0). Similarly, current smokers with HPV tumors (HR = 6.80, 95% CI = 1.11-41.67) had increased mortality compared to never/former smokers.

Conclusions: Current smoking is associated with poor prognosis, independent of HPV status, in CCRT-treated OPSCC patients. Current smoking produced an approximately four- to sevenfold increase in risk of mortality for HPV and HPV patients, respectively. Regardless of pack years and HPV status, efforts should be made to achieve smoking cessation before CCRT.

Level Of Evidence: 4. Laryngoscope, 126:2733-2738, 2016.
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http://dx.doi.org/10.1002/lary.26083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880216PMC
December 2016

Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib.

Cold Spring Harb Mol Case Stud 2015 Oct;1(1):a000380

Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;

Granular cell tumors are an uncommon soft tissue neoplasm. Malignant granular cell tumors comprise <2% of all granular cell tumors, are associated with aggressive behavior and poor clinical outcome, and are poorly understood in terms of tumor etiology and systematic treatment. Because of its rarity, the genetic basis of malignant granular cell tumor remains unknown. We performed whole-genome sequencing of one malignant granular cell tumor with metabolic response to pazopanib. This tumor exhibited a very low mutation rate and an overall stable genome with local complex rearrangements. The mutation signature was dominated by C>T transitions, particularly when immediately preceded by a 5' G. A loss-of-function mutation was detected in a newly recognized tumor suppressor candidate, BRD7. No mutations were found in known targets of pazopanib. However, we identified a receptor tyrosine kinase pathway mutation in GFRA2 that warrants further evaluation. To the best of our knowledge, this is only the second reported case of a malignant granular cell tumor exhibiting a response to pazopanib, and the first whole-genome sequencing of this uncommon tumor type. The findings provide insight into the genetic basis of malignant granular cell tumors and identify potential targets for further investigation.
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http://dx.doi.org/10.1101/mcs.a000380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850888PMC
October 2015

Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma.

J Biomed Opt 2016 Jan;21(1):18002

Roswell Park Cancer Institute, Department of Cell Stress Biology, Elm and Carlton Streets, Buffalo, New York 14263, United StatesbWright State University, Department of Biomedical, Industrial and Human Factors Engineering, 207 Russ Center, Dayton, Ohio 45.

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http://dx.doi.org/10.1117/1.JBO.21.1.018002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996863PMC
January 2016

Impact of Short-term 1,25-Dihydroxyvitamin D3 on the Chemopreventive Efficacy of Erlotinib against Oral Cancer.

Cancer Prev Res (Phila) 2015 Sep 22;8(9):765-76. Epub 2015 Jun 22.

Department of Pharmacology and Therapeutics. Roswell Park-Mazumdar Shaw Cancer Center Collaborative Research Program. Department of Oral Medicine and Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York.

Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, targeting EGFR for chemoprevention of head and neck squamous cell carcinomas (HNSCC) has received considerable attention. In the present study, we examined the impact of 1,25(OH)2D3, the active metabolite of the nutritional supplement vitamin D on the chemopreventive efficacy of the EGFR inhibitor, erlotinib, against HNSCC. Experimental studies were conducted in patient-derived xenografts (PDX) and the 4-nitroquinoline-1-oxide (4NQO) carcinogen-induced model of HNSCC. Short-term treatment (4 weeks) of PDX-bearing mice with 1,25(OH)2D3 and erlotinib resulted in significant inhibition of tumor growth. Noninvasive MRI enabled longitudinal monitoring of disease progression in the 4NQO model with 100% of control animals showing evidence of neoplastic lesions by 24 weeks. Among the experimental groups, animals treated with the combination regimen showed the greatest reduction in tumor incidence and volume (P < 0.05). Combination treatment was well tolerated and was not associated with any significant change in body weight. Histopathologic assessment revealed a significant reduction in the degree of dysplasia with combination treatment. Immunoblot analysis of whole tongue extracts showed downregulation of phospho-EGFR and phospho-Akt with the combination regimen. These results highlight the potential of 1,25(OH)2D3 to augment the efficacy of erlotinib against HNSCC. Further optimization of schedule and sequence of this combination regimen along with investigation into the activity of less calcemic analogues or dietary vitamin D is essential to fully realize the potential of this approach.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560661PMC
September 2015

Interdigitating dendritic cell sarcoma.

J Natl Compr Canc Netw 2015 Feb;13(2):128-32

From the Department of Medical Oncology and Department of Pathology, Roswell Park Cancer Institute; Department of Medicine, State University of New York; and Department of Head & Neck and Plastic & Reconstructive Surgery, Erie County Medical Center, Buffalo, New York.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare dendritic cell tumor with slightly more than 100 cases reported in the English literature. This report discusses a case of localized IDCS involving cervical lymph nodes and provides a literature review of clinicopathologic aspects and treatment outcomes.
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http://dx.doi.org/10.6004/jnccn.2015.0020DOI Listing
February 2015

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

Head Neck 2016 04 29;38 Suppl 1:E377-83. Epub 2015 Jun 29.

Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, New York.

Background: The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses.

Methods: A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response.

Results: Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD.

Conclusion: HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016.
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http://dx.doi.org/10.1002/hed.24003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499022PMC
April 2016

A highly curable lymphoma occurs preferentially in the proximal tibia of young patients.

Mod Pathol 2014 Nov 18;27(11):1430-1437. Epub 2014 Apr 18.

The presentation of two 19-year-old male subjects with stage I non-Hodgkin lymphoma in the proximal tibia prompted an extensive review of institutional and national databases to assess whether there is any statistical evidence that these reflected a previously overlooked syndromic pattern of presentation. The institutional records of a single institution were reviewed for presentation of non-Hodgkin lymphoma in the bone. The records of two additional institutions were reviewed for all reports of non-Hodgkin lymphoma in the tibia. Analysis was performed on data from Surveillance, Epidemiology, and End Results (SEER) dichotomized to bone presentation in the lower extremity versus other bones. Institutional databases included 20 patients with tibial presentation of lymphoma with a median age of 22.5 years (versus 42 for all bone lymphomas; P<0.001). Eighteen out of twenty patients had diffuse large B-cell lymphoma, and all patients aged ≤40 achieved remission and apparent cure. Distinctive and unusual features were a tendency for bilateral involvement of the tibia and sclerotic changes on X-ray. SEER data included 808 cases of bone lymphoma; the fraction of cases presenting in the lower extremity versus other bone sites is higher at ages ≤40 years (38% versus 19%; P<0.0001). Presentation in the lower extremity, as compared with other bone sites, confers 97% overall survival in patients aged ≤40 (versus 82%; P=0.01). This survival effect was independent of stage. In contrast, no significant difference in overall survival was identified for lower extremity versus non-lower extremity site for age >40. These data show a previously undescribed syndromic pattern of disease presentation: bone lymphoma in young patients is likely to present in the lower extremity-specifically the proximal tibia-has atypical sclerotic features on X-ray, is often bilateral, and has an excellent prognosis compared with bone lymphomas at other sites matched for stage and age.
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http://dx.doi.org/10.1038/modpathol.2014.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201907PMC
November 2014

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity.

Clin Cancer Res 2013 Dec 2;19(23):6605-13. Epub 2013 Oct 2.

Authors' Affiliations: Photodynamic Therapy Center at the Department of Cell Stress Biology, Departments of Head and Neck Surgery, Molecular and Cellular Biology, Biostatistics and Bioinformatics, Dentistry, and Pathology, Roswell Park Cancer Institute (RPCI), Buffalo, New York.

Purpose: The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction.

Experimental Design: Patients with histologically proven oral dysplasia, carcinoma in situ, or early-stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies used an HPPH dose of 4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of STAT3 were assessed as potential indicators of PDT effective reaction.

Results: Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and carcinoma in situ and 82% for squamous cell carcinomas (SCC) lesions at 140 J/cm(2). The responses in the carcinoma in situ/dysplasia cohort are not durable. The PDT-induced STAT3 cross-links is significantly higher (P = 0.0033) in SCC than in carcinoma in situ/dysplasia for all light doses.

Conclusion: HPPH-PDT is safe for the treatment of carcinoma in situ/dysplasia and early-stage cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to HPPH-PDT in comparison with premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT-mediated photoreaction.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911775PMC
December 2013

Human papillomavirus and tobacco use in tongue base cancers.

Ear Nose Throat J 2013 Aug;92(8):372-80

Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, N.Y., USA.

Human papillomavirus 16 (HPV-16) infection and tobacco use are associated with human oropharyngeal cancers. We conducted a study of the role of HPV and tobacco use in base of the tongue (BOT) cancers. DNA from 34 such cancers was subjected to HPV-16 and HPV-18-specific polymerase chain reaction analysis. Demographic and clinicopathologic data were obtained from each patient's medical record. HPV-16 was detected in 68% of tumors. Tobacco use was the only factor found to be significantly associated with HPV status. Tumors from 100% of patients who had never used tobacco tested positive for HPV, compared with only 56% of those who had ever used tobacco (Fisher exact test, p = 0.024). All tumors were associated with either tobacco use or HPV infection. These findings are consistent with the hypothesis that either tobacco use or HPV infection is necessary to the etiology of BOT tumors, and they suggest that tongue base carcinoma may be prevented by combining HPV vaccination with tobacco avoidance.
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http://dx.doi.org/10.1177/014556131309200812DOI Listing
August 2013

Vascular priming enhances chemotherapeutic efficacy against head and neck cancer.

Oral Oncol 2013 Sep 23;49(9):893-902. Epub 2013 Jul 23.

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Dentistry & Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Electronic address:

Purpose: The need to improve chemotherapeutic efficacy against head and neck squamous cell carcinomas (HNSCC) is well recognized. In this study, we investigated the potential of targeting the established tumor vasculature in combination with chemotherapy in head and neck cancer.

Methods: Experimental studies were carried out in multiple human HNSCC xenograft models to examine the activity of the vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in combination with chemotherapy. Multimodality imaging (magnetic resonance imaging, bioluminescence) in conjunction with drug delivery assessment (fluorescence microscopy), histopathology and microarray analysis was performed to characterize tumor response to therapy. Long-term treatment outcome was assessed using clinically-relevant end points of efficacy.

Results: Pretreatment of tumors with VDA prior to administration of chemotherapy increased intratumoral drug delivery and treatment efficacy. Enhancement of therapeutic efficacy was dependent on the dose and duration of VDA treatment but was independent of the chemotherapeutic agent evaluated. Combination treatment resulted in increased tumor cell kill and improvement in progression-free survival and overall survival in both ectopic and orthotopic HNSCC models.

Conclusion: Our results show that preconditioning of the tumor microenvironment with an antivascular agent primes the tumor vasculature and results in enhancement of chemotherapeutic delivery and efficacy in vivo. Further investigation into the activity of antivascular agents in combination with chemotherapy against HNSCC is warranted.
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http://dx.doi.org/10.1016/j.oraloncology.2013.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772633PMC
September 2013

Survival rates and prognostic factors for infiltrating salivary duct carcinoma: Analysis of 228 cases from the Surveillance, Epidemiology, and End Results database.

Head Neck 2014 May 7;36(5):694-701. Epub 2013 Oct 7.

Department of Head and Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, New York; Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, New York.

Background: The survival rates and prognostic factors for salivary duct carcinoma (SDC) are not clear.

Methods: Survival estimates and prognostic factors were evaluated for 228 patients with SDC identified from the Surveillance, Epidemiology, and End Results (SEER) database.

Results: Median overall survival (OS) duration for patients with SDC was 79 months and 5-year disease-specific survival (DSS) rate was 64%. Among patients with SDC with lymph node involvement, larger primary tumor size (>3 cm) was associated with twice the risk of death (p < .03). Factors predictive of improved DSS were age (p = .01), tumor size (p = .006), tumor grade (p = .02), and lymph node involvement (p < .001). Adjuvant radiotherapy did not improve survival when compared to surgery alone for early-stage (I-II) disease (p = .28).

Conclusion: Younger patients with SDC (<50 years) showed a better prognosis. Primary tumor size and lymph node involvement were independent and additive risk factors for poor prognosis. The role of adjuvant radiotherapy in the treatment of SDC needs to be explored further.
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http://dx.doi.org/10.1002/hed.23350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524549PMC
May 2014

Case study interpretation--Portland: Case 4. Acute leukemia of ambiguous lineage, unclassifiable.

Cytometry B Clin Cytom 2012 May 19;82(3):186-91. Epub 2012 Mar 19.

Department of Pathology and Laboratory Medicine, Roswell Park Cancer institute, Buffalo, New York 14263, USA.

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http://dx.doi.org/10.1002/cyto.b.21015DOI Listing
May 2012

Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, 1985-2010.

Oral Oncol 2011 Nov 3;47(11):1048-54. Epub 2011 Aug 3.

Department of Dentistry and MFP, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Human papillomavirus (HPV) types 16 and 18 are causally related to a sub-set of oral cavity and oropharyngeal squamous cell cancers. However, a clear estimate of the prevalence of HPV-16/18 in oral cavity and oropharyngeal dysplasia (OOPD) is not available. This literature review and meta-analysis was conducted to provide a prevalence estimate for HPV-16/18 in OOPD. Twenty-two studies that reported prevalence of HPV-16 and/or 18 in 458 OOPD lesions were analyzed. Meta-analysis was used to evaluate the prevalence of HPV-16/18 and logistic regression was used for stratified analysis by age, gender, and histological grade. The overall prevalence of HPV-16/18 in OOPD lesions was 24.5% [95% confidence interval (CI), 16.4-36.7%)]. The individual prevalence for HPV-16 alone was 24.4%. The prevalence of HPV-16/18 in oral cavity lesions alone was 25.3% (95% CI, 14.2-45.2%). The odds of detection of HPV-16/18 in dysplastic lesions in males were twice that of females [odds ratio (OR), 2.44]. HPV-16/18 were 3 times more common in dysplastic lesions (OR, 3.29; 95% CI, 1.95-5.53%) and invasive cancers (OR, 3.43; 95% CI, 2.07-5.69%), when compared to normal biopsies. There was no significant difference in HPV-16/18 rates between dysplastic lesions and cancers or between mild, moderate or severe dysplastic lesions. This meta-analysis provides a quantification of the prevalence of HPV types 16/18 in OOPD lesions. These results also support the assumption that HPV-16/18 infection occurs during the early phase of the oral cavity and oropharyngeal carcinogenesis.
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http://dx.doi.org/10.1016/j.oraloncology.2011.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640331PMC
November 2011

Improved survival following surgery and radiation therapy for olfactory neuroblastoma: analysis of the SEER database.

Radiat Oncol 2011 Apr 25;6:41. Epub 2011 Apr 25.

Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York, USA.

Background: Olfactory Neuroblastoma is a rare malignant tumor of the olfactory tract. Reports in the literature comparing treatment modalities for this tumor are limited.

Methods: The SEER database (1973-2006) was queried by diagnosis code to identify patients with Olfactory Neuroblastoma. Kaplan-Meier was used to estimate survival distributions based on treatment modality. Differences in survival distributions were determined by the log-rank test. A Cox multiple regression analysis was then performed using treatment, race, SEER historic stage, sex, age at diagnosis, year at diagnosis and SEER geographic registry.

Results: A total of 511 Olfactory Neuroblastoma cases were reported. Five year overall survival, stratified by treatment modality was: 73% for surgery with radiotherapy, 68% for surgery only, 35% for radiotherapy only, and 26% for neither surgery nor radiotherapy. There was a significant difference in overall survival between the four treatment groups (p < 0.01). At ten years, overall survival stratified by treatment modality and stage, there was no significant improvement in survival with the addition of radiation to surgery.

Conclusions: Best survival results were obtained for surgery with radiotherapy.
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http://dx.doi.org/10.1186/1748-717X-6-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098784PMC
April 2011

Small lymphocytic lymphoma obscuring microscopic tonsillar squamous cell carcinoma: an unknown occurrence with a known primary.

Head Neck Pathol 2012 Mar 1;6(1):125-9. Epub 2010 Dec 1.

Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Head and neck squamous cell carcinoma (HNSCC) often presents with cervical lymph node metastases and at times the primary tumor cannot be identified despite extensive workup. Lymphoma is the second most common neoplasm in the head and neck region but is seldom synchronous with HNSCC and rarely involves regional mucosal sites. We report herein a rare occurrence of tonsillar involvement by small lymphocytic lymphoma (SLL) incidentally detected during the workup for a cervical lymph node SCC metastasis of a 52-year-old non-smoker male. The microscopic human papillomavirus-positive SCC involving the tonsillar surface and crypts was obscured by SLL leading to the initial designation of 'unknown primary'. The occult HNSCC are likely explained by small tumor size, quality and quantity of sampling, thoroughness of endoscopic, radiological and pathological assessment or a combination of the above. The coexistence of another tumor such as lymphoma has not yet been reported as a confounding factor in the workup for cervical SCC metastasis. Since oropharyngeal SCC can be very small and Waldeyer's ring is a common site for lymphoma involvement, identification of such rare collision tumors requires pathologists' awareness, extensive sampling and occasionally ancillary studies for the accurate diagnosis and staging essential for the correct management.
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http://dx.doi.org/10.1007/s12105-010-0228-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311942PMC
March 2012

Autofluorescence-guided surveillance for oral cancer.

Cancer Prev Res (Phila) 2009 Nov;2(11):966-74

Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Early detection of oral premalignant lesions (OPL) and oral cancers (OC) is critical for improved survival. We evaluated if the addition of autofluorescence visualization (AFV) to conventional white-light examination (WLE) improved the ability to detect OPLs/OCs. Sixty high-risk patients, with suspicious oral lesions or recently diagnosed untreated OPLs/OCs, underwent sequential surveillance with WLE and AFV. Biopsies were obtained from all suspicious areas identified on both examinations (n = 189) and one normal-looking control area per person (n = 60). Sensitivity, specificity, and predictive values were calculated for WLE, AFV, and WLE + AFV. Estimates were calculated separately for lesions classified by histopathologic grades as low-grade lesions, high-grade lesions (HGL), and OCs. Sequential surveillance with WLE + AFV provided a greater sensitivity than WLE in detecting low-grade lesions (75% versus 44%), HGLs (100% versus 71%), and OCs (100% versus 80%). The specificity in detecting OPLs/OCs decreased from 70% with WLE to 38% with WLE + AFV. Thirteen of the 76 additional biopsies (17%) obtained based on AFV findings were HGLs/OCs. Five patients (8%) were diagnosed with a HGL/OC only because of the addition of AFV to WLE. In seven patients, additional HGL/OC foci or wider OC margins were detected on AFV. Additionally, AFV aided in the detection of metachronous HGL/OC in 6 of 26 patients (23%) with a history of previously treated head and neck cancer. Overall, the addition of AFV to WLE improved the ability to detect HGLs/OCs. In spite of the lower specificity, AFV + WLE can be a highly sensitive first-line surveillance tool for detecting OPLs/OCs in high-risk patients.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653312PMC
November 2009

Establishment and characterization of patient tumor-derived head and neck squamous cell carcinoma xenografts.

Cancer Biol Ther 2009 Dec 19;8(23):2275-83. Epub 2009 Dec 19.

Departments of Cancer Biology and Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY, USA.

The overall purpose of this study was to establish human head and neck squamous cell carcinoma (HNSCC) xenografts in mice by transplantation of surgical tumor tissue and to characterize the growth, histologic and vascular properties of these xenografts. Primary surgical specimens of HNSCC were xenografted into eight-to-twelve week old severe combined immunodeficiency (SCID) mice. Histologic features of primary HNSCC specimens, initial and established xenografts were compared for tumors established from three different head and neck subsites, namely, oral cavity, larynx and base of tongue (one tumor per site). Growth rates of xenografts were compared along with magnetic resonance imaging (MRI) measures of tumor vascularity and correlative CD31-immunostaining. Initial and established xenografts from all three sites demonstrated a squamous phenotype similar to the original patient tumor histology. Established xenografts of oral cavity and larynx exhibited increased keratinization (H&E) compared to initial xenografts and the primary tumor. No differences in tumor growth rates were observed between established xenografts from the different subsites. Xenografts established from SCC of the larynx exhibited increased microvessel density and lumen area (CD31 staining) along with enhanced permeability to the MR contrast agent compared to oral cavity and base of tongue tumors. Our results show that the combination of non-invasive imaging along with histologic evaluation of patient tumor xenografts offers a valuable platform for preclinical investigations in head and neck cancer. However, it is important to recognize the influence of tumor-host interactions on the histologic phenotype of transplanted tumors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906774PMC
http://dx.doi.org/10.4161/cbt.8.23.10137DOI Listing
December 2009

Chronic periodontitis and the incidence of head and neck squamous cell carcinoma.

Cancer Epidemiol Biomarkers Prev 2009 Sep;18(9):2406-12

Department of Oral Diagnostic Sciences, The State University of New York, Buffalo, New York 14214, USA.

Substantial evidence supports an association between chronic infections/inflammation, and cancer. The aim of this study was to assess the effect of chronic periodontitis on head and neck squamous cell carcinoma (HNSCC). The study population consisted of new patients at the Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute between 1999 and 2005. Cases were patients diagnosed with primary HNSCC. Controls were all patients seen during the same time period but negative for malignancy. Patients age <21 years, edentulous, immunocompromised, and those with history of cancer were excluded. Periodontitis was measured by alveolar bone loss (ABL) from panoramic radiographs by one examiner blind to cancer status. A total of 473 patients (266 cases and 207 controls) were included in the study. Each millimeter of ABL was associated with >4-fold increased risk of HNSCC (odds ratio, 4.36; 95% confidence interval, 3.16-6.01) after adjustment for age, gender, race/ethnicity, marital status, smoking status, alcohol use, and missing teeth. The strength of the association was greatest in the oral cavity, followed by oropharynx and larynx. The association persisted in subjects who never used tobacco and alcohol. There was a significant interaction between smoking and ABL (P = 0.03). Patients with periodontitis were more likely to have poorly differentiated oral cavity SCC than those without periodontitis (32.8% versus 11.5%; P = 0.038). This study suggests that chronic periodontitis is an independent risk factor for HNSCC and smoking modifies this association. These results have implications for practical and safe strategies for prevention, diagnosis, and treatment of HNSCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0334DOI Listing
September 2009

Subclinical chronic lymphocytic leukemia with atypical cutaneous presentation.

J Cutan Pathol 2011 Feb;38(2):236-40

Department of Pathology, University at Buffalo, State University of New York, Buffalo, NY, USA.

Chronic lymphocytic leukemia (CLL) involving skin is a rare but well-documented occurrence, mainly reported in advanced disease. In contrast, CLL presenting with skin lesions is exceedingly rare, only few reports existing to date. We report a 70-year-old man who presented with two non-pruritic, papular lesions on the lower abdomen and proximal thigh. Biopsies showed dense lymphohistiocytic infiltrates involving the reticular dermis and subcutis without epidermotropism consisting mostly of small, CD20 and PAX-5-positive B-cells expressing CD5, CD23, CD43 and BCL2. Numerous large B-cells were present in a T-cell, histiocyte-rich background. A staging bone marrow biopsy showed a clonal B-cell proliferation with typical CLL flow cytometry immunophenotyping but neither lymphadenopathy nor absolute lymphocytosis was present. Numerous B and T-cell cutaneous lymphoproliferative disorders can be associated with increased numbers of histiocytes occasionally masquerading as benign disorders. This was the case with our patient's lesions, originally interpreted as cutaneous Rosai-Dorfman disease. A high index of suspicion from both the pathologist and the dermatologist is essential in identifying these rare but probably underrecognized occurrences of early systemic lymphoproliferative disorders presenting as cutaneous lesions with an unexpected cellular composition.
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http://dx.doi.org/10.1111/j.1600-0560.2009.01402.xDOI Listing
February 2011

Idiosyncrasies of scalp melanoma.

Laryngoscope 2007 Aug;117(8):1354-8

Department of Head and Neck Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.

Objectives/hypothesis: Examine the accuracy of sentinel lymph node biopsy (SNB) in scalp melanoma (SM), patterns of nodal metastases, patient outcomes, and the utility of immunohistochemistry (IHC) in SNB evaluation.

Study Design: Retrospective.

Methods: There were 22 patients, 4 females and 18 males. Sentinel lymph nodes (SLN) were localized via preoperative lymphoscintigraphy, intraoperative gamma probe, and Lymphazurin injection. SLNs were stained with hematoxylin-eosin, S-100, HMB-45, Melan-A, micropthalmia transcription factor, and tyrosinase. SLNs were grouped into cervical (levels 1-5) and extracervical (parotid, suboccipital, retroauricular) regions.

Results: There were 13 posterior and 9 anterior SMs. The first SNB were mapped to the extracervical regions in 77% of posterior and 78% of anterior lesions. SLN number ranged from 1 to 5. Ten patients had positive SLNs (PSLN). Forty percent of the PSLN group had SLNs mapped in both cervical and extracervical sites. Six underwent completion lymphadenectomy, with no additional positive nodes identified. No significant difference between PSLN and negative sentinel node (NSLN) patients was seen when compared by SLN number, Breslow's thickness, tumor ulceration, and clinical outcomes. Mean follow-up was 35 months. One patient died of disease. One isolated regional recurrence occurred. Sixty percent of PSLN and 92% of NSLN patients were recurrence free at last follow-up. One distant metastasis occurred in the NSLN group, and one local, one regional, and two patients with distant metastases were in the PSLN group at the time of last follow-up. Additional IHC did not detect other metastases in the NSLN group.

Conclusions: SM is aggressive, as demonstrated by the high rate of SLN metastases, and there were no significant histopathologic factors in the primary tumor that predicted the presence of SLN metastases. SNB was accurate. The majority of first SLNs were localized in extracervical basins.
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http://dx.doi.org/10.1097/mlg.0b013e31806146e5DOI Listing
August 2007

Necrotizing sialometaplasia associated with bulimia: case report and literature review.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 Feb 7;103(2):e39-42. Epub 2006 Nov 7.

Department of Oral Diagnostic Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA.

Necrotizing sialometaplasia (NSM) is a self-limiting disorder affecting mainly the minor salivary glands. The significance of NSM resides in its clinical and histopathological resemblance to carcinoma. Few cases of NSM associated with eating disorders have been reported to date. We present here the clinical features and histomorphology of an additional case of bulimia-associated NSM closely mimicking an invasive carcinoma. A high index of suspicion and good communication between clinician and pathologist are essential in recognizing this entity and preventing unnecessary surgical therapy.
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http://dx.doi.org/10.1016/j.tripleo.2006.08.005DOI Listing
February 2007

Nuclear BCL-10 expression is common in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and does not correlate with p65 NF-kappaB activation.

Mod Pathol 2006 Jul 21;19(7):891-8. Epub 2006 Apr 21.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

B-cell lymphoma 10 (BCL-10) is expressed in the cytoplasm of normal germinal center and marginal zone B-cells and is involved in lymphocyte development and activation. Aberrant nuclear expression of BCL-10 occurs in a subset of extranodal marginal zone B-cell lymphomas (MALT lymphomas), primarily those with the t(1;14)(p22;q32) or t(11;18)(q21;q21). Little is known about BCL-10 expression in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM). We assessed for BCL-10 in 51 bone marrow (BM) specimens involved by LPL/WM using immunohistochemical methods. All patients had monoclonal IgM in serum. Extent of BM involvement was assessed using PAX-5/BSAP and CD20 immunostains and the pattern and percentage of B-cells positive for BCL-10 was determined. The p65 subunit of nuclear factor-kappa B (NF-kappaB), a molecule downstream of BCL-10, was also assessed immunohistochemically. Nuclear BCL-10 staining was present in 28/51 (55%) specimens. BCL-10 expression correlated with greater extent of BM involvement (P=0.001), but did not correlate with serum IgM paraprotein levels, type of immunoglobulin light chain, or clinical variables. Nuclear expression of the p65 subunit of NF-kappaB was detected in 17/50 (34%) specimens, suggesting that NF-kappaB is active in a subset of LPL/WM. p65 NF-kappaB activation did not correlate with nuclear BCL-10 immunostaining. Cytogenetic analysis in 29 cases showed no evidence of the t(1;14) or t(11;18). These results indicate that nuclear BCL-10 expression is common in LPL/WM and does not correlate with MALT lymphoma-associated translocations or p65 NF-kappaB nuclear staining.
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http://dx.doi.org/10.1038/modpathol.3800609DOI Listing
July 2006

inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases.

Am J Clin Pathol 2005 Nov;124(5):807-14

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Blast phase (BP) in chronic myelogenous leukemia (CML) frequently is accompanied by cytogenetic abnormalities in addition to t(9;22)(q34;q11.2). We describe 5 patients with CML in blast phase (CML-BP) in which t(9;22) and inv(16)(p13q22) were identified by conventional cytogenetics, with confirmation of BCR-ABL and CBFss-MYH11 by fluorescence in situ hybridization. The morphologic findings at the time of BP resembled de novo acute myeloid leukemia (AML) carrying inv(16)(p13q22), with abnormal eosinophils in the bone marrow and monocytosis in the peripheral blood in all cases. In 1 patient, inv(16)(p13q22) and abnormal eosinophils were detected in the bone marrow 2 months before CML-BP. The clinical course of these patients was similar to patients with CML-BP without evidence of inv(16)(p13q22). These cases illustrate that inv(16)(p13q22) is a form of cytogenetic evolution that rarely occurs in patients with CML at the time of BP. In this setting, unlike de novo AML, inv(16)(p13q22) in CML-BP is not associated with a favorable prognosis.
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http://dx.doi.org/10.1309/3HFE-16DK-MB1D-BFMNDOI Listing
November 2005