Michael J. Kaplan

All Publications

• Probe-based fluorescence dosimetry of an antibody-dye conjugate to identify head and neck cancer as a first step to fluorescence-guided tissue preselection for pathological assessment. Head & neck Nishio, N., van Keulen, S., van den Berg, N. S., Lu, G., LaRochelle, E. P., Davis, S. C., Martin, B. A., Fakurnejad, S., Zhou, Q., Birkeland, A. C., Kaplan, M. J., Divi, V., Colevas, A. D., Pogue, B. W., Rosenthal, E. L. 2019

  Abstract

  BACKGROUND: Despite the rapid growth of fluorescence imaging, accurate sampling of tissue sections remains challenging. Development of novel technologies to improve intraoperative assessment of tissue is needed.METHODS: A novel contact probe-based fluorescence dosimeter device, optimized for IRDye800CW quantification, was developed. After evaluation of the device in a phantom setup, its clinical value was defined ex vivo in patients with head and neck squamous cell carcinoma who received panitumumab-IRDye800CW.RESULTS: Ten patients were enrolled with a total of 216 data points obtained. Final histopathology showed tumor in 119 spots and normal tissue in 97 spots. Fluorescence-to-excitation ratios in tumor tissue were more than three times higher than those in normal tissue. The area under the curve was 0.86 (95% CI: 0.81-0.91) for tumor detection.CONCLUSIONS: Fluorescence-guided tissue preselection using a fluorescence dosimeter could have substantial impact on tissue sampling for frozen section analysis and potentially reduce sampling errors.

  View details for DOI 10.1002/hed.25964

  View details for PubMedID 31571335

• Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Nishio, N., van den Berg, N. S., van Keulen, S., Martin, B. A., Fakurnejad, S., Zhou, Q., Lu, G., Chirita, S. U., Kaplan, M. J., Divi, V., Colevas, A. D., Rosenthal, E. L. 2019

  Abstract

  PURPOSE: To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.PROCEDURES: Patients (n=24) received either 0.5 or 1.0mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.RESULTS: A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate-strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R2=0.42) and for dose/weight (mg/kg) (R2=0.54). Results indicated that the optimal MFI was at approximately 50mg for fixed dose and 0.75mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2days (vs. 3days or more, p<0.05).CONCLUSIONS: Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.

  View details for PubMedID 31054001

• Depth of invasion alone as a prognostic factor in low-risk early-stage oral cavity carcinoma. The Laryngoscope Kozak, M. M., Shah, J., Chen, M., Schaberg, K., von Eyben, R., Chen, J. J., Bui, T., Kong, C., Kaplan, M., Divi, V., Hara, W. 2019

  Abstract

  OBJECTIVES: To evaluate the significance of increasing depth of invasion (DOI) as the sole risk factor for recurrence in patients with low-risk early-stage oral cavity squamous cell carcinoma (OCSCC).METHODS: We retrospectively reviewed 560 patients with OCSCC treated at our institution between 2003 and 2013. Patients were included if they had low-risk early-stage OCSCC treated with surgical resection ± neck dissection and no adjuvant therapy. Low risk was defined as absence of positive or close margins, lymphovascular invasion, perineural invasion, and positive lymph nodes. Patients with tumor (T)3-T4 disease were excluded. Pathology specimens were independently re-reviewed by two board-certified pathologists to confirm proper measurement of DOI. Kaplan-Meier and Cox proportional hazards regression analyses were performed to identify factors predictive for recurrence as well as progression-free survival (PFS) and overall survival (OS).RESULTS: A total of 126 patients with low-risk early-stage T1-2N0 OCSCC were included. Median follow-up time was 42.5 months and median DOI was 4 mm. There was no significant difference in incidence of local (P = 0.95), regional (P = 0.81), or distant recurrence (P = 0.96) among patients with DOI < 4 mm versus ≥4 mm. On multivariable analysis, DOI was significant for both PFS (P = 0.03) and OS (P = 0.002).CONCLUSION: In this study, we show that in the absence of other high-risk pathologic features, DOI ≥ 4 mm does not portend for increased incidence of local, regional, or distant relapse in patients treated with surgery alone; however, increasing DOI is a marker for worse PFS and OS in patients with low-risk, early-stage OCSCC.LEVEL OF EVIDENCE: 4. Laryngoscope, 2019.

  View details for DOI 10.1002/lary.27753

  View details for PubMedID 30604435

• Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence CANCER RESEARCH Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. J., Gomez, A. J., Holsinger, F., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018; 78 (17): 5144–54

  View details for DOI 10.1158/0008-5472.CAN-18-0878

  View details for Web of Science ID 000443753700029

• Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence. Cancer research Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. S., Gomez, A. J., Holsinger, F. C., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018

  Abstract

  For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor-mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. 21 adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n=3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n=5) received 0.5mg/kg, cohort 2B (n=7) received 1mg/kg, and cohort 3 (n=6) received 50 mg. Patients were followed 30 days post-infusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2-3, compared to ex vivo specimen imaging TBR of 5-6. We obtained clear differentiation between tumor and normal tissue, with a three-fold signal difference between positive and negative specimens (p<0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy which are otherwise less amenable to image guidance.

  View details for PubMedID 29967260

• Panitumumab-IRDye800 as an Optical Agent for Image-Guided Surgery in Patients With Squamous Cell Carcinoma Gao, R. W., Teraphongphom, N., van den Berg, N. S., Hong, S., Martin, B. A., Divi, V., Kaplan, M. J., Ertsey, R., Oberhelman, N. J., Lu, G., Kong, C. S., Colevas, A. D., Rosenthal, E. L. ELSEVIER SCIENCE INC. 2018: 1312–13

  View details for Web of Science ID 000428145600052

• IRX-2 natural cytokine biologic for immunotherapy in patients with head and neck cancers ONCOTARGETS AND THERAPY Wolf, G. T., Moyer, J. S., Kaplan, M. J., Newman, J. G., Egan, J. E., Berinstein, N. L., Whiteside, T. L. 2018; 11: 3731–46

  Abstract

  Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy characterized by tumor-driven immune-system abnormalities that contribute to disease progression. For patients with surgically resectable HNSCC, treatment is often curative surgery followed by irradiation or chemoradiation in high-risk settings to reduce the risk of recurrence. Poor survival and considerable morbidity of current treatments suggest the need for new therapeutic modalities that can improve outcomes. Defects in antitumor immunity of HNSCC patients include suppressed dendritic cell (DC) maturation, deficient antigen-presenting cell function, compromised natural killer (NK)-cell cytotoxicity, increased apoptosis of activated T lymphocytes, and impaired immune-cell migration to tumor sites. Strategies for relieving immunosuppression and restoring antitumor immune functions could benefit HNSCC patients. IRX-2 is a primary cell-derived biologic consisting of physiologic levels of T-helper type 1 cytokines produced by stimulating peripheral blood mononuclear cells of normal donors with phytohemagglutinin. The primary active components in IRX-2 are IL2, IL1β, IFNγ, and TNFα. In vitro, IRX-2 acts on multiple immune-system cell types, including DCs, T cells, and NK cells, to overcome tumor-mediated immunosuppression. In clinical settings, IRX-2 is administered as part of a 21-day neoadjuvant regimen, which includes additional pharmacologic agents (low-dose cyclophosphamide, indomethacin, and zinc) to promote anticancer immunoresponses. In a Phase IIA trial in 27 patients with surgically resectable, previously untreated HNSCC, neoadjuvant IRX-2 increased infiltration of T cells, B cells, and DCs into tumors and was associated with radiological reductions in tumor size. Event-free survival was 64% at 2 years, and overall 5-year survival was 65%. Follow-up and data analysis are under way in the multicenter, randomized, Phase IIB INSPIRE trial evaluating the IRX-2 regimen as a stand-alone therapy for activating the immune system to recognize and attack tumors.

  View details for PubMedID 29988729

• Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers THERANOSTICS Gao, R. W., Teraphongphom, N., de Boer, E., van den Berg, N. S., Divi, V., Kaplan, M. J., Oberhelman, N. J., Hong, S. S., Capes, E., Colevas, A., Warram, J. M., Rosenthal, E. L. 2018; 8 (9): 2488–95

  Abstract

  Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.

  View details for PubMedID 29721094

• The INSPIRE trial: A randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity Wolf, G. T., Patel, M., Erman, A., Newman, J. G., Krempl, G., Nieva, J., Bell, R., Kaplan, M., Kraus, D., Moyer, J., Panwar, A., Valentino, J. AMER ASSOC CANCER RESEARCH. 2017

  View details for Web of Science ID 000416946500047

• Clinical Outcomes in Elderly Patients Treated for Oral Cavity Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, J., Shah, J. L., Harris, J. P., Bui, T. T., Schaberg, K., Kong, C. S., Kaplan, M. J., Divi, V., Schoppy, D., Quynh-Thu Le, Hara, W. Y. 2017; 98 (4): 775–83

  Abstract

  Oral cavity squamous cell carcinoma (OCSCC) commonly occurs in elderly patients. This study explores the clinical outcomes in elderly patients with OCSCC based on their functional status and clinical comorbidities.We retrospectively reviewed 180 patients aged ≥70 who were treated with definitive intent with surgery followed by adjuvant therapy if indicated for newly diagnosed OCSCC from 1998 to 2013. Pathology review was conducted, and Eastern Cooperative Oncology Group (ECOG) performance status and the Head and Neck Charlson Comorbidity Index (HN-CCI) were assessed. We performed Kaplan-Meier analyses and cumulative incidence estimates to assess overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LRR). Univariate and multivariate analyses were used to test age, adjuvant therapy, adverse pathologic features, ECOG status, and HN-CCI status as predictors.The median age was 80 years (range, 70-95 years), with a median follow-up time of 23 months. The median OS was 18 months and 46 months for patients aged 70 to 84 and ≥85, respectively (P=.0017). The LRR was 24% at 1 year and 30% at 2 years for all patients. On univariate analysis, ECOG score ≥2 (hazard ratio [HR] = 1.96; confidence interval [CI] 1.19-3.21; P=.008) and HN-CCI score ≥2 (HR=1.97; CI 1.17-3.34; P=.011) were predictors of worse OS. On multivariate analysis, HN-CCI score was a better predictor of OS, PFS, and LRR than was ECOG score. Predictors of worse OS were age ≥85 (HR=1.78; CI 1.07-2.96; P=.026), HN-CCI score of ≥2 (HR=2.21; CI 1.20-4.08; P=.011), and adverse features (HR=2.35; CI 1.34-4.13; P=.003). Adjuvant therapy did not have a significant impact on OS or LRR for patients with adverse features even though 48% of them did not receive it.Elderly patients with good health and performance status may live long enough to experience disease progression from OCSCC. ECOG and HN-CCI scores may be useful to evaluate the candidacy of elderly patients for adjuvant therapy. However, the benefit of adjuvant therapy in this population remains elusive and should be investigated prospectively.

  View details for PubMedID 28602409

• BRAF inhibitor therapy of primary ameloblastoma ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A., West, R. B. 2016; 122 (4): 518–19

  View details for PubMedID 27651290

• Design and rationale of a prospective, multi-institutional registry for patients with sinonasal malignancy. Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W., Colevas, A. D., Le, Q., Berry, G. J., Hwang, P. H. 2016; 126 (9): 1977-1980

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

  View details for PubMedID 27283472

• Faster Triage of Veterans With Head and Neck Cancer. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Kligerman, M., Asaly, A., Kwan, M., Kaplan, M., Fee, W. E., Yuan, A., Benedam-Lenrow, E., Song, Y., Pham, R., Sirjani, D. 2016; 33 (Suppl 5): 24S–29S

  Abstract

  High-risk patients with a growing mass require proper assessment, including a thorough history, physical examination, and fine-needle aspiration for diagnosis.

  View details for PubMedID 30766220

• BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY Tan, S., Pollack, J. R., Kaplan, M. J., Colevas, A. D., West, R. B. 2016; 122 (1): E5-E7

  Abstract

  Molecular characterization of ameloblastoma has indicated a high frequency of driver mutations in BRAF and SMO. Preclinical data suggest that Food and Drug Administration-approved BRAF-targeted therapies may be immediately relevant for patients with ameloblastoma positive for the BRAF V600E mutation.A neoadjuvant treatment regime of dabrafenib was given to a patient with recurrent BRAF-mutant mandibular ameloblastoma. The patient subsequently underwent left mandible composite resection of the tumor and pathologic evaluation of treatment response.The ameloblastoma had a slow but dramatic response with >90% tumor volume reduction. The inner areas of the tumor underwent degeneration and squamous differentiation, and intact ameloblastoma was present in the outer areas associated with bone.Targeted neoadjuvant therapy for ameloblastoma may be useful in certain clinical settings of primary ameloblastoma. These might include tumors of advanced local stage when a neoadjuvant reduction could alter the extent of surgery and instances of local recurrence when surgical options are limited.

  View details for DOI 10.1016/j.oooo.2015.12.016

  View details for Web of Science ID 000377426600002

  View details for PubMedID 27209484

• Design and rationale of a prospective multi-institutional registry for patients with sinosodal malignancy The Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W. Y., Colevas, A. D., Le, Q. T., Berry, G. J., Hwang, P. H. 2016

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

• A prospective study of electronic quality of life assessment using tablet devices during and after treatment of head and neck cancers. Oral oncology Pollom, E. L., Wang, E., Bui, T. T., Ognibene, G., von Eyben, R., Divi, V., Sunwoo, J., Kaplan, M., Dimitri Colevas, A., Le, Q., Hara, W. Y. 2015; 51 (12): 1132-1137

  Abstract

  Electronic data collection is increasingly used for quality of life (QOL) assessments in the field of oncology. It is important to assess the feasibility of these new data capture technologies.Patients at our institution who were 18years or older with a pathological diagnosis of head and neck cancer were prospectively enrolled. Each patient completed two questionnaires [EORTC-QLQ-C30 and EORTC-QLQ-H&N35] administered on a touch-screen tablet device (iPad™) at initial consult, during treatment, at the completion of treatment and at each subsequent follow up visit for one year after treatment.A total of 50 patients were included in this study. Although all patients completed the surveys at the initial consult, 86% of initially enrolled patients completed surveys at the end of radiation treatment, and 48% of initially enrolled patients completed surveys by the fourth follow-up visit. Average time to complete the survey for all patients over all time points was 9.8min (standard deviation 6.1). Age as a continuous variable was significantly associated with time for survey completion (p<0.001), with older age associated with longer survey completion times.QOL assessment using tablet devices in head and neck cancer patients is feasible, but may be more challenging in elderly patients. Patients ⩾70years old may benefit from more assistance with electronic forms and should be allotted more time for completing tablet-based QOL surveys.

  View details for DOI 10.1016/j.oraloncology.2015.10.003

  View details for PubMedID 26475062

• Outcomes of elderly patients treated for oral cavity squamous cell carcinoma Shah, J., Kaplan, M., Colevas, A., Quynh-Thu Le, Hara, W. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901393

• Low pre-operative absolute monocyte count to predict overall survival benefit for oral cavity squamous cell carcinoma Bui, T., Shah, J., Kaplan, M., Colevas, A., Quynh-Thu Le, Hara, W. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901394

• CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget Murillo-Sauca, O., Chung, M. K., Shin, J. H., Karamboulas, C., Kwok, S., Jung, Y. H., Oakley, R., Tysome, J. R., Farnebo, L. O., Kaplan, M. J., Sirjani, D., Divi, V., Holsinger, F. C., Tomeh, C., Nichols, A., Le, Q. T., Colevas, A. D., Kong, C. S., Uppaluri, R., Lewis, J. S., Ailles, L. E., Sunwoo, J. B. 2014; 5 (16): 6854-6866

  Abstract

  Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.

  View details for PubMedID 25149537

• Radiotherapy for adenoid cystic carcinomas of the head and neck: clinical outcomes and patterns of failure JOURNAL OF RADIATION ONCOLOGY Shultz, D. B., Zeidan, Y. H., Murphy, J. D., Hara, W., Kaplan, M. J., Le, Q., Chang, D. T. 2014; 3 (1): 49–56

  View details for DOI 10.1007/s13566-013-0098-3

  View details for Web of Science ID 000218741800005

• Long-Term Outcomes of Surgery Followed by Radiation Therapy for Minor Salivary Gland Carcinomas LARYNGOSCOPE Zeidan, Y. H., Shultz, D. B., Murphy, J. D., Chan, C., Kaplan, M. J., Colevas, A. D., Kong, C., Chang, D. T., Le, Q. 2013; 123 (11): 2675-2680

  Abstract

  Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.Retrospective cohort study.We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy.Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival.Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control.

  View details for DOI 10.1002/lary.24081

  View details for PubMedID 23553253

• Radiotherapy for nonadenoid cystic carcinomas of major salivary glands. American journal of otolaryngology Chung, M. P., Tang, C., Chan, C., Hara, W. Y., Loo, B. W., Kaplan, M. J., Fischbein, N., Le, Q., Chang, D. T. 2013; 34 (5): 425-430

  Abstract

  To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients ≥65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed ≥grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

  View details for DOI 10.1016/j.amjoto.2013.03.007

  View details for PubMedID 23583094

• Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. American journal of clinical oncology Tang, C., Fischbein, N. J., Murphy, J. D., Chu, K. P., Bavan, B., Dieterich, S., Hara, W., Kaplan, M. J., Colevas, A. D., Le, Q. 2013; 36 (3): 293-298

  Abstract

  : To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI).: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns.: At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation.: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

  View details for DOI 10.1097/COC.0b013e3182468019

  View details for PubMedID 22547009

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence. Cancer Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Le, Q., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for PubMedID 23225544

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence CANCER Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Quynh-Thu Le, Q. T., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for Web of Science ID 000316811900010

• CD44+cells have cancer stem cell-like properties in nasopharyngeal carcinoma INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Janisiewicz, A. M., Shin, J. H., Murillo-Sauca, O., Kwok, S., Quynh-Thu Le, Q. T., Kong, C., Kaplan, M. J., Sunwoo, J. B. 2012; 2 (6): 465-470

  Abstract

  A subpopulation of cells within a tumor appears to have the exclusive ability to initiate tumors, self-renew, and differentiate. These "cancer stem cells" (CSCs) are CD44(+) in several epithelial malignancies. We examined the potential of CD44 to identify the CSC population in nasopharyngeal carcinoma (NPC).C666, an Epstein-Barr virus-positive (EBV(+) ) human NPC cell line, was stained for CD44 and sorted by fluorescence-activated cell sorting (FACS). CD44(+) and CD44(-) subpopulations were evaluated for (1) proliferative potential, (2) ability to differentiate, (3) expression of markers of epithelial-to-mesenchymal transition (EMT) and EBV genes, and (4) the ability to initiate tumors in vivo. Immunocompromised mice were injected with CD44(+) and CD44(-) populations to assess the tumor-initiating capacity. Immunohistochemistry for CD44 was performed on an 87-patient tissue microarray (TMA), and clinical correlations were examined.Heterogeneous expression of CD44 was seen among C666 cells. CD44(+) cells differentiated into CD44(-) cells, indicating a hierarchical relationship. Further, CD44(+) cells exhibited a more robust tumor-initiating capacity in the xenograft model. However, no differences were seen in proliferation rates in vitro, EBV gene expression, or expression of EMT markers between CD44(+) and CD44(-) subsets. Patient tumors were heterogeneous for CD44 staining, and a trend toward an association between CD44 expression and clinical outcome was observed.NPC contains a CD44(+) subpopulation with features consistent with CSCs. There was a trend toward an association between CD44 expression within NPC tumors and decreased time to local failure/relapse in patients.

  View details for DOI 10.1002/alr.21068

  View details for PubMedID 22887934

• Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 243–51

  Abstract

  To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients.Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade ≥3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8 patients (15%). Six patients had Grade ≥3 late toxicity including one optic toxicity.IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

  View details for DOI 10.1016/j.ijrobp.2011.05.044

  View details for PubMedID 22019239

• Targeted endoscopic salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Ho, A. S., Kaplan, M. J., Fee, W. E., Yao, M., Sunwoo, J. B., Hwang, P. H. 2012; 2 (2): 166-173

  Abstract

  Despite modern radiotherapy and open surgical techniques, treatment of recurrent nasopharyngeal carcinoma (NPC) remains challenging, with substantial morbidity involved. Targeted endoscopic nasopharyngectomy was evaluated as a viable oncologic alternative to open nasopharyngectomy or radiation for recurrent NPC.Thirteen patients who underwent endoscopic nasopharyngectomy for recurrent NPC between August 2005 and August 2010 were retrospectively reviewed. Average age at surgery was 55.7 years, with mean follow-up period 24.2 months. Two-year disease-free survival, 2-year overall survival, margin status, and complication rate were measured.Including resections for subsequent recurrences, 19 endoscopic procedures were performed with curative intent. Mean operating room (OR) time was 278 minutes, mean estimated blood loss was 197 mL, and mean length of hospitalization was 1.0 days. Negative margins were obtained in 78.9% of procedures: positive margins involved the parapharyngeal space, oropharynx, fossa of Rosenmuller, and infratemporal fossa. Stereotactic radiation was given postoperatively for localized positive margins. Four patients required repeat endoscopic nasopharyngectomy for re-recurrence, despite having their margins cleared or controlled with adjuvant treatment. Two-year local disease-free and overall survival rates were 69.2% and 100.0%, respectively. The overall minor complication rate was 52.6%, with no major complications.Targeted endoscopic nasopharyngectomy is beneficial in locally recurrent NPC, with favorable morbidity and complication rates. Endoscopic surveillance and serial imaging together facilitate the early identification of re-recurrences, which often may be treated with additional directed resection. Postoperative stereotactic radiation may serve as an appropriate adjunct modality for disease control at positive margins.

  View details for DOI 10.1002/alr.20111

  View details for PubMedID 22170783

• FREQUENCY OF CELLS EXPRESSING CD44, A HEAD AND NECK CANCER STEM CELL MARKER: CORRELATION WITH TUMOR AGGRESSIVENESS HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Joshua, B., Kaplan, M. J., Doweck, I., Pai, R., Weissman, I. L., Prince, M. E., Ailles, L. E. 2012; 34 (1): 42-49

  Abstract

  We previously identified by flow cytometry a Lineage-CD44+ (Lin-CD44+) subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma (HNSCC). We now correlate clinical and histologic factors with Lin-CD44+ cell frequency.The study included 31 patients with HNSCC, of whom 87% had stage IV disease. The frequency of Lin-CD44+ cells and the success of xenografting patient tumors in mice were correlated with clinical and pathologic data.The mean frequency of Lin-CD44+ cells was 25% (0.4%-81%). It was 36% in patients who had recurrence versus 15% for those without recurrence (p = .04). Successful xenograft implantation occurred in 53%. Seventy-five percent of patients with successful xenografts had recurrence versus 21% of patients with unsuccessful xenografts (p = .003).Successful xenograft implantation and a high frequency of Lin-CD44+ cells correlate with known poor prognostic factors such as advanced T classification and recurrence. These findings may support the stem cell concept in HNSCC.

  View details for DOI 10.1002/hed.21699

  View details for PubMedID 21322081

• A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272

  Abstract

  To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

  View details for DOI 10.1158/1078-0432.CCR-11-0179

  View details for PubMedID 21998334

• NOVEL NEOADJUVANT IMMUNOTHERAPY REGIMEN SAFETY AND SURVIVAL IN HEAD AND NECK SQUAMOUS CELL CANCER HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Wolf, G. T., Fee, W. E., Dolan, R. W., Moyer, J. S., Kaplan, M. J., Spring, P. M., Suen, J., Kenady, D. E., Newman, J. G., Carroll, W. R., Gillespie, M. B., Freeman, S. M., Baltzer, L., Kirkley, T. D., Brandwein, H. J., Hadden, J. W. 2011; 33 (12): 1666-1674

  Abstract

  Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity.Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection.Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI.Immunotherapy regimen was tolerated. Survival results are encouraging.

  View details for DOI 10.1002/hed.21660

  View details for Web of Science ID 000297850400002

  View details for PubMedID 21284052

• Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity RADIOTHERAPY AND ONCOLOGY Murphy, J. D., Chisholm, K. M., Daly, M. E., Wiegner, E. A., Truong, D., Iagaru, A., Maxim, P. G., Loo, B. W., Graves, E. E., Kaplan, M. J., Kong, C., Le, Q. 2011; 101 (3): 356-361

  Abstract

  To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R(2) range 0.29-0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R(2)=0.63).Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.

  View details for DOI 10.1016/j.radonc.2011.05.040

  View details for PubMedID 21665308

• INTENSITY-MODULATED RADIOTHERAPY FOR ORAL CAVITY SQUAMOUS CELL CARCINOMA: PATTERNS OF FAILURE AND PREDICTORS OF LOCAL CONTROL INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Quynh-Thu Le, Q. T., Kozak, M. M., Maxim, P. G., Murphy, J. D., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Chang, D. T. 2011; 80 (5): 1412-1422

  Abstract

  Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients.Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks).Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade ≥ 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04).Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

  View details for DOI 10.1016/j.ijrobp.2010.04.031

  View details for PubMedID 20675073

• INTENSITY-MODULATED RADIOTHERAPY FOR LOCALLY ADVANCED CANCERS OF THE LARYNX AND HYPOPHARYNX HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Daly, M. E., Le, Q., Jain, A. K., Maxim, P. G., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Colevas, A. D., Pinto, H., Chang, D. T. 2011; 33 (1): 103-111

  Abstract

  Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

  View details for DOI 10.1002/hed.21406

  View details for PubMedID 20848427

• Transoral Robotic Surgery (TORS): The Natural Evolution of Endoscopic Head and Neck Surgery KAPLAN ARTICLE REVIEWED ONCOLOGY-NEW YORK Kaplan, M. J., Damrose, E. J. 2010; 24 (11): 1022-1030

  View details for Web of Science ID 000293341200008

  View details for PubMedID 21155452

• HIGHER INCIDENCE OF HEAD AND NECK CANCERS AMONG VIETNAMESE AMERICAN MEN IN CALIFORNIA HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Filion, E. J., McClure, L. A., Huang, D., Seng, K., Kaplan, M. J., Colevas, A. D., Gomez, S. L., Chang, E. T., Le, Q. 2010; 32 (10): 1336-1344

  Abstract

  Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey.Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women.The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.

  View details for DOI 10.1002/hed.21330

  View details for Web of Science ID 000282707500008

  View details for PubMedID 20091688

  View details for PubMedCentralID PMC4349526

• Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 NATURE Boiko, A. D., Razorenova, O. V., van de Rijn, M., Swetter, S. M., Johnson, D. L., Ly, D. P., Butler, P. D., Yang, G. P., Joshua, B., Kaplan, M. J., Longaker, M. T., Weissman, I. L. 2010; 466 (7302): 133-U155

  Abstract

  The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and re-suspended in a matrigel vehicle were implanted into T-, B- and natural-killer-deficient Rag2(-/-)gammac(-/-) mice. The CD271(+) subset of cells was the tumour-initiating population in 90% (nine out of ten) of melanomas tested. Transplantation of isolated CD271(+) melanoma cells into engrafted human skin or bone in Rag2(-/-)gammac(-/-) mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271(-) cells. We also show that in mice, tumours derived from transplanted human CD271(+) melanoma cells were capable of metastatsis in vivo. CD271(+) melanoma cells lacked expression of TYR, MART1 and MAGE in 86%, 69% and 68% of melanoma patients, respectively, which helps to explain why T-cell therapies directed at these antigens usually result in only temporary tumour shrinkage.

  View details for DOI 10.1038/nature09161

  View details for PubMedID 20596026

• INTENSITY-MODULATED RADIOTHERAPY IN THE TREATMENT OF OROPHARYNGEAL CANCER: CLINICAL OUTCOMES AND PATTERNS OF FAILURE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Le, Q., Maxim, P. G., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Pinto, H., Chang, D. T. 2010; 76 (5): 1339-1346

  Abstract

  To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

  View details for DOI 10.1016/j.ijrobp.2009.04.006

  View details for PubMedID 19540068

• Metastatic Squamous Cell Carcinoma Presenting as Diffuse and Punctate Cervical Lymph Node Calcifications Sonographic Features and Utility of Sonographically Guided Fine-Needle Aspiration Biopsy JOURNAL OF ULTRASOUND IN MEDICINE Shin, L. K., Fischbein, N. J., Kaplan, M. J., Jeffrey, R. B. 2009; 28 (12): 1703-1707

  Abstract

  The purpose of this series was to show the sonographic appearance of calcified cervical lymph nodes and the utility of sonographically guided fine-needle aspiration biopsy (FNAB) in the setting of metastatic squamous cell carcinoma (SCC).Two cases of confirmed metastatic SCC to cervical lymph nodes were identified. Sonography and sonographically guided FNAB were performed in both cases with positron emission tomography (PET)/computed tomography (CT) correlation.In case 1, sonography identified a diffusely calcified, avascular cervical lymph node. Positron emission tomography/CT suggested granulomatous disease as a cause for hypermetabolism; however, sonographically guided FNAB identified metastatic SCC. In the second case, FNAB initially performed without sonographic guidance did not show malignancy. Subsequent FNAB with sonographic guidance identified an abnormal cervical lymph node with focal calcifications and internal color Doppler flow. Metastatic SCC was diagnosed on histopathologic examination. Subsequent PET/CT confirmed multiple punctate calcifications in a hypermetabolic lymph node.Calcifications in cervical lymph nodes from metastatic SCC are very rare. These 2 cases show the variable sonographic appearances and the utility of sonographically guided FNAB in establishing the correct diagnosis.

  View details for Web of Science ID 000272375100015

  View details for PubMedID 19933485

• Association of reactive oxygen species levels and radioresistance in cancer stem cells NATURE Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L., Clarke, M. F. 2009; 458 (7239): 780-U123

  Abstract

  The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

  View details for DOI 10.1038/nature07733

  View details for PubMedID 19194462

• Excellent local control with stereotactic radiotherapy boost after external beam radiotherapy in patients with nasopharyngeal carcinoma 87th Annual Meeting of the American-Radium-Society Hara, W., Loo, B. W., Goffinet, D. R., Chang, S. D., Adler, J. R., Pinto, H. A., Fee, W. E., Kaplan, M. J., Fischbein, N. J., Le, Q. ELSEVIER SCIENCE INC. 2008: 393–400

  Abstract

  To determine long-term outcomes in patients receiving stereotactic radiotherapy (SRT) as a boost after external beam radiotherapy (EBRT) for locally advanced nasopharyngeal carcinoma (NPC).Eight-two patients received an SRT boost after EBRT between September 1992 and July 2006. Nine patients had T1, 30 had T2, 12 had T3, and 31 had T4 tumors. Sixteen patients had Stage II, 19 had Stage III, and 47 had Stage IV disease. Patients received 66 Gy of EBRT followed by a single-fraction SRT boost of 7-15 Gy, delivered 2-6 weeks after EBRT. Seventy patients also received cisplatin-based chemotherapy delivered concurrently with and adjuvant to radiotherapy.At a median follow-up of 40.7 months (range, 6.5-144.2 months) for living patients, there was only 1 local failure in a patient with a T4 tumor. At 5 years, the freedom from local relapse rate was 98%, freedom from nodal relapse 83%, freedom from distant metastasis 68%, freedom from any relapse 67%, and overall survival 69%. Late toxicity included radiation-related retinopathy in 3, carotid aneurysm in 1, and radiographic temporal lobe necrosis in 10 patients, of whom 2 patients were symptomatic with seizures. Of 10 patients with temporal lobe necrosis, 9 had T4 tumors.Stereotactic radiotherapy boost after EBRT provides excellent local control for patients with NPC. Improved target delineation and dose homogeneity of radiation delivery for both EBRT and SRT is important to avoid long-term complications. Better systemic therapies for distant control are needed.

  View details for DOI 10.1016/j.ijrobp.2007.10.027

  View details for Web of Science ID 000255971100013

  View details for PubMedID 18164839

• Radiology quiz case 1: Diagnosis: Multicystic ameloblastoma ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Walker, T., Chen, T., Bergeron, C. M., Fischbein, N. J., Kaplan, M. J., Monfared, A. 2008; 134 (3): 328-+

  View details for DOI 10.1001/archotol.134.3.328

  View details for Web of Science ID 000253878200018

  View details for PubMedID 18347263

• Patterns of failure after combined-modality approaches incorporating radiotherapy for sinonasal undifferentiated carcinoma of the head and neck INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, A. M., Daly, M. E., El-Sayed, I., Garcia, J., Lee, N. Y., Bum, M. K., Kaplan, M. J. 2008; 70 (2): 338-343

  Abstract

  To report the clinical outcome of patients treated with combined-modality approaches for sinonasal undifferentiated carcinoma (SNUC) of the head and neck.The records of 21 patients with SNUC treated with curative intent at the University of California, San Francisco between 1990 and 2004 were analyzed. Patient age ranged from 33 to 71 years (median, 47 years). Primary tumor sites included the nasal cavity (11 patients), maxillary sinus (5 patients), and ethmoid sinus (5 patients). All patients had T3 (4 patients) or T4 (17 patients) tumors. Local-regional treatment included surgery followed by postoperative radiotherapy (PORT) with or without adjuvant chemotherapy for 17 patients; neoadjuvant chemoradiotherapy followed by surgery for 2 patients; and definitive chemoradiotherapy for 2 patients. Median follow-up among surviving patients was 58 months (range, 12-70 months).The 2- and 5-year estimates of local control were 60% and 56%, respectively. There was no difference in local control according to initial treatment approach, but among the 19 patients who underwent surgery the 5-year local control rate was 74% for those with gross tumor resection, compared with 24% for those with subtotal tumor resection (p = 0.001). The 5-year rates of overall and distant metastasis-free survival were 43% and 64%, respectively. Late complications included cataracts (2 patients), lacrimal stenosis (1 patient), and sino-cutaneous fistula (1 patient).The suboptimal outcomes suggest a need for more effective therapies. Gross total resection should be the goal of all treatments whenever possible.

  View details for DOI 10.1016/j.ijrobp.2007.06.057

  View details for Web of Science ID 000252521700003

  View details for PubMedID 18207030

• Recurrent salivary gland carcinomas treated by surgery with or without intraoperative radiation therapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Chen, A. M., Garcia, J., Bucci, M. K., Chan, A. S., Kaplan, M. J., Singer, M. I., Phillips, T. L. 2008; 30 (1): 2-9

  Abstract

  The optimal treatment for patients with locally recurrent carcinomas of the salivary glands is unclear.Ninety-nine patients underwent salvage surgery for locally recurrent salivary gland carcinomas. Eighty-one (82%) had previously received radiation. Thirty-seven patients (37%) received intraoperative radiation therapy (IORT) to a median dose of 15 Gy (range, 12-18 Gy) at the time of salvage.The 1-, 3-, and 5-year estimates of local control after salvage surgery were 88%, 75%, and 69%, respectively. A Cox proportional hazard model identified positive margins (0.01) and the omission of IORT (p = .001) as independent predictors of local failure. The 5-year overall survival was 34%. Distant metastasis was the most common site of subsequent failure, occurring in 42% of patients.IORT significantly improves disease control for patients with locally recurrent carcinomas of the salivary glands. The high rate of distant metastasis emphasizes the need for effective systemic therapies.

  View details for DOI 10.1002/hed.20651

  View details for Web of Science ID 000252350700001

  View details for PubMedID 17828788

• Cancer stem cells in head and neck squamous carcinoma Ailles, L., Prince, M., Joshua, B., Doweck, I., Kaplan, M., Clarke, M., Weissman, I. AMER ASSOC CANCER RESEARCH. 2007: 3630S–3630S

  View details for Web of Science ID 000251969000893

• Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: Are we making improvement? INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, A. M., Daly, M. E., Bucci, M. K., Xia, P., Akazawa, C., Quivey, J. M., Weinberg, V., Garcia, J., Lee, N. Y., Kaplan, M. J., El-Sayed, I., Eisele, D. W., Fu, K. K., Phillips, T. L. 2007; 69 (1): 141-147

  Abstract

  To compare clinical outcomes of patients with carcinomas of the paranasal sinuses and nasal cavity according to decade of radiation treatment.Between 1960 and 2005, 127 patients with sinonasal carcinoma underwent radiotherapy with planning and delivery techniques available at the time of treatment. Fifty-nine patients were treated by conventional radiotherapy; 45 patients by three-dimensional conformal radiotherapy; and 23 patients by intensity-modulated radiotherapy. Eighty-two patients (65%) were treated with radiotherapy after gross total tumor resection. Nineteen patients (15%) received chemotherapy. The most common histology was squamous cell carcinoma (83 patients).The 5-year estimates of overall survival, local control, and disease-free survival for the entire patient population were 52%, 62%, and 54%, respectively. There were no significant differences in any of these endpoints with respect to decade of treatment or radiotherapy technique (p > 0.05, for all). The 5-year overall survival rate for patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s was 46%, 56%, 51%, 53%, and 49%, respectively (p = 0.23). The observed incidence of severe (Grade 3 or 4) late toxicity was 53%, 45%, 39%, 28%, and 16% among patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s, respectively (p = 0.01).Although we did not detect improvements in disease control or overall survival for patients treated over time, the incidence of complications has significantly declined, thereby resulting in an improved therapeutic ratio for patients with carcinomas of the paranasal sinuses and nasal cavity.

  View details for DOI 10.1016/j.ijrobp.2007.02.031

  View details for Web of Science ID 000248978300020

  View details for PubMedID 17459609

• Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinoma 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Daly, M. E., Lieskovsky, Y., Pawlicki, T., Yau, J., Pinto, H., Kaplan, M., Fee, W. E., Koong, A., Goffinet, D. R., Xing, L., Le, Q. JOHN WILEY & SONS INC. 2007: 211–20

  Abstract

  Our aim was to correlate patterns of failure with target volume delineations in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) and to report subjective xerostomia outcomes after IMRT as compared with conventional radiation therapy (CRT).Between January 2000 and April 2005, 69 patients with newly diagnosed nonmetastatic HNSCC underwent curative parotid-sparing IMRT at Stanford University. Sites included were oropharynx (n = 39), oral cavity (n = 8), larynx (n = 8), hypopharynx (n = 8), and unknown primary (n = 6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received postoperative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Posttreatment salivary gland function was evaluated by a validated xerostomia questionnaire in 29 IMRT and 75 matched CRT patients >6 months after completing radiation treatment.At a median follow-up of 25 months for living patients (range, 10-60), 7 locoregional failures were observed, 5 in the gross target or high-risk postoperative volume, 1 in the clinical target volume, and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan-Meier estimates for locoregional control and overall survival were 92% and 74% for definitive IMRT and 87% and 87% for postoperative IMRT patients, respectively. The mean total xerostomia questionnaire score was significantly better for IMRT than for CRT patients (p = .006).The predominant pattern of failure in IMRT-treated patients is in the gross tumor volume. Parotid sparing with IMRT resulted in less subjective xerostomia and may improve quality of life in irradiated HNSCC patients.

  View details for DOI 10.1002/hed.20505

  View details for Web of Science ID 000244459100002

  View details for PubMedID 17111429

• Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Prince, M. E., Sivanandan, R., Kaczorowski, A., Wolf, G. T., Kaplan, M. J., Dalerba, P., Weissman, I. L., Clarke, M. F., Ailles, L. E. 2007; 104 (3): 973-978

  Abstract

  Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We show that a minority population of CD44(+) cancer cells, which typically comprise <10% of the cells in a HNSCC tumor, but not the CD44(-) cancer cells, gave rise to new tumors in vivo. Immunohistochemistry revealed that the CD44(+) cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44(-) cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44(+) cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Taken together, these data demonstrate that cells within the CD44(+) population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis.

  View details for DOI 10.1073/pnas.0610117104

  View details for Web of Science ID 000243761100053

  View details for PubMedID 17210912

• Clinical role of F-18-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma JOURNAL OF NUCLEAR MEDICINE Quon, A., Fischbein, N. J., McDougall, I. R., Le, Q., Loo, B. W., Pinto, H., Kaplan, M. J. 2007; 48: 58S-67S

  Abstract

  18F-FDG PET/CT has rapidly become a widely used imaging modality for evaluating a variety of malignancies, including squamous cell carcinoma of the head and neck and thyroid cancer. Using both published data and the multidisciplinary experience at our institution, we provide a practical set of guidelines and algorithms for the use of 18F-FDG PET/CT in the evaluation and management of head and neck cancer and thyroid cancer.

  View details for Web of Science ID 000243420900008

  View details for PubMedID 17204721

• Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Chen, A. M., Bucci, M. K., El-Sayed, I., Xia, P., Kaplan, M. J., Eisele, D. W. 2007; 67 (1): 151-157

  Abstract

  To report the clinical outcome of patients treated with intensity-modulated radiation therapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses.Between 1998 and 2004, 36 patients with malignancies of the sinonasal region were treated with IMRT. Thirty-two patients (89%) were treated in the postoperative setting after gross total resection. Treatment plans were designed to provide a dose of 70 Gy to 95% or more of the gross tumor volume (GTV) and 60 Gy to 95% or more of the clinical tumor volume (CTV) while sparing neighboring critical structures including the optic chiasm, optic nerves, eyes, and brainstem. The primary sites were: 13 ethmoid sinus, 10 maxillary sinus, 7 nasal cavity, and 6 other. Histology was: 12 squamous cell, 7 esthesioneuroblastoma, 5 adenoid cystic, 5 undifferentiated, 5 adenocarcinoma, and 2 other. Median follow-up was 51 months among surviving patients (range, 9-82 months).The 2-year and 5-year estimates of local control were 62% and 58%, respectively. One patient developed isolated distant metastasis, and none developed isolated regional failure. The 5-year rates of disease-free and overall survival were 55% and 45%, respectively. The incidence of ocular toxicity was minimal with no patients reporting decreased vision. Late complications included xerophthalmia (1 patient), lacrimal stenosis (1 patient), and cataract (1 patient).Although IMRT for malignancies of the sinonasal region does not appear to lead to significant improvements in disease control, the low incidence of complications is encouraging.

  View details for DOI 10.1016/j.ijrobp.2006.07.1389

  View details for Web of Science ID 000243292000022

  View details for PubMedID 17189068

• Intraoperative radiation therapy for recurrent head-and-neck cancer: The UCSF experience INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, A. M., Bucci, M. K., Singer, M. I., Garcia, J., Kaplan, M. J., Chan, A. S., Phillips, T. L. 2007; 67 (1): 122-129

  Abstract

  To review a single-institutional experience with the use of intraoperative radiation therapy (IORT) for recurrent head-and-neck cancer.Between 1991 and 2004, 137 patients were treated with gross total resection and IORT for recurrence or persistence of locoregional cancer of the head and neck. One hundred and thirteen patients (83%) had previously received external beam radiation as a component of definitive therapy. Ninety-four patients (69%) had squamous cell histology. Final surgical margins were microscopically positive in 56 patients (41%). IORT was delivered using either a modified linear accelerator or a mobile electron unit and was administered as a single fraction to a median dose of 15 Gy (range, 10-18 Gy). Median follow-up among surviving patients was 41 months (range, 3-122 months).The 1-year, 2-year, and 3-year estimates of in-field control after salvage surgery and IORT were 70%, 64%, and 61%, respectively. Positive margins at the time of IORT predicted for in-field failure (p = 0.001). The 3-year rates of locoregional control, distant metastasis-free survival, and overall survival were 51%, 46%, and 36%, respectively. There were no perioperative fatalities. Complications included wound infection (4 patients), orocutaneous fistula (2 patients), flap necrosis (1 patient), trismus (1 patient), and neuropathy (1 patient).Intraoperative RT results in effective disease control with acceptable toxicity and should be considered for selected patients with recurrent or persistent cancers of the head and neck.

  View details for DOI 10.1016/j.ijrobp.2006.08.038

  View details for Web of Science ID 000243292000018

  View details for PubMedID 17084543

• Plasma osteopontin is an independent prognostic marker for head and neck cancers 41st Annual Meeting of the American-Society-of-Clinical-Oncology Petrik, D., Lavori, P. W., Cao, H., Zhu, Y., Wong, P., Christofferson, E., Kaplan, M. J., Pinto, H. A., Sutphin, P., Koong, A. C., Giaccia, A. J., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2006: 5291–97

  Abstract

  To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study.One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group.Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival.In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

  View details for DOI 10.1200/JCO.2006.06.8627

  View details for Web of Science ID 000242342800017

  View details for PubMedID 17114663

• Advanced-staged tonsillar squamous carcinoma: Organ preservation versus surgical management of the primary site 90th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America Shirazi, H. A., Sivanandan, R., Goode, R., Fee, W. E., Kaplan, M. J., Pinto, H. A., Goffinet, D. R., Le, Q. JOHN WILEY & SONS INC. 2006: 587–94

  Abstract

  Our aim was to review our experience in the management of advanced tonsillar squamous cell carcinoma (SCC) and to compare treatment outcomes between patients treated with and without surgery to the primary site.The records of 74 patients with advanced-stage tonsillar SCC were reviewed. The median age at diagnosis was 58 years. Thirty-eight patients received definitive surgery to the primary site, and 36 were treated with an organ-preservation approach (OP) using radiotherapy +/- chemotherapy.No significant difference in overall survival (OS) or freedom from relapse (FFR) by treatment was found. T classification and N status were significant independent predictors on multivariate analysis for OS and FFR. Major late toxicity was noted in 10 patients in the surgical group and nine in the OP group.Patients treated with OP and primary surgery had comparable OS and FFR. T classification and N status were significant independent predictors for tumor relapse and survival. On the basis of these results, we favor organ-preservation therapy for patients with advanced-stage tonsillar SCC.

  View details for DOI 10.1002/hed.20372

  View details for Web of Science ID 000238690100003

  View details for PubMedID 16475199

• Anterior skull base surgery OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA Kaplan, M. J., Fischbein, N. J., Harsh, G. R. 2005; 38 (1): 107-?

  Abstract

  This article focuses on selected key anatomic considerations in anterior skull base surgery, briefly reviews common pathologies of the paranasal sinuses, and provides an overview of surgical approaches, complications, and results.

  View details for DOI 10.1016/j.otc.2004.09.010

  View details for Web of Science ID 000226736500011

  View details for PubMedID 15649503

• The "small, dark tonsil" in patients presenting with metastatic cervical lymphadenopathy from an unknown primary AMERICAN JOURNAL OF NEURORADIOLOGY Jumper, J. R., Fischbein, N. J., Kaplan, M. J., Klein, H. Z., Dillon, W. P. 2005; 26 (2): 411-413

  Abstract

  When squamous cell carcinoma (SCC) involves the palatine tonsils, they are generally enlarged and demonstrate intermediate to high signal intensity on T2-weighted MR images and enhance after gadolinium administration. We have identified two patients with SCC of the tonsil where the affected tonsil has low signal intensity on T2-weighted MR images and is smaller than the contralateral normal tonsil. We present the "small, dark tonsil" as an alternative imaging presentation of SCC and a new sign to look for when evaluating the patient with metastatic lymphadenopathy from an unknown primary tumor.

  View details for Web of Science ID 000227073900034

  View details for PubMedID 15709146

• Long-term results of 100 consecutive comprehensive neck dissections - Implications for selective neck dissections ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sivanandan, R., Kaplan, M. J., Lee, K. J., Lebl, D., PINTO, H., Le, Q. T., Goffinet, D. R., Fee, W. E. 2004; 130 (12): 1369-1373

  Abstract

  The optimal surgical procedure for the neck in patients with squamous head and neck cancers is controversial. Selective neck dissections have replaced modified radical neck dissections as the procedure of choice for the clinically negative (N0) neck and are now being considered for patients with early-stage neck disease. We report the long-term local recurrence rates in 100 consecutive patients undergoing a radical or modified radical neck dissection for clinically positive (N+) and N0 neck disease and review comprehensively the literature reporting and comparing regional control rates for both neck dissection types.The clinical records of 100 consecutive patients who underwent a comprehensive neck dissection (levels I-V) for squamous head and neck cancers with a minimum of a 2-year follow-up were retrospectively reviewed for primary site of disease, clinical and pathologic neck status, histopathologic grade, neck dissection type, and the site and time of recurrence.Complete data were available for 97 patients on whom 99 neck dissections were performed. Three patients died from unknown causes. Seventy-six patients with N+ disease underwent a therapeutic neck dissection, while 24 patients with clinically N0 disease underwent an elective dissection. The overall neck recurrence rate in patients with controlled primary disease was 7%. The neck or regional failure rate for patients completing the recommended adjuvant radiotherapy was 4%. Six (25%) of 24 patients with clinically N0 disease had occult metastases. The recurrence rate for this group was 4%.Further study is needed to determine the optimal surgical management of the N0 and limited N+ neck.

  View details for PubMedID 15611394

• Laryngeal embryonal rhabdomyosarcoma - A case of cervical metastases 13 years after treatment and a 25-year review of existing literature ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sivanandan, R., Kong, C. S., Kaplan, M. J., Fee, W. E., Thu-Le, Q., Goffnet, D. R. 2004; 130 (10): 1217-1222

  Abstract

  Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, the majority of which are of the embryonal rhabdomyosarcoma (ER) variety. Present day treatment protocols involve a combination of aggressive surgery, chemotherapy, and radiation therapy. Embryonal rhabdomyosarcoma of the larynx is rare and unlike ER of other regions exhibits excellent response to multimodality treatment without the need for extensive surgery. We report a case of cervical metastases in a 29-year-old man 13 years after treatment of his laryngeal ER. To our knowledge, this is the first reported case of late neck metastases in ER of the larynx and the second reported case of delayed presentation of recurrent disease. A 25-year review of all published reports of ER of the larynx was conducted that highlights the move toward organ preservation with the multimodality treatment protocols. Embryonal rhabdomyosarcoma of the larynx is highly responsive to combination chemoradiotherapy, allowing for excellent cure rates without the need for extensive surgery. Late relapses warrant long-term follow-up.

  View details for PubMedID 15492173

• Lymph node metastasis in maxillary sinus carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q. T., Fu, K. K., Kaplan, M. J., Terris, D. J., Fee, W. E., Goffinet, D. R. 2000; 46 (3): 541-549

  Abstract

  To evaluate the incidence and prognostic significance of lymph node metastasis in maxillary sinus carcinoma.We reviewed the records of 97 patients treated for maxillary sinus carcinoma with radiotherapy at Stanford University and at the University of California, San Francisco between 1959 and 1996. Fifty-eight patients had squamous cell carcinoma (SCC), 4 had adenocarcinoma (ADE), 16 had undifferentiated carcinoma (UC), and 19 had adenoid cystic carcinoma (AC). Eight patients had T2, 36 had T3, and 53 had T4 tumors according to the 1997 AJCC staging system. Eleven patients had nodal involvement at diagnosis: 9 with SCC, 1 with UC, and 1 with AC. The most common sites of nodal involvement were ipsilateral level 1 and 2 lymph nodes. Thirty-six patients were treated with definitive radiotherapy alone, and 61 received a combination of surgical and radiation treatment. Thirty-six patients had neck irradiation, 25 of whom received elective neck irradiation (ENI) for N0 necks. The median follow-up for alive patients was 78 months.The median survival for all patients was 22 months (range: 2.4-356 months). The 5- and 10-year actuarial survivals were 34% and 31%, respectively. Ten patients relapsed in the neck, with a 5-year actuarial risk of nodal relapse of 12%. The 5-year risk of neck relapse was 14% for SCC, 25% for ADE, and 7% for both UC and ACC. The overall risk of nodal involvement at either diagnosis or on follow-up was 28% for SCC, 25% for ADE, 12% for UC, and 10% for AC. All patients with nodal involvement had T3-4, and none had T2 tumors. ENI effectively prevented nodal relapse in patients with SCC and N0 neck; the 5-year actuarial risk of nodal relapse was 20% for patients without ENI and 0% for those with elective neck therapy. There was no correlation between neck relapse and primary tumor control or tumor extension into areas containing a rich lymphatic network. The most common sites of nodal relapse were in the ipsilateral level 1-2 nodal regions (11/13). Patients with nodal relapse had a significantly higher risk of distant metastasis on both univariate (p = 0.02) and multivariate analysis (hazard ratio = 4.5, p = 0.006). The 5-year actuarial risk of distant relapse was 29% for patients with neck control versus 81% for patients with neck failure. There was also a trend for decreased survival with nodal relapse. The 5-year actuarial survival was 37% for patients with neck control and 0% for patients with neck relapse.The overall incidence of lymph node involvement at diagnosis in patients with maxillary sinus carcinoma was 9%. Following treatment, the 5-year risk of nodal relapse was 12%. SCC histology was associated with a high incidence of initial nodal involvement and nodal relapse. None of the patients presenting with SCC histology and N0 necks had nodal relapse after elective neck irradiation. Patients who had nodal relapse had a higher risk of distant metastasis and poorer survival. Therefore, our present policy is to consider elective neck irradiation in patients with T3-4 SCC of the maxillary sinus.

  View details for Web of Science ID 000085412400004

  View details for PubMedID 10701732

• Treatment of maxillary sinus carcinoma - A comparison of the 1997 and 1977 American Joint Committee on Cancer staging systems CANCER Le, Q. T., Fu, K. K., Kaplan, M., Terris, D. J., Fee, W. E., Goffinet, D. R. 1999; 86 (9): 1700-1711

  Abstract

  This study was conducted to assess the effectiveness of the 1997 American Joint Committee on Cancer (AJCC) staging system to predict survival and local control of patients with maxillary sinus carcinoma and to identify significant factors for overall survival, local control, and distant metastases in patients with these tumors.Ninety-seven patients with maxillary sinus carcinoma were treated with radiotherapy at Stanford University and the University of California, San Francisco between 1959-1996. The histologic type of carcinoma among the 97 patients were: 58 squamous cell carcinomas, 4 adenocarcinomas, 16 undifferentiated carcinomas, and 19 adenoid cystic carcinomas. All patients were restaged clinically according to the 1977 and 1997 AJCC staging systems. The T classification of the tumors of the patients was as follows: 8 with T2, 18 with T3, and 71 with T4 according to the 1977 system and 8 with T2, 36 with T3, and 53 with T4 according to the 1997 system. Eleven patients had lymph node involvement at diagnosis. Thirty-six patients were treated with radiotherapy alone and 61 received a combination of surgical and radiation treatments. The median follow-up for surviving patients was 78 months.The 5-year and 10-year actuarial survival rates for all patients were 34% and 31%, respectively. The 5-year survival estimate by the 1977 AJCC system (P = 0.06) was 75% for Stage II, 19% for Stage III, and 34% for Stage IV and by the 1997 AJCC system (P = 0.006) was 75% for Stage II, 37% for Stage III, and 28% for Stage IV. Significant prognostic factors for survival by multivariate analysis included age (favoring younger age, P<0.001), 1997 T classification (favoring T2-3, P = 0. 001), lymph node involvement at diagnosis (favoring N0, P = 0.002), treatment modality of the primary tumor site (favoring surgery and radiotherapy, P = 0.009), and gender (favoring female patients, P = 0.04). The overall radiation time was of borderline significance (favoring shorter time, P = 0.06). The actuarial 5-year local control rate was 43%. By the 1977 AJCC system (P = 0.78) it was 62% with T2, 36% with T3, and 45% with T4 and using the 1997 AJCC system (P = 0.29) it was 62% with T2, 53% with T3, and 36% with T4. The only significant prognostic factor for local control for all patients by multivariate analysis was local therapy, favoring surgery and radiotherapy over radiotherapy alone (P< 0.001). For patients treated with surgery, pathologic margin status correlated with local control (P = 0.007) and for patients treated with radiation alone, higher tumor dose (P = 0.007) and shorter overall treatment time (P = 0.04) were associated with fewer local recurrences. The 5-year estimate of freedom from distant metastases was 66%. The 1997 T classification, N classification, and lymph node recurrence were adverse prognostic factors for distant metastases on multivariate analysis. There were 22 complications in 16 patients, representing a 30% actuarial risk of developing late complications at 10 years.The 1997 AJCC staging system was found to be superior to the 1977 AJCC staging system in predicting both survival and local control in this patient population. Combined surgical and radiation treatment to the primary tumor yielded higher survival and local control than radiotherapy alone. Other significant prognostic factors for survival were patient age, gender, and lymph node (N) classification. Prolonged overall radiation time was associated with poorer survival and local control. Late severe toxicity from the treatment of these tumors was a significant problem in long term survivors. Improved radiotherapy techniques should lead to decreased injury to the surrounding normal tissues. (c) 1999 American Cancer Society.

  View details for Web of Science ID 000083430700011

  View details for PubMedID 10547542

• Magnetic resonance imaging of the central skull base. Topics in magnetic resonance imaging Fischbein, N. J., Kaplan, M. J. 1999; 10 (5): 325-346

  Abstract

  The central skull base is an anatomically complex region whose foundation is the sphenoid bone. It includes the sphenoid sinus, clivus, and sella turcica, as well as adjacent soft tissues such as the cavernous sinuses and nasopharynx. The central skull base may be affected by pathologies intrinsic to the sphenoid bone or by processes that arise in adjacent soft tissue and extend centrally to affect the central skull base. In general, this region is optimally imaged with magnetic resonance scanning, although in some cases computed tomography can provide complementary information. In this review, we will discuss a variety of pathologies that can affect the central skull base, such as neoplasms, infections, trauma, congenital malformations, and a variety of miscellaneous pathologies. We will discuss processes that can mimic neoplasia, such as aggressive polyposis and chronic inflammatory disease. For each pathology we will review clinical and imaging findings.

  View details for PubMedID 10643825