Head Squamous Cell Research Articles

Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in Japanese drinkers.

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetaldehyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection rates of esophageal squamous cell carcinoma (SCC; 4.1%) and head and neck SCC (1.0%). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple SCC/dysplasia, were increased in a multiplicative fashion by the presence of a combination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2 because of prolonged exposure to higher concentrations of ethanol/acetaldehyde. A questionnaire asking about current and past facial flushing after drinking a glass (≈180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2. We invented a health-risk appraisal (HRA) model including the flushing questionnaire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a high rate by endoscopic mass-screening in high HRA score persons. A total of 5.0% of 4,879 alcoholics had a history of (4.0%) or newly diagnosed (1.0%) gastric cancer. Their high frequency of a history of gastric cancer is partly explained by gastrectomy being a risk factor for alcoholism because of altered ethanol metabolism, e.g., by blood ethanol level overshooting. The combination of H. pylori-associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric cancer in alcoholics. High detection rates of advanced colorectal adenoma/carcinoma were found in alcoholics, 15.7% of 744 immunochemical fecal occult blood test (IFOBT)-negative alcoholics and 31.5% of the 393 IFOBT-positive alcoholics. Macrocytosis with an MCV≥106 fl increased the risk of neoplasia in the entire aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/acetaldehyde exposure plays an important role in neoplasia.

Abstract 987: Comprehensive characterization of urothelial bladder cancer: a TCGA Project update

Abstract Urothelial carcinoma (UC) is a major cause of morbidity and mortality for which there are no approved molecularly targeted agents and few good treatment options beyond cisplatin-based chemotherapy. As part of The Cancer Genome Atlas (TCGA) Project, we analyzed 131 chemotherapy-naive, muscle-invasive UC tumors for somatic mutations, DNA copy number variants (CNVs), mRNA and microRNA expression, protein expression and phosphorylation, DNA methylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology (TCGA Research Network, Nature, in press). Whole-exome sequencing showed 29 recurrently mutated genes. Potential therapeutic targets include altered PIK3CA, ERBB2, FGFR3, TSC1, and ERBB3, plus mutated chromatin-regulating genes MLL, MLL2, MLL3, CREBBP, CHD7, SRCAP, ARID1A, KDM6A (UTX), and EP300. There were 22 arm-level CNVs and 27 focally amplified or deleted regions. CDKN2A was deleted in 47%. Low-pass whole genome sequencing identified FGFR3-TACC3 fusions. Viral DNA was identified in 6% (CMV, HHV6B, HPV16, BK polyoma), and viral transcripts were identified in 4% (CMV, BK polyoma, HPV16). . mRNA-seq identified 4 tumor clusters. Cluster I shows papillary morphology and FGFR3 dysregulation. Clusters I and II express high HER2 (ERBB2) and estrogen receptor beta signaling signature, sharing features with Luminal A breast cancer. Cluster III shows similarities to Basal-like breast and squamous cell head and neck carcinomas. . Integrated analyses confirm alteration of multiple pathways, including cell cycle regulation (93%), kinase and PI3-K signaling (72%), and epigenetic regulation (histone-modifiers: 89%; SWI/SNF nucleosome remodeling complex: 64%). Recurrent alterations in the PI3-kinase/AKT/mTOR pathway (42%) and RTK/RAS pathway (44%) are potentially actionable. . Overall, this study and others have identified multiple druggable targets in UC. FGFR3 is activated by mutation, gene fusion, and overexpression, suggesting clinical trials of FGFR3 inhibitors. PI3-kinase/mTOR/AKT/TSC1 pathway alterations are frequent, and mutation in TSC1 has been associated with response to mTOR inhibitors. ERBB2 amplifications and activating mutations may be targetable with agents such as trastuzumab, trastuzumab-DM1, lapatinib, and neratinib. The frequent alterations in epigenetic regulatory pathways suggest trials of agents such as the bromodomain inhibitors. The project is now being updated on the basis of data on 117 additional tumors. Citation Format: John N. Weinstein, Jaegil Kim, Chad J. Creighton, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Margaret B. Morgan, Toshinori Hinoue, Andrew Cherniack, Xiaoping Su, Andrew J. Mungall, Michael C. Ryan, Jonathan E. Rosenberg, Dean F. Bajorin, Bogdan Czerniak, Donna Hansel, Victor E. Reuter, Brian D. Robinson, Hikmat A. Al-Ahmadie, Jeffrey S. Damrauer, Wei Zhang, Yuexin Liu, Dmitry Gordenin, Joshua M. Stuart, Nikolaus Schultz, Gordon Robertson, Raju Kucherlapati, Peter W. Laird, Gordon B. Mills, David J. Kwiatkowski, Seth P. Lerner, representing TCGA's Bladder Cancer Working Group. Comprehensive characterization of urothelial bladder cancer: a TCGA Project update. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2014-987

Abstract 4743: Analysis of a protein expression biomarkers in HPV negative SCCHN

Abstract Background: Human papillomavirus negative (HPV) (-) squamous cell head and neck cancer (SCCHN) is associated with a poor prognosis and decreased response to treatment. We sought to study the correlation between protein-based biomarkers related to DNA repair, mitotic regulators and apoptosis in a tissue microarray (TMA) of HPV(-) SCCHN. Methods: TMAs were constructed with SCCHN samples from patients treated at Fox Chase Cancer Center from 1990-2002. The TMA contained 85 p16 -surgical specimens from predominantly oral cavity tumors; 72 received adjuvant radiation. Slides were stained by a modified indirect immunofluorescence method. Sections were incubated with antibodies against ERCC1 (HPA029773, Sigma), Aurora A, (Bethyl Laboratory, IHC-00062), pAuroraA ( Bethyl Laboratory, IHC-00067), survivin (Novus Biological, NB100-56168) and a wide-spectrum screening mouse cytokeratin ab (Dako M3515). Prolong Gold mounting medium (P36931; Molecular Probes) containing 4,6-Diamidino-2-phenylindole (DAPI) defined nuclei. A tumor mask (TM) image was created from the cytokeratin stain of each histospot. ERCC1 levels were measured using fluorescent IHC on the HistoRx PM-2000 image analysis platform and data analyzed using AQUA algorithms. We assessed relationships between markers using Spearman's correlation, explored associations between markers and overall survival using Kaplan-Meier curves, and tested significance using the t-statistic. Parallel analysis of The Cancer Genome Atlas (TCGA) resources was used to establish whether correlative relationships observed at the protein level reflected commensurate changes in mRNA expression, in an independent study cohort. For this purpose, mRNA expression values were imported from the (provisional) TCGA data set encompassing 295 SCCHN samples, and Spearman's correlation coefficients were calculated. Results: Correlation coefficients indicated a significant positive association between nuclear expression of the following markers: ERCC1 and AuroraA (p<0.0001); ERCC1 and pAurora (p=0.0027); Aurora A and pAurora (p<0.0001); survivin and Aurora A (p=0.0064); and survivin and ERCC1 (p=0.0084). Review of mRNA levels of Aurora A and survivin in the TCGA database indicated a highly significant correlation between these two markers (r=0.59, p=0.0002). This striking correlation did not represent common amplification of a chromosomal locus, given distinct chromosomal locations of Aurora A (20q13), and survivin (17q25). The relation of elevated expression of the biomarkers to prognosis was analyzed, considering biomarkers alone and in combination. A particularly important role for survivin was established, independent of other variables. Conclusions: ERCC1, Aurora A, and survivin displayed significantly correlated expression in HPV (-) SCCHN, supporting linked function in SCCHN. This works suggests a cluster of biomarkers worthy of future study. Citation Format: Ranee Mehra, Donghua Yang, Elizabeth Handorf, Ilya Serebriiskii, Eric Ross, Miriram Lango, John A. Ridge, Erica Golemis, Barbara Burtness. Analysis of a protein expression biomarkers in HPV negative SCCHN. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4743. doi:10.1158/1538-7445.AM2014-4743

Abstract 5546: Impact of DNA repair and apoptosis gene polymorphisms on clinical outcome in head and neck cancer patients treated with radiotherapy

Abstract Introduction: The effects of single nucleotide polymorphisms (SNPs) in DNA repair (ERCC1, ERCC2, ERCC5, XRCC1) and apoptosis genes (TP53, MDM2) on response rate, survival and toxicity were tested in a group of squamous cell head and neck cancer (SCCHN) patients receiving a radiotherapy (RT)-based treatment. Materials and Methods: A retrospective cohort of 122 locally advanced SCCHN patients non-eligible for surgery, treated by RT (N=38) or chemoRT (CRT, N=84) between 1992 and 2006 was selected. The following SNPs were analyzed on tumor DNA: ERCC1 259Lys>Thr (rs735482), ERCC2 751Lys>Gln (rs13181), ERCC5 46His C>T (rs1047768), XRCC1 399Arg>Gln (rs25487), TP53 72Arg>Pro (rs1042522) and MDM2 309T>G (rs2279744). Tumor response 6 months after treatment cessation (ORR), progression-free survival (PFS), cancer-specific survival (CSS) and RT-related toxicity (G0-2 vs G3-4 according to CTCAE v4.0) were assessed. Results: ORR was 70%. Median PFS was 15.8 months and median CSS was 33.1 months. In total, 104/114 patients (91 %) experienced RT-related G3-4 toxicity at any time. 99/122 (81 %) patients had acute side-effects (during RT), among them 46 had epithelitis. 98/116 (85%) developed an early G3-4 DMEX toxicity (dysphagia, mucocitis, epithelitis and/or xerostomia up to 3 months after end of RT). 29/95 patients (31%) developed any G3-4 late toxicity (3 months after end of RT), with skin fibrosis for 3 patients and xerostomia for 13 patients. No relationship was found between any SNPs and ORR, PFS or CSS. The presence of the G allele of MDM2 or the Thr allele of ERCC1 were associated with a higher risk of early DMEX. Focusing on each toxicity separately, MDM2 GG genotype was related to a higher risk of acute G3-4 epithelitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Conclusion: SNPs in ERCC1 and ERCC5 DNA repair genes, as well as MDM2 apoptosis gene may influence RT-induced toxicity. Genotypes and G3-4 toxicity G0-2G3-4RR (95% CI)Global pEarly DMEXMDM2 309T>GTT113110.018TG3491.28 (1.05-1.55)GG3181.16 (0.90-1.49)Early DMEXERCC1 259Lys>ThrLys/Lys166810.038Lys/Thr + Thr/Thr1311.20 (1.06-1.35)Acute EpithelitisMDM2 309T>GTT2241910.037TG40140.59 (0.33-1.03)GG10121.23 (0.74-2.05)Late Skin FibrosisERCC5 46His C>TCC280Not assessable0.012CT450TT203Late XerostomiaERCC5 46His C>TCC23510.023CT4320.25 (0.05-1.20)TT1761.46 (0.51-4.18) Citation Format: Marie-Christine Etienne-Grimaldi, Delphine Borchiellini, Laurence LLorca, Jean-Louis Formento, Patricia Formento, Yann Château, Gérard Milano. Impact of DNA repair and apoptosis gene polymorphisms on clinical outcome in head and neck cancer patients treated with radiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2014-5546

Relation between carbonic anhydrase IX serum level, hypoxia and radiation resistance of head and neck cancers

Hypoxia of locally advanced head and neck cancers is one of the main causes of their radiation resistance that presents clinically as a persistence of residual tumor disease after radiation therapy. Therefore, detection of tumor hypoxia could be an important predictor of treatment efficacy. Carbonic anhydrase IX (CA IX) is a protein, coded by a homonymous gene, the expression of which increases in tumor tissues at hypoxic conditions. Hence, CA IX represents an endogenic marker of tumor hypoxia, identifiable in tumor tissues, and its soluble extracellular domain can also be detected in body fluids of the patient. The primary endpoint of this study was to explore whether a correlation exists between CA IX serum level and the residual tumor disease after therapy. The secondary endpoint was to find out how the serum concentration of CA IX changes during the course of fractionated radiation therapy. The presented prospective monocentric clinical study evaluated a population of 30 patients with locally advanced squamous cell head and neck cancers, treated by radiation therapy or concurrent chemo radiation therapy with a curative intent. The serum concentration of the soluble form of CA IX was examined from a venous blood sample, using sandwich enzyme linked immunosorbent assay (ELISA). The blood samples were obtained before the treatment initiation, in the middle of radiation therapy, at the time of finishing radiation therapy and six weeks after the treatment completion. We found a substantial variability in the CA IX levels measured in the examined population, ranging 0- 1,696 pg/ ml. We found no significant changes in the mean value of CA IX concentration during the course of radiation therapy and after the treatment completion. In 11 patients (36.7%), the treatment resulted in complete remission of the disease. In these patients, lower average pretreatment levels of CA IX were noted when compared to patients with persistence of residual tumor disease (37.57 vs 77.47; p = 0.154). The results indicate that serum level of CA IX in patients with locally advanced head and neck cancers does not change significantly during the course of fractionated radiation therapy. The relation between CA IX serum level and residual tumor disease after radiation therapy requires verification on a larger population of patients.

Late Surgical Outcomes of Carotid Resection and Saphenous Vein Graft Revascularization in Patients with Advanced Head and Neck Squamous Cell Carcinoma

In head and neck squamous cell carcinoma, invasion of the carotid artery is a severe mortality predictor. We report an updated experience of 19 patients who underwent head and neck resection for squamous cell carcinoma with concomitant carotid reconstruction. This study aims to analyze overall survival rates, primary patency of the reconstructions, vascular and nonvascular complications, radiotherapy dosing as well as late follow-up and outcomes. From September 1997 to 2011, 19 patients with advanced squamous cell carcinoma with carotid artery invasion were submitted to resection and concomitant vascular reconstruction in a single referred oncological institution. Patient follow-up was done by means of periodic outpatient returns, where clinical and duplex scan evaluations were performed to study graft patency. The average length of follow-up was 23.3 (± 34.4) months. Nonvascular complications occurred in 6 patients (31.6%). Only 1 (5.3%) vascular complication was observed, resulting from the immediate occlusion of the carotid graft. All patients were submitted to preoperative, adjuvant, or curative intent radiotherapy during the course of the oncologic treatment, with varying doses. Overall disease-free survival, primary patency, and survival with patent graft rates in 5 years are respectively 12.9%, 93.1%, and 13.0%. Three patients (15.9%) are still alive, all without tumor recurrence, and present a disease-free long-term follow-up with patent grafts 21 months, 68 months, and 151 months after surgery. Aggressive surgical approach for patients with advanced squamous cell head and neck carcinoma with carotid invasion can lead to cure in a select group of patients. Saphenous vein grafts demonstrated favorable outcomes with low infection and high patency rates, suggesting a valid alternative for arterial reconstruction in these cases.

The role of 18F-FDG-PET/CT in initial staging and re-staging of head and neck cancer

The aim of this study is to have a solid basis for the effectiveness of the 18F-FDG-PET/CT imaging technique, which hasknown advantages for patients with head and neck cancers during staging and restaging prior to treatment and to comparethis method with the corresponding clinical and radiological methods. A total of 139 patients with squamous cell head and neck carcinoma underwent PET/CT imaging. A total of 146 PET/CTimaging was performed in all patients. PET/CT imaging performed for staging and restaging in 36 and 103 patients,respectively. At least one conventional imaging (CI) as CT and/or MRI was performed for each one of the total patients.PET/CT studies revealed 66 true positive, 72 true negative, 4 false positive and 4 false negative results whereas the samevalues for CI were 65, 64, 4 and 6, respectively. When all studies were analyzed on the basis of lesion for PET/CT, specificity was 94.7%, and sensitivity being 94.2%,where as corresponding values for conventional imaging methods were found 94.1% and 91.5% respectively. Recurrentlesions have been detected with PET/CT and treatment management was changed in 29 of 139 patients.FDG-PET/CT improves the diagnostic accuracy in head and neck cancer patients.

Comprehensive molecular profiling of urothelial bladder cancer at the DNA, RNA, and protein levels: A TCGA project.

4509 Background: Urothelial carcinoma (UC) is a major cause of mortality with no approved molecularly targeted agents or good treatment options beyond cisplatin-based chemotherapy. Methods: For The Cancer Genome Atlas (TCGA), we profiled muscle-invasive UCs for mutations, DNA copy number variants (CNVs), mRNA and microRNA expression, protein expression and phosphorylation, DNA methylation, transcript splicing, gene fusion, viral integration, pathway perturbation, clinical correlates, and histopathology. The finding here are based on the first 131 tumors, but >250 more are being processed as of 1/2014. Results: Whole-exome sequencing revealed 29 recurrently mutated genes. Potential therapeutic targets included altered PIK3CA, ERBB2, FGFR3, TSC1, and ERBB3, plus mutated chromatin-regulating genes MLL, MLL2, MLL3, CREBBP, CHD7, SRCAP, ARID1A, KDM6A (UTX), and EP300. There were 27 focal CNVs, including CDKN2A deletion in 47%. Low-pass whole-genome sequencing identified 3 tumors with FGFR3-TACC3 fusions. Viral DNA was found in 6% (CMV, HHV6B, HPV16, BK polyoma), and viral transcripts were identified in 4% (CMV, BK polyoma, HPV16). mRNA-seq showed 4 tumor clusters: (I) papillary morphology, FGFR3 dysregulation. (I and II) high HER2 (ERBB2), estrogen receptor beta signaling signature (like Luminal A breast cancer). (III) similar to basal-like breast and squamous cell head and neck. Integrated analyses confirmed changes in cell cycle regulation (93%), kinase and PI3-K signaling (72%), and epigenetic regulation (histone-modifiers: 89%; SWI/SNF nucleosome remodeling complex: 64%). Recurrent defects in PI3-kinase/AKT/mTOR (42%) and RTK/RAS (44%) pathways may be actionable. Conclusions: This study and others identify druggable targets in UC. FGFR3 is activated by mutation, gene fusion, and overexpression, suggesting trials of FGFR3 inhibitors. PI3-kinase/mTOR/AKT/TSC1 pathway defects are frequent, and mutations in TSC1 suggest trial of mTOR inhibitors. ERBB2 amplifications and activating mutations suggest agents such as trastuzumab, trastuzumab-DM1, lapatinib, and neratinib. The mutations in epigenetic regulatory genes suggest potential for chromatin modifying agents.

A phase 1 study of LJM716 in patients with esophageal squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic breast or gastric cancer.

2517 Background: The HER3 receptor is important for maintenance of EGFR- and HER2-driven cancers and targeted therapy resistance. LJM716 is a fully human HER3 monoclonal antibody active in ligand-d...

The ACCROBAT I study: Three-year follow-up of a prospective phase II study with neoadjuvant TPF before bioradiotherapy for stage III-IV unresectable squamous cell head and neck cancer.

e17004 Background: Concomittant cisplatinbased chemoradiotherapy increases tumour control compared to radiation alone. However, both acute and late toxicity can be important and the influence on ra...

Association between severe treatment‐related lymphopenia and progression‐free survival in patients with newly diagnosed squamous cell head and neck cancer

Severe treatment-related lymphopenia occurs commonly in many cancers and is associated with early tumor progression. Data are lacking as to whether this occurs in squamous cell head and neck cancer. Serial total lymphocyte counts were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. The median baseline total lymphocyte count in 56 patients was 1660 cells/mm(3) , which fell by 73% to 445 cells/mm(3) 2 months after initiating chemoradiation (p < .0001). Human papillomavirus negative (HPV-) patients with a total lymphocyte count <500 cells/mm(3) at 2 months had significantly earlier disease progression than those with higher total lymphocyte counts (hazard ratio [HR], 5.75; p = .045). Baseline total lymphocyte counts were normal, but at 2 months approximately 60% of patients had severe treatment-related lymphopenia regardless of HPV status. Severe treatment-related lymphopenia in HPV- patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings, which suggest that immune preservation is important in this cancer.

Cetuximab, Paclitaxel, Carboplatin, and Radiation for Head and Neck Cancer

To assess the effect on progression-free and overall survival from the addition of cetuximab to paclitaxel-based chemoradiation for patients with squamous cell head and neck cancer from Brown University Oncology Group studies. BrUOG HN-204 patients with stage III or IV locally advanced squamous cell cancer of the head and neck without distant organ metastases received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Recurrence and survival data were compared with previous Brown University studies utilizing the same paclitaxel-based chemoradiation with and without induction chemotherapy. The progression-free survival and overall survival at 3 years for all 37 patients initiating chemoradiation was 54% and 57%, respectively. All surviving patients were followed for at least 3 years and the median follow-up is 4.4 years. Of 14 patients who recurred within 3 years, 7 patients recurred locally only, 5 had a systemic recurrence, and 2 recurred both locally and systemically. The addition of cetuximab to paclitaxel, carboplatin, and radiation achieves overall survival that is virtually identical to prior Brown University Oncology Group studies of paclitaxel-based chemoradiation without cetuximab. Improvements in locoregional control are needed despite the use of 3 agents to enhance the effects of radiation.

Combined concurrent photodynamic and gold nanoshell loaded macrophage‐mediated photothermal therapies: An in vitro study on squamous cell head and neck carcinoma

Treatment modalities, such as hyperthermia and photodynamic therapy (PDT) have been used in the treatment of a variety of head and neck squamous cell carcinoma (HNSCC), either alone or as an adjuvant therapy. Macrophages loaded with gold nanoshells, which convert near-infrared light to heat, can be used as transport vectors for photothermal hyperthermia of tumors. The purpose of this study was to investigate the effects of combined macrophage mediated photothermal therapy (PTT) and PDT on HNSCC cells. Gold nanoshell loaded rat macrophages either alone or combined with human FaDu squamous cells in hybrid monolayers were subjected to PTT, PDT, or a simultaneous combination of the two light treatments. Therapies were given concurrently employing two laser light sources of λ = 670 nm (PDT) and λ = 810 nm (PTT), respectively. Significant uptake of gold nanospheres (AuNS) by rat alveolar macrophages was observed thus providing the rationale for their use as delivery vectors. Viability of the AuNS-loaded Ma was reduced to 35 and 12% of control values at an irradiance of 14 or 28 W/cm(2) administered over a 5 minute period respectively. No significant cytotoxicity was observed for empty Ma for similar PTT exposure. AlPcS2a mediated PDT at a fluence level of 0.25 J/cm(2) and PTT at 14 W/cm(2) irradiance had little effect on cell viability for the FaDu/Ma (ratio 2:1) hybrid monolayers. In contrast, combined treatment reduced the cell viability to less than 40% at these same laser power settings. The results of this study provide proof of concept for the use of macrophages as a delivery vector of AuNS for photothermal enhancement of the effects of PDT on squamous cell carcinoma. A significant synergy was demonstrated with combined PDT and PTT compared to each modality applied separately.

An Immunohistochemical Analysis of a Newly Developed, Mouse Monoclonal p40 (BC28) Antibody in Lung, Bladder, Skin, Breast, Prostate, and Head and Neck Cancers

Immunohistochemistry is important to the pathologist for accurate diagnosis of lung cancer. In recent studies, a rabbit polyclonal p40 (RPp40) antibody demonstrated equivalent staining versus anti-p63 in lung squamous cell carcinoma, and superior specificity because it stains a lesser percentage of lung adenocarcinoma. To develop an anti-p40 mouse monoclonal antibody (MMp40) for immunohistochemistry, and to evaluate its sensitivity and specificity in normal and neoplastic tissues, with emphasis on lung cancer. The MMp40 (BC28) antibody was developed and tested for specificity and sensitivity on normal (n = 34) and neoplastic tissues (n = 493). Staining of MMp40, p63, and RPp40 were directly compared in lung cancers, and MMp40 was evaluated in breast, bladder, skin, prostate, and head and neck cancers. Benign prostate glands and prostatic intraepithelial neoplasia were also tested in a direct comparison of MMp40 versus p63. The MMp40 provided equivalent staining versus RPp40 and p63 in lung squamous cell carcinoma, but stained a lesser percentage of lung adenocarcinoma than p63 did. The MMp40 staining was observed in a greater percentage of urothelial carcinomas, squamous and basal cell skin cancers, and head and neck cancers of squamous cell origin. No breast-infiltrating ductal carcinomas or prostatic adenocarcinomas were stained. The MMp40 expression in basal cells of prostate glands and prostatic intraepithelial neoplasia were almost identical to those of p63. The MMp40 (BC28) monoclonal antibody is a high-quality screening antibody for determining squamous cell carcinoma in lung cancers, skin cancers of squamous or basal cell origin, squamous cell head and neck cancers, and urothelial carcinomas.

Comparison between anatomical cross-sectional imaging and 18F-FDG PET/CT in the staging, restaging, treatment response, and long-term surveillance of squamous cell head and neck cancer

The outcome of head and neck squamous cell cancer depends primarily on its prompt diagnosis and treatment. Unfortunately, in many cases ominous prognostic factors such as lymph node metastases or osteomandibular extension are present at the time of diagnosis. We review the relative efficacy of contrast-enhanced computed tomography (ceCT), MRI, and F-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the early detection of head and neck squamous cell cancer, as well as its impact on treatment management and outcomes. Medline and Web of Knowledge databases, from 2000 to January 2013, were evaluated. Ninety-seven reports were selected, but only 11 studies comparing PET or PET/CT with CT and 11 comparing PET or PET/CT with MRI were found appropriate for analysis. ceCT and MRI continue to be the reference imaging modalities for the study of primary tumors, especially in the evaluation of the extension of disease and its relationship with nearby anatomical structures. There is increasing evidence that F-FDG PET/ceCT can provide accurate anatomical details similar to ceCT alone, as well as accurate information on osteomandibular tumor invasion similar to MRI. The major advantage of PET/CT over other imaging methods is its ability to detect relatively small lymph node metastases located in difficult-to-interpret positions. PET/CT is also highly sensitive for the detection of distant metastases and in assessing the response to chemotherapy or chemoradiation treatment and in predicting outcome. ceCT and MRI are the gold standards for evaluating primary and osteomandibular tumoral infiltration. F-FDG PET/CT plays a major role in the detection of lymph node and distant metastases, in assessing the response to neoadjuvant/adjuvant chemotherapy or chemoradiation therapy, and in predicting outcome.

Robust Prognostic Gene Expression Signatures in Bladder Cancer and Lung Adenocarcinoma Depend on Cell Cycle Related Genes

Few prognostic biomarkers are approved for clinical use primarily because their initial performance cannot be repeated in independent datasets. We posited that robust biomarkers could be obtained by identifying deregulated biological processes shared among tumor types having a common etiology. We performed a gene set enrichment analysis in 20 publicly available gene expression datasets comprising 1968 patients having one of the three most common tobacco-related cancers (lung, bladder, head and neck) and identified cell cycle related genes as the most consistently prognostic class of biomarkers in bladder (BL) and lung adenocarcinoma (LUAD). We also found the prognostic value of 13 of 14 published BL and LUAD signatures were dependent on cell cycle related genes, supporting the importance of cell cycle related biomarkers for prognosis. Interestingly, no prognostic gene classes were identified in squamous cell lung carcinoma or head and neck squamous cell carcinoma. Next, a specific 31 gene cell cycle proliferation (CCP) signature, previously derived in prostate tumors was evaluated and found predictive of outcome in BL and LUAD cohorts in univariate and multivariate analyses. Specifically, CCP score significantly enhanced the predictive ability of multivariate models based on standard clinical variables for progression in BL patients and survival in LUAD patients in multiple cohorts. We then generated random CCP signatures of various sizes and found sets of 10–15 genes had robust performance in these BL and LUAD cohorts, a finding that was confirmed in an independent cohort. Our work characterizes the importance of cell cycle related genes in prognostic signatures for BL and LUAD patients and identifies a specific signature likely to survive additional validation.

Prognostic significance and predictive performance of volume-based parameters of F-18 FDG PET/CT in squamous cell head and neck cancers.

It has been previously reported that metabolic tumor volume on positron emission tomography-computed tomography predicts disease recurrence and death in head-and-neck cancer. In this study, we assessed the prognostic value of metabolic tumor volume measured using F18-Fluorodeoxyglucose PET/CT in patients with head and neck squamous cell carcinoma. We analyzed the imaging findings of 74 patients (age 57±16) retrospectively, with head and neck cancer who underwent PET/CT scan for staging and after treatment. Forty-tree patients had nasopharynx, 15 patients had hypopharynx, 9 patients had larynx, and 7 patients had oropharynx cancer. The MTVs of primary sites with or without lymph nodes were measured, and outcomes were assessed using the treatment response evaluation by the Response Evaluation Criteria in Solid Tumors and recurrence events during follow-up. A total of 48 patients had complete response or no recurrence was detected as of in the last follow-up. Of the first PET/CT scan, the median primary tumor SUVmax was 18.8 and the median nodal SUVmax was 13.4. The median primary tumor MTV% 50s ranged from 11.12 cm3 to 16.28 cm3, and the MTV after the therapy ranged from 1.18 cm3 to 3.51 cm3. Metabolic tumor volume (MTV) represents tumor burden, which shows F18-Fluorodeoxyglucose uptake and has a potential value in predicting short-term outcome and disease-free survival in patients with head and neck cancer.

Usefulness of 64Cu-ATSM in Head and Neck Cancer

Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a hypoxia-avid, positron emitter radiotracer. The primary aim of this study is to assess the efficacy of pretherapy Cu-ATSM PET/CT as a prognostic factor of response to therapy. The secondary aims are to investigate if there is a difference between early and late PET/CT scans and if there is a difference between the biologic tumor volume (BTV) in radiotherapy treatment planning calculated between Cu-ATSM and F-FDG, and to assess if Cu-ATSM is a prognostic marker of disease progression. Eleven patients with head and neck cancer treated with chemoradiotherapy were enrolled prospectively; both Cu-ATSM and F-FDG PET/CT scans before and after treatment were obtained. The Cu-ATSM scans were performed after 1 hour (early) and 16 hours (late). All patients had stage III or IV squamous cell head and neck cancer; 7 of 11 patients had nodal metastasis, and 22 cancer foci were detected with Cu-ATSM. SUVmax was 16.2 ± 7.9, and there was no significant SUVmax difference between early and late imaging. F-FDG SUVmax before therapy was 15.6 ± 9.4, whereas F-FDG SUVmax after therapy was 1.5 ± 1.2. Sensitivity and specificity values of Cu-ATSM calculated with receiver operating characteristic curves were 100% and 50% considering the SUVmax and 100% and 33% considering the volume, respectively. No difference has been found between the BTV contoured with Cu-ATSM and F-FDG. The Cu-ATSM scans showed high sensitivity but low specificity in predicting neoadjuvant chemoradiotherapy response. No difference was noted between early and late scans. F-FDG and Cu-ATSM provided similar results about delineation of BTV.

PO-0668: Patterns of failure after intensity modulated radiation therapy for squamous cell head and neck carcinoma

PO-0668: Patterns of failure after intensity modulated radiation therapy for squamous cell head and neck carcinoma

Antibody response to human papillomavirus vaccine in subjects with inherited bone marrow failure syndromes

Patients with Fanconi anemia (FA) and other inherited bone marrow failure syndromes (IBMFS) have extremely high risks of squamous cell head and neck, and gynecologic carcinomas. In the general population, these sites are often associated with infection with human papillomaviruses (HPV), particularly HPV16 and HPV18. Our objectives were to measure the levels of HPV antibodies in unvaccinated patients, and to determine whether these patients developed and maintained similar levels of antibodies as those observed in healthy women, following vaccination with the currently licensed HPV L1 virus-like particles (VLP) vaccines. We measured anti-HPV IgG antibody levels in sera from patients using an HPV16 or HPV18 L1 VLP enzyme-linked immunoabsorbent assay. Most unvaccinated patients did not have detectable antibody levels, except for a few women above age 25. Both FA and other IBMFS patients developed antibody levels following vaccination that were similar to those previously described in healthy women, and those levels appeared to be sustained out to 5 years after immunization. Thus, antibody responses to the HPV L1 VLP vaccine in patients with FA and other IBMFS appeared to be similar to the responses reported in the general population, implying potential efficacy against future infections with the HPV types contained in the vaccine.