Specific Subsites Research Articles

Oncogenic mutations and microsatellite instability phenotype predict specific anatomical subsite in colorectal cancer patients

In colorectal cancer (CRC) oncogenic mutations such as KRAS alterations, are considered standard molecular biomarkers that predict the clinical benefit for targeted intervention with epidermal growth factor receptor (EGFR) inhibitors. In addition, these mutations are associated with specific anatomical area in colon tumor development, as BRAF mutations with the microsatellite instability (MSI). In this translational study, we aimed to assess the mutation frequencies of the EGFR (hotspot area and polyadenine deletions A13_del), KRAS, BRAF(V600E), and PIK3CA oncogenes in a series of 280 CRC patients. MSI phenotypes are also considered in this series. All patients' clinicopathological data were assessed for statistical analysis and its associations were validated. We verified multiple associations between oncogenic mutations and determined clinicopathological tumor features (1) EGFR A13_deletions are associated with right colon carcinoma (P<0.005), mucinous histotype (P=0.042), G3 grading (P=0.024), and MSI status (P<0.005); (2) PIK3CA mutations are related mucinous histotype (P=0.021); (3) KRAS(G12) and KRAS(G13) mutations are correlated, respectively, with the left and right colon cancer development (P<0.005), and finally (4) MSI is associated with right colon tumors (P<0.005). Mostly, we verified a higher frequency rate of the KRAS(G13) and EGFR A13_del oncogene mutations in right colon cancer; whereas KRAS(G12) codon mutation occurs more frequently in left colon cancers. In particular, we assessed that right vs left colon cancer are associated with specific molecular characteristics. These evidences, in association with clinicopathological data, can delineate novel approaches for the CRC classification and targeted intervention.

Update on the Effect of Botulinum Toxin Pretreatment on Laser Resurfacing Results

Background: Facial laser resurfacing and chemodenervation with botulinum toxin type A are used independently as means of nonsurgical facial rejuvenation. Recent reports in the literature have described combining these 2 therapies, claiming improved and longer-lasting laser resurfacing results. To date, no scientific investigation has been undertaken to prove or disprove this theory. Design: Institutional review board–approved, prospective, randomized, blinded study at university-affiliated outpatient cosmetic surgery offices. Intervention: Patients had one side of their face injected, at specific anatomic subsites (crow’s feet, horizontal forehead furrows, and glabellar frown lines), with botulinum toxin 1 week before laser resurfacing. After receiving an injection, patients underwent cutaneous laser exfoliation on both sides of the face with either a carbon dioxide or an erbium dual-mode laser. Main Outcome Measures: Patients’ injected (experimental) and noninjected (control) sides were compared after laser resurfacing. Follow-up was documented at 6 weeks, 3 months, and 6 months after laser resurfacing. Subjective evaluation, based on a visual analog scale, was performed in person by a blinded observer. Furthermore, a blinded panel of 3 expert judges (1 facial plastic surgeon, 1 oculoplastic surgeon, and 1 cosmetic dermatologist) graded 35-mm photographs taken during postoperative follow-up visits. Results: Ten female patients were enrolled in the study. A 2-tailed t test showed that all sites that were pretreated with botulinum toxin showed statistically significant improvement (P .05) over the nontreated side, with the crow’s feet region showing the greatest improvement. Comparing results between the carbon dioxide and erbium lasers did not result in any statistically significant differences. Conclusions: Hyperdynamic facial lines, pretreated with botulinum toxin before laser resurfacing, heal in a smoother rhytid-diminished fashion. These results were clinically most significant in the crow’s feet region. We recommend pretreatment of movement-associated rhytids with botulinum toxin before laser resurfacing. For optimum results, we further recommend continued maintenance therapy with botulinum toxin postoperatively.

Specific and Sensitive Hydrolysis Probe-Based Real-Time PCR Detection of Epidermal Growth Factor Receptor Variant III in Oral Squamous Cell Carcinoma

BackgroundThe tumor-specific EGFR deletion mutant, EGFRvIII, is characterised by ligand-independent constitutive signalling. Tumors expressing EGFRvIII are resistant to current EGFR-targeted therapy. The frequency of EGFRvIII in head and neck squamous cell carcinoma (HNSCC) is disputed and may vary by specific sub-site. The purpose of this study was to measure the occurrence of EGFRvIII mutations in a specific HNSCC subsite, oral squamous cell carcinoma (OSCC), using a novel real-time PCR assay.MethodologyPre-treatment Formalin Fixed Paraffin Embedded (FFPE) cancer specimens from 50 OSCC patients were evaluated for the presence of EGFRvIII using a novel hydrolysis probe-based real-time PCR assay. EGFR protein expression in tumor samples was quantified using fluorescent immunohistochemistry (IHC) and AQUA® technology.Principal findingsWe detected EGFRvIII in a single OSCC patient in our cohort (2%). We confirmed the validity of our detection technique in an independent cohort of glioblastoma patients. We also compared the sensitivity and specificity of our novel real-time EGFRvIII detection assay to conventional RT-PCR and direct sequencing. Our assay can specifically detect EGFRvIII and can discriminate against wild-type EGFR in FFPE tumor samples. AQUAnalysis® revealed that the presence of EGFRvIII transcript is associated with very high EGFR protein expression (98th percentile). Contrary to previous reports, only 44% of OSCC over-expressed EGFR in our study.Conclusion and SignificanceOur results suggest that the EGFRvIII mutation is rare in OSCC and corroborate previous reports of EGFRvIII expression only in tumors with extreme over-expression of EGFR. We conclude that EGFRvIII-specific therapies may not be ideally suited as first-line treatment in OSCC. Furthermore, highly specific and sensitive methods, such as the real-time RT-PCR assay and AQUAnalysis® described here, will provide accurate assessment of EGFR mutation frequency and EGFR expression, and will facilitate the selection of optimal tailored therapies for OSCC patients.

Diabetes Mellitus Is an Independent Risk Factor for Colorectal Cancer

Epidemiological studies have suggested positive associations between diabetes and colorectal cancer. However, the findings were inconsistent, especially regarding specific sex or cancer subsite. To conduct a systematic review with meta-analysis to examine the association of diabetes mellitus with risk of colorectal cancer and to investigate whether the association is dependent on sex, cancer subsite, race/ethnicity, or duration of diabetes. Relevant studies were identified by searching Pubmed to May 12, 2011. The reference lists of identified articles were also reviewed. Two authors independently selected the studies and extracted relevant data. The study quality was assessed. Thirty-nine studies (28 cohort studies and 11 case-control studies) were included in the final analysis. Compared with non-diabetic subjects, the pooled risk estimate of colorectal cancer for diabetic subjects was 1.29 (95% CI = 1.23-1.35). The subgroup analyses revealed that the risk was significantly increased for both genders, for every cancer subsite, and for both short duration and long duration of diabetes. Exposure to diabetes increased the risk of colorectal cancer for White and Asian, whereas there was no evidence of such an association either among Black or native Hawaiians. Our results confirmed that subjects with diabetes are at modestly increased risk of developing colorectal cancer.

Trends and inequalities in laryngeal cancer survival in men and women: England and Wales 1991–2006

Laryngeal cancer in men is a relatively common malignancy, with a marked socioeconomic gradient in survival between affluent and deprived patients. Cancer of the larynx in women is rare. Survival tends to lower than for men, and little is known about the association between deprivation and survival in women with laryngeal cancer. This paper explores the trends and socio-economic inequalities in laryngeal cancer survival in women, with comparison to men. We examined relative survival among men and women diagnosed with laryngeal cancer in England and Wales during 1991-2006, followed up to 31 December 2007. We estimated the difference in survival between the most deprived and most affluent groups (the 'deprivation gap') at one and five years after diagnosis, for each sex, anatomical subsite and calendar period. Five year survival for all laryngeal cancers combined was up to 8% lower in women than in men. This difference is only partially explained by the differential distribution of anatomical subsites in men and women. Disparities in survival between men and women were also present within specific subsites. In contrast to men, there was little evidence of a consistent deprivation gap in survival for women at any of the anatomical subsites. The stark socioeconomic inequalities in laryngeal cancer survival in men do not appear to be replicated in women. The origins of the socio-economic inequalities in survival among men, and the disparities in survival between men and women at specific tumour subsites remains unclear.

The Contribution of Imaging-Based Treatment Planning Quality Assurance Rounds in Head and Neck Radiotherapy Planning

While standard guidelines for Intensity Modulated radiation therapy (IMRT) may assist in target delineation for some head and neck (HN) cancers, the complex anatomy, varying patterns of spread, frequent occurrence of unusual or advanced presentations, and risk of treatment-related toxicities from overly generous delineation render HN treatment planning (TP) very challenging. Since 2007 we have had weekly Treatment Planning Quality Assurance (TPQA) rounds with radiation oncologists and a specialized diagnostic neuroradiologist present to review TP contours for all new patients. This study quantifies the impact of this process. From 8/2010 - 2/2011, IMRT contours for 84 consecutively treated HN cancer patients were reviewed. Almost always, pre-treatment magnetic resonance imaging (MRI) was reviewed independently and fused in multiple orientations to the computed tomography TP scan using a commercial software package; thus the contours could be viewed by the group directly opposed to the MRI if desired. Pre- and post-TPQA rounds contours were saved. For this study, the pre- and post-TPQA contours were compared to record alterations in the coverage of major components (gross tumor, clinical target volume (CTV), lymph nodes, perineural invasion, or bone invasion) and the volume of change. The tumors were mostly advanced stage (III-IV) and included various subsites: oral cavity (21%), oropharynx (19%), sinonasal (12%), skin (12%), nasopharynx (10%), salivary gland (8%), and hypopharynx (6%). Of the 84 cases, 47 (56%) were altered, including: CTV, 30/47 cases (64%); gross tumor, 25/47 cases (53%); lymph nodes, 7/47 (15%); perineural invasion, 6/47 (13%); and bone invasion, 3/47 (6%). The absolute volume change resulting from TPQA review ranged from -169.12 cc to 124.76 cc (0.03% to 636.88% of absolute pre-TPQA volume), with a mean absolute change of 32.32 cc (39.48%) and a median change of 13.54 cc (8.96%). Volumes were equally likely to be increased (49%) or decreased (51%). The most frequently altered subsites were: hypopharynx (4/5, 80%), sinonasal (7/10, 70%), and skin (7/10, 70%). This study demonstrates the impact of a neuroradiology-based approach to HN TPQA. Changes were suggested to half of the cases, and the changes were equally likely to increase or decrease the target volume, suggesting a balance between tumor coverage and desire to avoid toxicity. High frequencies of changes were seen in delineation of gross tumor and CTVs because of the wide applicability of these issues, but in addition, there are specific anatomic subsites with challenging patterns of infiltrative, intracranial, or perineural spread which warrant intensive imaging-based review in collaboration with a diagnostic specialist.

Conserved Core Substructures in the Overlay of Protein–Ligand Complexes

The method of conserved core substructure matching (CSM) for the overlay of protein-ligand complexes is described. The method relies upon distance geometry to align structurally similar substructures without regard to sequence similarity onto substructures from a reference protein empirically selected to include key determinants of binding site location and geometry. The error in ligand position is reduced in reoriented ensembles generated with CSM when compared to other overlay methods. Since CSM can only succeed when the selected core substructure is geometrically conserved, misalignments only rarely occur. The method may be applied to reliably overlay large numbers of protein-ligand complexes in a way that optimizes ligand position at a specific binding site or subsite or to align structures from large and diverse protein families where the conserved binding site is localized to only a small portion of either protein. Core substructures may be complex and must be chosen with care. We have created a database of empirically selected core substructures to demonstrate the utility of CSM alignment of ligand binding sites in important drug targets. A Web-based interface can be used to apply CSM to align large collections of protein-ligand complexes for use in drug design using these substructures or to evaluate the use of alternative core substructures that may then be shared with the larger user community. Examples show the benefit of CSM in the practice of structure-based drug design.

Predicting Binding to P-Glycoprotein by Flexible Receptor Docking

P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an “induced-fit” ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.

Abstract LB-198: Design and synthesis of non-ATP competitive inhibitors of CDK4/Cyclin D using REPLACE

Abstract CDK4/Cyclin D is an established anticancer drug target closely associated with breast and non-small cell lung cancers. Conventionally, the ATP binding site of CDKs has been the focus of inhibitor design. Here we present an alternative strategy to target CDK4 which allows us to design non-ATP competitive inhibitors by exploring the cyclin binding groove (CBG) present in Cyclin D, its positive regulatory subunit. The CBG of Cyclin D recognizes a cyclin binding motif (CBM) possessed by both natural inhibitors and substrates of CDK4/Cyclin D and is composed of primary and secondary hydrophobic pockets separated by a polar subsite; In addition, we recently described a hydrophobic extension to the major pocket and which is unique to Cyclin D1. The REPLACE method has been previously applied, through which determinants in known potent peptide inhibitors (binding in an extended conformation) are replaced with non-peptidic surrogates. In this study, a new series of non-peptidic surrogates to replace the original C-terminal residues (C-capping groups) that are key to binding to the primary hydrophobic pocket have been ligated to truncated peptides. Also using this approach, additional series of N-capping groups, (surrogates for N-terminal residues) which are important for the binding to the secondary hydrophobic pocket have been ligated to peptides. Both N- and C-capping groups have been selected to obtain more potent binding to their specific subsite. In addition, through guided docking of a small set of compounds into the hydrophobic extension unique to the cyclin D1 CBG, we have identified compounds with high predicted affinity to cyclin D, suggesting that appropriate modification of an inhibitor could lead to an increase in potency and selectivity. In order to do this, a virtual library composed of low molecular weight fragments has been modeled. Fragments were selected based on several criteria: 1) Log P ≤ 3; 2) Rotational bonds ≤ 3; 3) MW between 170 and 280. After docking, formation and energy minimization of the protein-fragment peptide complex enabled the prediction of capping groups with the highest potential for binding to the Cyclin D pocket. In order to evaluate these compounds in a facile and straightforward manner and to eliminate ATP competitive inhibitors, a competitive binding assay based on fluorescence polarization, has been developed for the first time for cyclin D1. The FP assay for Cyclin D provided insights into the binding of peptidic inhibitors to cyclin D1, as well as SAR for both N- and C-capping groups. By virtue of the establishment of computational, synthetic and in vitro testing work, the prediction of more potent capping groups will be facilitated. These experiments will serve as a useful guide for future direction of drug development for the design of inhibitors with selectivity towards Cyclin D and with potential as anti-tumor therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2011-LB-198

Potential Pitfalls and Therapeutic Implications of Pretherapeutic Radiologic Staging in Glottic Cancers

Objectives: The aim of this study was to compare the radiologic findings with histological results of anatomically matched whole organ sections and to analyze the accuracy of pretherapeutic radiologic staging of glottic cancers. Methods: The histologic findings of surgical specimens of 30 patients who had undergone total or conservative partial laryngectomy for glottic cancers were matched and compared with the pretherapeutic radiologic findings using CT and MR imaging. The accuracy of pretherapeutic radiologic staging was assessed for specific subsites for staging of glottic cancers. Results: The overall accuracy of pretherapeutic staging with CT and MR imaging was 84.9%; 12.1% associated with false positive and 3% associated with false-negative assessments. For all subsites, the overall sensitivity was 88%, specificity 84%, positive predictive value 65%, and negative predictive value 95%. Subsites such as the anterior commissure, paraglottic space, and preepiglottic space showed lower specificity (42%, 65%, and 79% respectively) than the overall specificity. The radiologic evaluation for cartilage invasion showed the accuracy of 84.8% and yielded acceptable specificity (89%) and high negative predictive value (98%). Conclusion: Although pretherapeutic radiological examination is a very useful technique for the evaluation of tumor invasion into specific laryngeal subsites, the pretherapeutic radiologic staging can be challenging when distinguishing tumor from peritumoral inflammation.

Histopathological Evaluation of the Nervous System in National Toxicology Program Rodent Studies

This article outlines the changes and underlying rationale for modifications to the histopathological evaluation of the nervous system during toxicology and carcinogenesis studies conducted by the National Toxicology Program (NTP). In the past, routine evaluation of the nervous system was mostly limited to three sections of brain, and occasionally the spinal cord and peripheral nerves. Factors such as the increasing occurrence of human neurological diseases and associated economical cost burden, the role of unidentified environmental stressors in neurodegenerative disorders, multiple therapeutic drug-induced neuropathies noted in human clinical trials, and the exponential use of environmental chemicals with unknown neurotoxic potential necessitate a more extensive evaluation of the nervous system. The NTP has modified its protocol to include examination of key anatomic subsites related to neurodegenerative diseases such as Parkinson's disease. Modifications include four additional sections of the brain. Increasing the number of brain sections permits examination of a greater number of specific anatomic subsites with unique vulnerability. In addition, the spinal cord, peripheral nerves, trigeminal ganglion, and intestinal autonomic ganglia will be evaluated as needed. It is expected that this modified approach will increase the sensitivity of detecting neurotoxicants and neurocarcinogens important in human neurologic and neurodegenerative disorders.

Colon carcinoma – Classification into right and left sided cancer or according to colonic subsite? – Analysis of 29 568 patients

Background It is common to distinguish between right and left colon cancer (RCC and LCC). But, little is known about the influence of its exact location on the tumor stage and characteristics when considering the colonic subsite within the right or left colon. Methods During a five-year period, 29 568 consecutive patients were evaluated by data from the German multi-centered observational study “Colon/Rectal Carcinoma”. Patients were split into 7 groups, each group representing a colonic subsite. They were compared regarding demographic factors, tumor stage, metastatic spread and histopathological characteristics. Results Analysis of tumor differentiation and histological subtype revealed a linear correlation to the ileocecal valve, supporting the right and left side classification model. However, cancers arising from the RCC’s cecum (52.3%) and LCC’s splenic flexure (51.0%) showed the highest proportion of UICC stage III/IV tumors and lymphatic invasion, whereas the RCC’s ascending colon (46.5%) and LCC’s descending (44.7%) showed the lowest, which supports a more complex classification system, breaking down the right and left sides into colonic subsites. Conclusions Age, tumor grade and histological subtype support the right and left side classification model. However, gender, UICC stage, metastatic spread, T and N status, and lymphatic invasion correlated with a specific colonic subsite, irrespective of the side. The classification of RCC or LCC provides a general understanding of the tumor, but identification of the colonic subsite provides additional prognostic information. This study shows that the standard right and left side classification model may be insufficient.

Evidence for a possible anatomical subsite-mediated effect of tobacco in oral potentially malignant disorders and carcinoma

To test the hypothesis that cigarette smokers develop oral potentially malignant disorders or carcinomas in preferential anatomical subsites. The association of smoking habit with the presence of oral lesions in specific anatomical subsites was assessed in 123 patients using the odds ratio analysis. When compared to all the other subsites, the relative frequency of smokers with lesions was higher in the buccal mucosa and in the floor of the mouth (FOM) (P=0.002 and P=0.005), while it was lower in the tongue (P<0.0005). Smokers were about 7 years younger than non-smokers (P=0.008). The association of smoking and age suggests that smoking may contribute to generate a field of injury that leads to lesions in shorter periods than other causes. The stronger relationship of smoking with lesions in the buccal mucosa and FOM than in the tongue suggests that tissue characteristics mediate the effects of tobacco.

Neck dissections in the United States from 2000 to 2006: Volume, indications, and regionalization

The purpose of this study was to examine trends in neck dissection and regionalization. This cross-sectional and longitudinal study used the years 2000, 2004, and 2006 data from the Nationwide Inpatient Sample. Chi-square tests compared trends for total neck dissections and specific subsites. To test regionalization, we examined the distribution of procedures across hospital and procedure volume quartiles. From 2000 to 2006, the number of neck dissections increased from 18,112 to 22,918. Three-fourths of the total increase was associated with thyroid and parathyroid gland or skin neoplasms. There was an increase in neck dissections for upper aerodigestive tract (UADT) subsites and no decline for the oropharynx and tongue base. Regionalization occurred as high-volume hospitals and providers performed a greater proportion of neck dissections over time. Neck dissections increased from the year 2000 to 2006. There were no decreases in neck dissections for certain subsites with a greater role for primary chemoradiotherapy. Regionalization has occurred.

Radiotherapy for Head and Neck Cancer

Treatment for patients with head and neck cancer requires a multidisciplinary approach. Radiotherapy is employed as a primary treatment or as an adjuvant to surgery. Each specific subsite dictates the appropriate radiotherapy techniques, fields, dose, and fractionation scheme. Quality of life is also an important issue in the management of head and neck cancer. The radiation-related complications have a tremendous impact on the quality of life. Modern radiotherapy techniques, such as intensity-modulated radiotherapy and image-guided radiotherapy, can offer precise radiation delivery and reduce the dose to the surrounding normal tissues without compromise of target coverage. In the future, efforts should be made in the exploration of novel strategies to improve treatment outcome in patients with head and neck cancer.

The role of human papillomavirus in the increased incidence of base of tongue cancer

Numerous reports have shown that the incidence for oropharyngeal cancer is increasing and that human papillomavirus (HPV) is a risk factor. However, few studies have investigated the specific subsites of the oropharynx. Following our previous research on tonsillar cancer, we assessed the increase in the incidence of base of tongue cancer and the prevalence of HPV in this disease. Between 1998 and 2007, 109 patients were diagnosed for base of tongue cancer in Stockholm county. Ninety-five paraffin-embedded diagnostic tumor biopsies from patients were obtained and tested for HPV, both by general HPV PCR and HPV-16/HPV-33 type-specific PCR. Expression of HPV-16 RNA was analyzed to confirm E6 and/or E7 expression. Incidence data were obtained from the Swedish Cancer Registry. An overall increase in the incidence of base of tongue cancer from 0.15/100,000 person-years during 1970-1974 to 0.47/100,000 person-years during 2005-2007 was found in Sweden. The prevalence of HPV in base of tongue cancer in Stockholm county increased from 58% during 1998-2001 to 84% during 2004-2007 (p < 0.05). In the HPV-positive tumors, HPV-16 dominated (86%) but interestingly, HPV33 was detected in as many as 10%. E6 and/or E7 RNA were found in 85% of the samples tested. The incidence of base of tongue cancer, as well as the proportion of HPV-positive tumors, has increased in Sweden during the study period, suggesting that HPV may contribute to this increase.

A review of risk factors and genetic alterations in head and neck carcinogenesis and implications for current and future approaches to treatment

Head and neck cancer is the fifth most common cancer worldwide but the most common malignant disease site in central Asia. The treatment of head and neck cancer is one of the most challenging in clinical oncology because of the high content of hypoxic cells of the cancer which increases resistance to therapy and also because of the high capacity of the cancer to regrow during treatment. For unresectable tumours, radiotherapy and chemotherapy alone or more often in combination is the treatment of choice. The aim of this paper is to review current understanding of carcinogenesis of head and neck cancer in relation to predisposing risk factors in general and for specific sub-sites and how these risk factors interact with the main reported genetic alterations in the progression of the cancer. The implications of these changes in determining choice of therapy are also discussed from a brief historical perspective of the various treatment approaches of head and neck cancer.

Use of preoperative ultrasonography as guidance for neck dissection in patients with papillary thyroid carcinoma

Preoperative neck ultrasonography (US) may detect nodal metastases of papillary thyroid carcinoma (PTC) but its utility in detecting metastases at specific neck subsites and levels is not known. We therefore evaluated preoperative US in detecting cervical metastases of PTC according to neck subsites and levels. Preoperative US was performed in 133 new patients to detect metastases at three central cervical subsites and five lateral cervical levels. All patients underwent total thyroidectomy and bilateral central neck dissection. Thirty-four patients with lateral nodal metastases underwent modified radical neck dissection. Lymph node metastases to the central and lateral cervical compartments were identified in 57.9% and 25.6%, respectively. The sensitivity and specificity of US for detecting central nodal metastasis were 61.0% and 92.8%, respectively. In the lateral neck, US detected non-palpable lymph node metastases in 6 of 34 patients (17.6%). Overall, US was >85.0% specific at all cervical subsites and levels. Preoperative US may detect cervical metastases of PTC and may assist in determining the necessity and extent of neck dissection in PTC patients.

Alcohol consumption, type of alcoholic beverage and risk of colorectal cancer at specific subsites

Within the Netherlands Cohort Study on diet and cancer, we investigated associations between total alcohol consumption, specific alcoholic beverage consumption and risk of colorectal cancer (CRC) according to anatomical subsite. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Analyses were performed on 2,323 CRC cases, available after 13.3 years of follow-up. Compared to abstaining, alcohol consumption of >/=30.0 g/day ( approximately 3 alcoholic drinks) was positively associated with the risk of CRC (HR: 1.32, 95% CI: 1.06-1.65). Analyses restricted to subjects who reported to have consumed equal amounts of alcohol 5 years before baseline compared to baseline, showed elevated risk estimates for consumers of >/=30.0 g of total alcohol per day as well (HR: 1.53, 95% CI: 1.16-2.01). Suggestive of a subsite-specific effect, cancer risk seemed to increase from proximal colon through rectum; HR: 1.29, 95% CI: 0.85-1.96 for proximal colon cancer, HR: 1.41, 95% CI: 0.94-2.11 for distal colon cancer, HR: 2.07, 95% CI: 1.03-4.18 for rectosigmoid cancer and HR: 1.69, 95% CI: 1.08-2.64 for rectal cancer. No associations were observed between consumption of alcoholic beverages and CRC risk when compared with the nondrinkers of the specific beverage and after adjustment for total alcohol intake. No evidence was found for sex-specific effects of alcohol and alcoholic beverages. In conclusion, our data showed a positive association between alcohol consumption and risk of CRC, which seemed to be mainly explained by the alcoholic content of alcoholic beverages, rather than other constituents. Also, cancer risk may vary according to anatomical subsite.

Pre- and post-radiotherapy MRI results as a predictive model for response in laryngeal carcinoma

The purpose was to determine if pre-radiotherapy (RT) and/or post-radiotherapy magnetic resonance (MR) imaging can predict response in patients with laryngeal carcinoma treated with RT. Pre- and post-RT MR examinations of 80 patients were retrospectively reviewed and associated with regard to local control. Pre-RT MR imaging parameters such as tumor involvement of specific laryngeal anatomic subsites including laryngeal cartilages and post-RT changes, i.e., complete resolution of the tumor or focal mass/asymmetric obliteration of laryngeal tissue and signal pattern on T2-weighted images, were evaluated. Local control was defined as absence of a recurrence at the primary site for 2 years. Local control rates based on pretreatment MR findings were 73% for low pre-RT risk-profile and 29% for high pre-RT risk-profile patients (p=0.0001). Based on posttreatment MR findings, local control rates were 100% score 1, 64% score 2, and 4% score 3 (p<0.0001). Using post-RT T2-weighted images, significant association was found between differences in signal pattern and local control: 77% hypointense, 54% isointense and 15% hyperintense lesions (p<0.001). Differences between means of delay of post-MRI examination were significantly associated with regard to local control (p=0.003); recurrent tumors followed 5 months after RT were more easily detectable on MRI than recurrent tumors within 4 months after RT. Sensitivity, specificity, accuracy, negative and positive predictive values of post-RT score 3 were 96%, 76%, 83%, 98% and 66%. Pre- and post-RT MRI evaluation of the larynx can identify patients at high risk for developing local failure.