Intensity-modulated radiation therapy with concurrent carboplatin and paclitaxel for locally advanced head and neck cancer: toxicities and efficacy.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) and alternative chemotherapy regimens strive to maintain efficacy while minimizing toxicity in locally advanced head and neck cancer (LAHNC) treatment. Our experience with concurrent IMRT and taxane-based chemotherapy is presented. METHODS: A retrospective review of 150 consecutive patients with LAHNC treated with IMRT and concurrent taxane-based chemotherapy with curative intent was performed. The IMRT fractionation regimen consisted of 69.3 Gy to gross disease (2.1 Gy/fraction) and 56.1 Gy to prophylactic nodal sites (1.7 Gy/fraction). Weekly paclitaxel (30 mg/m(2)) and carboplatin (area under the concentration-time curve [AUC], 1) were given concurrently to all patients, and 69% received weekly induction with paclitaxel (60 mg/m(2)) and carboplatin (AUC, 2). RESULTS: Over 90% of patients received the prescribed radiation dose. Ninety-six percent completed five or more cycles of concurrent chemotherapy, with similar tolerability for induction chemotherapy. A percutaneous endoscopic gastrostomy (PEG) tube was required in 80 patients, with 10 maintaining PEG use >18 months. Acute grade 4 mucositis and dermatitis developed in 2.0% and 4.0% of patients, respectively. No patient experienced nadir sepsis, grade ≥3 late xerostomia, or significant nephropathy or gastrointestinal toxicity. Median follow-up was 30 months. The 3-year locoregional control rate was 83.2% with disease-free survival and overall survival rates of 78.8% and 76.5%, respectively. CONCLUSION: Rates of acute and late toxicities were low, with excellent radiation dose delivery and impressive tumor control at 3 years, suggesting that concurrent carboplatin and paclitaxel with IMRT is a reasonable therapeutic option for the curative treatment of LAHNC.

Management of occult fractures in the skeletally immature patient: cost analysis of implementing a limited trauma magnetic resonance imaging protocol.

STUDY OBJECTIVE: Fractures in children may not be visible in the result of initial radiography, and undertreatment and overtreatment of such fractures routinely occur. The purpose of this study was to evaluate the potential cost of implementing limited magnetic resonance imaging (MRI) at initial encounter, when radiographs are unrevealing. METHODS: This was a retrospective review of 204 emergency department pediatric patients presenting between January 1, 2005 and February 28, 2006 with appendicular trauma, with initially negative radiographic result and follow-up. Emergency department treatment categorization of (1) no treatment, (2) ACE wrap, (3) brace, (4) splint, or (5) casting was evaluated. Final determination of presence or absence of fracture was based on follow-up. Patients with fractures were considered undertreated when they received categories 1 to 3 care; patients without fractures were considered overtreated when they received categories 4 and 5 care. The percentage of patients undertreated or overtreated and direct and total costs were determined and analyzed in conjunction with the cost of a limited MRI at initial encounter. Total costs include direct and indirect costs (lost wages for each day off work for the parent). Cost estimates assume patients determined to be without fractures at follow-up will not return for follow-up clinical care or obtain additional imaging after MRI at initial encounter. RESULTS: Twenty-eight (13.7%) of the 204 patients had fractures at follow-up. Fifty one percent of patients without fractures were overtreated; 29% with fractures were undertreated. Mean direct cost for all patients and cost estimation with limited MRI protocol were $843.81 and $891.79, respectively (P = 0.365). However, mean total cost for all patients and cost estimation with limited MRI protocol was $1059.49 and $929.10, respectively (P = 0.02). CONCLUSIONS: Based on clinical grounds and initially negative radiographic results, slightly more than half of patients without fractures can be overtreated, and nearly one third of patients with fractures can be undertreated. Instituting a protocol that includes limited trauma MRI lowers the total cost of care without increasing direct cost, and appropriate care may be instituted at the outset.

Lymphovascular invasion in colorectal cancer: an interobserver variability study.

BACKGROUND: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. DESIGN: Fifty cases of American Joint Committee on Cancer stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty hematoxylin and eosin (H&E) slides (1 from each case) were circulated to 6 gastrointestinal pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (kappa) statistics, which correct for agreement by chance, and for percentage agreement. RESULTS: The average kappa values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Fig. 1). Agreement was fair for H&E small vessel invasion [kappa=0.28; 95% confidence interval (CI): 0.22-0.34]. The least agreement was seen in interpretation of H&E large vessel invasion (kappa=0.18; 95%CI: 0.11-0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, kappa=0.42, 95%CI: 0.20-0.63, small vessel, kappa=0.26, 95%CI: 0.10-0.42) and D2-40 (kappa=0.32, 95%CI: 0.21-0.42). CONCLUSIONS: Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of LVI, as this assessment may impact patient prognosis and thus change the course of clinical treatment.

Minichromosome maintenance protein expression in benign nevi, dysplastic nevi, melanoma, and cutaneous melanoma metastases.

BACKGROUND: Minichromosome maintenance (MCM) proteins are a recently elucidated group of polypeptides intimately involved in DNA replication and appreciable only in cycling cells. In other organ systems their expression has proven more prognostically useful than cell proliferation markers such as Ki-67 and proliferating cell nuclear antigen. To date, the evaluation of MCM proteins in melanocytic neoplasms has not been undertaken. OBJECTIVE: We sought to determine whether MCM protein 2 (the most extensively evaluated of the MCM protein family) is present in melanocytes from benign nevi, dysplastic nevi, primary cutaneous melanomas, and cutaneous melanoma metastases and, if so, whether there exists a significant difference in expression among the 3 groups. METHODS: Immunohistochemical staining for MCM 2 was performed on tissue sections from 10 benign nevi, dysplastic nevi, and primary cutaneous melanomas and from 5 cutaneous melanoma metastases. Approximately 200 cells were evaluated microscopically in 5 separate fields for each specimen and the number of positively staining nuclei was counted. After a percentage was calculated for each lesion, the data were pooled and statistically analyzed. RESULTS: Melanocyte nuclear staining was readily visible microscopically. The percentage of positively staining nuclei in benign nevi (1.2%), dysplastic nevi (6.1%), primary cutaneous melanomas (49.1%), and cutaneous melanoma metastases (40.9%) was significantly different (P < .0001) among the 4 groups. Using paired comparisons, statistically significant differences were found between benign nevi and melanoma, dysplastic nevi and melanoma, benign nevi and cutaneous melanoma metastases, and dysplastic nevi and cutaneous melanoma metastases. There was no statistically significant difference between cutaneous melanoma metastases and primary cutaneous melanoma. LIMITATIONS: This is a small pilot study without blinded evaluation of the tissue sections and lacking correlation with patient clinical outcome or accepted histologic prognostic factors. CONCLUSION: MCM protein expression appears to differ significantly in melanocytic neoplasms and potentially provides an additional tool for distinguishing benign tumors from their malignant counterparts. Further evaluation of this expression may prove useful in delineating the biologic behavior of these tumors and warrants additional research.

Diagnostic accuracy of MALDI mass spectrometric analysis of unfractionated serum in lung cancer.

PURPOSE: There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls. PATIENTS AND METHODS: We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training-testing paradigm with application of the model profile defined in a training set to a blinded test cohort. RESULTS: Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A. CONCLUSIONS: We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.

Variability of in situ proteomic profiling and implications for study design in colorectal tumors.

Knowledge of intrinsic tumor heterogeneity is vital for understanding of tumor progression mechanisms as well as for providing efficient treatments. In situ proteomic profiling of tumors is a powerful technology with potential to enhance our understanding of tumor biology, but sources of variability due to patient and tumor heterogeneity are poorly understood and are the topic of this investigation. Clarification of variability within case and between cases is also important for designing future studies. Direct protein profiling by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a sensitive and powerful technology for obtaining hundreds of protein expression peaks from a thin tissue section. By combining robotic microspotting and laser capture microdissection with MALDI MS, we acquired multiple spectra per case to evaluate inter- and intra-case variability in human colorectal tumor and murine cecal carcinoma. We detected 256 peaks from 164 samples of 111 patients, which consisted of 55 normal colorectal mucosal samples, 24 adenomas, 71 primary carcinomas, and 14 hepatic metastases. In addition, we detected 291 peptide/protein peaks from 34 orthotopically transplanted murine cecal carcinomas and 14 hepatic metastases. In human colorectal samples, we observed that proteomic profiling in adenomas was more homogeneous across patients than in normal mucosa specimens (p=0.0008), but primary carcinoma exhibited greater heterogeneity than normal mucosa and adenomas (both p<0.0001). Murine cecal carcinomas were homogeneous within and between carcinomas, while their hepatic metastases tended toward greater intra-tumor differences (p<0.0001). Inter- and intra-case variability was approximately equal for many protein peaks. Acquiring up to 5 subsamples per case could reduce the total number of cases required, but further reduction from additional subsampling was modest unless intra-case variability comprises a greater proportion of total variation (e.g. >70%). In summary, this study characterizes intra- and inter-case variability of high-throughput protein expression in colorectal tumors, and provides guidance for the sample numbers required for in situ proteomic studies.

A Phase II multi-institutional trial of chemoradiation using weekly docetaxel and erythropoietin for high-risk postoperative head and neck cancer patients.

PURPOSE: To determine efficacy and toxicities of postoperative concurrent chemoradiation using docetaxel in high-risk head and neck cancer. METHODS AND MATERIALS: High-risk patients were enrolled 2-8 weeks after surgery. Treatment included 60 Gy for 6 weeks with weekly docetaxel 25 mg/m(2) and erythropoietin alpha 40,000 U for hemoglobin < or =12 g/dL. Primary endpoints included locoregional control (LC), disease-free survival (DFS), and patterns of failure (POF). Secondary endpoints were toxicity and quality of life. RESULTS: Eighteen patients were enrolled (14 male, 4 female), aged 24-70 years (median, 55 years). Primary site included oropharynx = 7, oral cavity = 8, hypopharynx = 1, and larynx = 2. Pathologic American Joint Committee on Cancer Stage was III = 3 patients, IV = 15 patients. High-risk eligibility included > or =2 positive lymph nodes = 13, extracapsular extension = 10, positive margins = 8 (11 patients with two or more risk factors). Docetaxel was reduced to 20 mg/m(2)/week after 5 patients had prolonged Grade 3 or higher mucositis. Overall, number of doses delivered was 2 of 6 = 1, 3 of 6 = 2, 4 of 6 = 2, 5 of 6 = 4, 6 of 6 = 9 patients. With median follow-up of 30 months (range, 5-66), 10 (56%) patients are alive and have no evidence of disease (NED); POF: three local recurrences (two with distant) and 1 distant only. One-year survival was 76%, median PFS and DFS had not been reached. Three-year LC was 82%. No Grade 3 or higher late toxicities were observed, although a few cases of prolonged mucositis and taste loss (>3 months) were seen, particularly at 25 mg/m(2)/week. CONCLUSION: Postoperative radiation therapy with weekly docetaxel 20 or 25 mg/m(2)/week for high-risk postoperative head and neck cancer caused intolerable mucosal toxicity, prompting early study termination. Further studies should consider 15 mg/m(2). Actuarial 3-year LC is 82%, similar to cisplatin-based chemoradiation regimens. Distant metastasis remains an important issue requiring additional systemic interventions.