Histopathologic features predictive of metastasis and survival in 230 patients with cutaneous squamous cell carcinoma of the head and neck and non-head and neck locations: a single-center retrospective study.

BACKGROUND: Staging systems for cutaneous squamous cell carcinoma (cSCC) produce inconsistent risk stratification. OBJECTIVE: The aim of this study was to identify further prognostic parameters for better stratification. METHODS: We retrospectively analysed the prognostic significance of clinicopathologic parameters of 230 patients who underwent primary excision of invasive cSCC of the head and neck (n = 115) and non-head and non-neck (n = 115) locations. In addition to known high-risk features, we analysed tumour nest shape, invasion pattern, lymphoid response pattern and tumour budding. RESULTS: On multivariable analysis, lymphovascular invasion (LVI) and high tumour budding predicted worse disease-specific survival, and ulceration, LVI and high tumour budding predicted worse overall survival. Only ulceration was independently associated with risk of nodal metastasis. CONCLUSION: High tumour budding, LVI and ulceration are independently associated with poor outcome in cSCC and may be used to refine cSCC prognostic stratification, which is crucial to optimize clinical decision and to identify patients who are more likely to benefit from more aggressive interventions or clinical trials.

Channel catfish ovarian fluid differentially enhances blue catfish sperm performance.

For externally fertilizing fishes, interactions between male and female gametes have been shown to have remarkable impacts on sperm performance. Ovarian fluid (OF) and its ability to alter the swimming behavior of fish sperm makes it a determining factor of fertility. With the expansion of channel catfish (Ictalurus punctatus) ♀ × blue catfish (Ictalurus furcatus) ♂ hybrid aquaculture, it is essential to understand the impacts during fertilization and the magnitude such gametic interactions have on sperm performance and subsequent male fertility potential. This study was conducted to address the following: 1) activate blue catfish sperm with/without channel catfish OF to determine impacts on sperm performance and 2) assess if sperm behave differently when activated in the OF from individual females. Sperm (n = 4 males) were activated without OF (control) and with diluted OF from unique females (n = 6), creating 24 experimental crosses. Sperm motility (%), velocity (VCL), and longevity were analyzed using computer assisted sperm analyses software. With OF incorporated in the activation media, sperm velocity was significantly higher than the control at 10, 20, and 30 s post-activation. OF did not have an impact on motility for any females at 10 s and 20 s post-activation but became significantly higher than the control at 30 s. In all cases, OF treatments greatly increased longevity. Male × female interactions were highly significant, such that motility, velocity, and longevity were dependent on specific male-female pairs. This information shows that OF should be incorporated in aquatic media to simulate natural spawning conditions and accurately assess the fluid mechanics of sperm propulsion for each male. Additionally, there are mechanisms that drive gamete interactions that need to be explored further, which may improve selection of male-female pairs for in-vitro fertilization. On a broad scale, our results also help to shed light on the complexities of fertilization and fish reproduction overall, which may have implications for recruitment variability and recovery strategies of threatened and/or endangered freshwater species.

Targeting the DNA Damage Response in OSCC with TP53 Mutations.

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors.

Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells.

Treatment of head and neck squamous cell carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53 whose alterations are predictive of poor radiation response. DNA-damaging reactive oxygen species (ROS) are a by-product of ionizing radiation that lead to the activation of p53, transcription of p21(cip1/waf1) and, in the case of wild-type TP53 HNSCC cells, cause senescence. The expression of p21 and production of ROS have been associated with the induction of cellular senescence, but the intricate relationship between p21 and ROS and how they work together to induce senescence remains elusive. For the first time, we show that persistent exposure to low levels of the ROS, hydrogen peroxide, leads to the long-term expression of p21 in HNSCC cells with a partially functional TP53, resulting in senescence. We conclude that the level of ROS is crucial in initiating p53's transcription of p21 leading to senescence. It is p21's ability to sustain elevated levels of ROS, in turn, that allows for a long-term oxidative stress, and ensures an active p53-p21-ROS signaling loop. Our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation as approaches in cancer therapy and emphasizes the importance of considering TP53 status when selecting a patient's treatment options.

CT imaging correlates of genomic expression for oral cavity squamous cell carcinoma.

BACKGROUND AND PURPOSE: Imaging correlates of genetic expression have been found for prognostic and predictive biomarkers of some malignant diseases, including breast and brain tumors. This study tests the hypothesis that imaging findings correlate with relevant genomic biomarkers in oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Surplus frozen tissue from 27 untreated patients with oral cavity squamous cell carcinoma who underwent preoperative CT imaging was analyzed for gene expression. A team of neuroradiologists blinded to the genomic analysis results reviewed an extensive list of CT findings. The imaging correlated with genomic expression for cyclin D1, angiogenesis-related genes (vascular endothelial growth factor receptors and ligands), which relate to enhancement on the basis of other tumor types; and epidermal growth factor receptor, which may relate to proliferation and mass effect. RESULTS: Expression of vascular endothelial growth factor receptors 1 and 2 correlated with the enhancement of the primary tumor (P = .018 and P = .025, respectively), whereas the epidermal growth factor receptor correlated with mass effect (P = .03). Other exploratory correlations included epidermal growth factor receptor to perineural invasion (P = .05), and certain vascular endothelial growth factor receptors and ligands to mass effect (P = .03) and increased (P = .01) or decreased (P = .02) primary tumor size. CONCLUSIONS: We report that CT imaging correlates with gene expression in untreated oral cavity squamous cell carcinoma. Enhancement of the primary tumor and degree of mass effect correlate with relevant genomic biomarkers, which are also potential drug targets. Eventually, treatment decisions may be aided by combining imaging findings into meaningful phenotypes that relate directly to genomic biomarkers.

Improving imaging diagnosis of persistent nodal metastases after definitive therapy for oropharyngeal carcinoma: specific signs for CT and best performance of combined criteria.

BACKGROUND AND PURPOSE: Criteria for detection of persistent nodal metastases in treated oropharyngeal tumors are sensitive but nonspecific, leading to unnecessary nodal dissections. Developing specific imaging criteria for persistent nodal metastases could improve diagnosis while decreasing patient morbidity. MATERIALS AND METHODS: Patients with oropharyngeal squamous cell carcinoma with nodal metastases treated by definitive radiation therapy and subsequent nodal dissection were retrospectively evaluated. One hundred thirty-eight patients had pre- and posttherapy contrast-enhanced CTs evaluated by radiologists blinded to the status of pathologically proved hemineck persistent nodal metastases. Composite scoring criteria for CT, combined from individual parameters, were compared with radiologists' opinions, previous multiparameter criteria, and outcome data. RESULTS: New low-attenuation areas and a lack of size change (<20% cross sectional area) were both highly specific for persistent nodal metastases (99%; P = .0004). Extranodal disease on pretherapy imaging was moderately specific (86%; P = .001). The CSC correctly placed 29 patients in a low-risk category compared with 14 by previously reported criteria and radiologist reports. With good second-rater reliability, the CSC cutoff values stratified patients at highest risk of persistent nodal metastases, thereby improving specificity while maintaining sensitivity. CONCLUSIONS: Comparing pre- and posttherapy examinations improves specificity by discriminating focal findings and size change compared with a single time point. The CSC can categorize the risk of persistent nodal metastases more accurately than previous CT methods. This finding has the potential to improve resource use and reduce surgical morbidity.

Sonographic examination of the neck after definitive radiotherapy for node-positive oropharyngeal cancer.

BACKGROUND AND PURPOSE: Radiographic determination of viable disease in cervical adenopathy following RT for head and neck cancer can be challenging. The purpose of this study was to evaluate the utility of US, with or without FNA, in regard to the postradiotherapy effects on documented metastatic adenopathy in patients with oropharyngeal cancer. MATERIALS AND METHODS: This study included 133 patients with node-positive oropharyngeal cancer who were irradiated from 1998 to 2004. Sonographic evaluation was performed within 6 months of completion of radiation. Posttreatment US results were compared with pretreatment CT images and were recorded as the following: progression, suspicious, indeterminate, posttreatment change, or regression (positive) versus nonsuspicious or benign (negative). FNAC was classified as nondiagnostic, negative, indeterminate, or positive. Results of US and US-guided FNAC were correlated with findings at neck dissection and disease outcome. RESULTS: Of 203 sonographic examinations, 90% were technically feasible and yielded a nonequivocal imaging diagnosis. Of 87 US-guided FNAs, 71% yielded a nonequivocal tissue diagnosis. The PPV and NPV of initial posttreatment US were 11% and 97%. Sensitivity and specificity were 92% and 28%. The PPV and NPV of US-guided FNA were 33% and 95%, and the sensitivity and specificity were 75% and 74%. On serial sonographic surveillance, of 33 patients with nonsuspicious findings, only 1 (3%) had neck recurrence. Of 22 patients with questionable findings on CT and negative findings on US, none had a neck recurrence. CONCLUSIONS: In experienced hands, serial US is an inexpensive noninvasive reassuring follow-up strategy after definitive head and neck RT, even when CT findings are equivocal.

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma.

Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10-20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.

Post-exercise heart rate recovery in individuals with spinal cord injury.

STUDY DESIGN: Prospective comparison of spinal cord injured (SCI) subjects and ambulatory subjects. OBJECTIVES: To determine the effects of the presence and level of SCI on heart rate recovery (HRR). SETTING: Outpatient SCI center. METHODS: HRR was determined in 63 SCI subjects (26 with tetraplegia, 22 with high-level paraplegia, 15 with low-level paraplegia) and 26 ambulatory subjects. To adjust for differences in heart rate reserve between groups (HR peak minus HR rest), HRR was also 'normalized' to a range of 1 at peak heart rate and to 0 at 8 min, and the shapes of HRR curves were compared. RESULTS: Although absolute HRR was similar between high- and low-level paraplegia, it was significantly more rapid in participants with paraplegia at 2, 5 and 8 min after exercise than in those with tetraplegia (39+/-14 vs 29+/-14 b.p.m., P<0.05; 51+/-14 vs 33+/-16 b.p.m., P<0.01 and 52+/-16 vs 36+/-17 b.p.m., P<0.01, respectively). HRR among ambulatory subjects was more rapid than among those with tetraplegia at all time points in recovery. However, when normalized for heart rate reserve, HRR was significantly more rapid in tetraplegic subjects (P<0.001 vs paraplegia and ambulatory subjects). CONCLUSION: In SCI, HRR is strongly associated with the peak exercise level and peak heart rate achieved during exercise testing.