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.

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.

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.

Beta-very low density lipoprotein is sequestered in surface-connected tubules in mouse peritoneal macrophages.

beta-very low density lipoprotein (VLDL) is a large lipoprotein with multiple apoprotein E (apoE) molecules that bind to the LDL receptors on mouse macrophages. Even though they bind to the same receptor, the endocytic processing of beta-VLDL differs from low density lipoprotein (LDL). LDL is rapidly delivered to perinuclear lysosomes and degraded, but much of the beta-VLDL is retained in peripheral compartments for several minutes. We have investigated the properties of these peripheral compartments. Measurement of the pH was made using FITC-phosphatidylethanolamine incorporated into the beta-VLDL, and we found that the peripheral compartments were near neutral in pH. These peripheral, beta-VLDL containing compartments were poorly accessible to antibodies, but a low molecular weight fluorescence quencher (trypan blue) entered the compartments within a few seconds. Intermediate voltage EM of cells labeled with colloidal-gold-beta-VLDL revealed that the peripheral compartments are tubular, surface-connected invaginations. Kinetic studies with fluorescent beta-VLDL showed that the compartments become fully sealed with a half-time of 6 min, and the beta-VLDL is then delivered rapidly to perinuclear lysosomes. By monitoring fluorescence energy transfer between lipid analogs incorporated into the beta-VLDL, some processing of the lipoprotein in the peripheral tubular compartments is demonstrated. The novel mode of uptake of beta-VLDL may account for the high cholesterol ester accumulation induced by this lipoprotein.

The influence of particle size and multiple apoprotein E-receptor interactions on the endocytic targeting of beta-VLDL in mouse peritoneal macrophages.

Low density lipoprotein (LDL) and beta-very low density lipoprotein (beta-VLDL) are internalized by the same receptor in mouse peritoneal macrophages and yet their endocytic patterns differ; beta-VLDL is targeted to both widely distributed and perinuclear vesicles, whereas LDL is targeted almost entirely to perinuclear lysosomes. This endocytic divergence may have important metabolic consequences since beta-VLDL is catabolized slower than LDL and is a more potent stimulator of acyl-CoA/cholesterol acyl transferase (ACAT) than LDL. The goal of this study was to explore the determinants of beta-VLDL responsible for its pattern of endocytic targeting. Fluorescence microscopy experiments revealed that large, intestinally derived, apoprotein (Apo) E-rich beta-VLDL was targeted mostly to widely distributed vesicles, whereas small, hepatically derived beta-VLDL was targeted more centrally (like LDL). Furthermore, the large beta-VLDL had a higher ACAT-stimulatory potential than the smaller beta-VLDL. The basis for these differences was not due to fundamental differences in the means of uptake; both large and small beta-VLDL were internalized by receptor-mediated endocytosis (i.e., not phagocytosis) involving the interaction of Apo E of the beta-VLDL with the macrophage LDL receptor. However, large beta-VLDL was much more resistant to acid-mediated release from LDL receptors than small beta-VLDL. Furthermore, partial neutralization of the multiple Apo Es on these particles by immunotitration resulted in a more perinuclear endocytic pattern, a lower ACAT-stimulatory potential, and an increased sensitivity to acid-mediated receptor release. These data are consistent with the hypothesis that the interaction of the multivalent Apo Es of large beta-VLDL with multiple macrophage LDL receptors leads to a diminished or retarded release of the beta-VLDL from its receptor in the acidic sorting endosome which, in turn, may lead to the widely distributed endocytic pattern of large beta-VLDL. These findings may represent a physiologically relevant example of a previously described laboratory phenomenon whereby receptor cross-linking by multivalent ligands leads to a change in receptor targeting.

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.

Constitutively activated nuclear factor-kappaB (NF-kappaB) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-kappaB in a series of HNSCC cell lines. We confirmed that NF-kappaB was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-kappaB-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-kappaB (IkappaBalpha), the natural inhibitor of NF-kappaB. Constitutive NF-kappaB activation in HNSCC was found to be due to constitutive activation of IkappaBalpha kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IkappaBalpha and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-kappaB activation. The expression of constitutively active NF-kappaB in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-kappaB reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor-beta-activated kinase 1 (TAK1), DN-kappa-Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-kappaB activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-kappaB and its ligand in HNSCC cells but not interleukin (IL)-1beta. All HNSCC cell lines expressed IL-6, a NF-kappaB-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-kappaB, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-kappaB is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.

Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy.

The development of oral squamous cell carcinoma (OSCC) is a multistep process requiring the accumulation of multiple genetic alterations, influenced by a patient's genetic predisposition as well as by environmental influences, including tobacco, alcohol, chronic inflammation, and viral infection. Tumorigenic genetic alterations consist of two major types: tumor suppressor genes, which promote tumor development when inactivated; and oncogenes, which promote tumor development when activated. Tumor suppressor genes can be inactivated through genetic events such as mutation, loss of heterozygosity, or deletion, or by epigenetic modifications such as DNA methylation or chromatin remodeling. Oncogenes can be activated through overexpression due to gene amplification, increased transcription, or changes in structure due to mutations that lead to increased transforming activity. This review focuses on the molecular mechanisms of oral carcinogenesis and the use of biologic therapy to specifically target molecules altered in OSCC. The rapid progress that has been made in our understanding of the molecular alterations contributing to the development of OSCC is leading to improvements in the early diagnosis of tumors and the refinement of biologic treatments individualized to the specific characteristics of a patient's tumor.

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.

Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis.

MMAC/PTEN, a tumor suppressor gene located on chromosome 10q, has recently been shown to act as a phosphatidylinositol 3,4,5-triphosphate phosphatase and to modulate cell growth and apoptosis. Somatic mutations of MMAC/PTEN have been reported in a number of human cancers, especially in glioblastoma multiforme (GBM), although the number of identified mutations (approximately 10-35%) is significantly lower than the frequency of LOH affecting the MMAC/PTEN locus in the specimens (approximately 75-95%). To further investigate the possible alterations that may affect MMAC/PTEN, we examined the expression of the gene by reverse transcription-PCR in a series of gliomas. A significant difference (P < 0.001) was observed between the expression of MMAC/PTEN in GBMs versus lower grades of gliomas, thus mimicking the difference in allelic deletion associated with the locus in these tumors. Furthermore, Kaplan-Meier survival plots, adjusted for age and tumor grade, showed a significantly better prognosis for patients whose tumors expressed high levels of MMAC/PTEN. Additionally, immunostaining of GBMs revealed little or no MMAC/PTEN expression in about two-thirds of the tumors, whereas the other approximately one-third of tumors had significantly higher levels of expression. However, in about two-thirds of the high-expressing specimens, a heterogeneous pattern of expression was observed, indicating that certain cells within the tumor failed to express MMAC/PTEN. The combination of these results suggest that, in addition to molecular alterations affecting the gene, altered expression of MMAC/PTEN may play a significant role in the progression of GBM and patient outcome.

Anti-receptor antibodies reverse the phenotype of cells transformed by two interacting proto-oncogene encoded receptor proteins.

The neu oncogene product, p185neu, is a tyrosine kinase receptor with structural similarity to the epidermal growth factor (EGF) receptor. We have recently described that coexpression of EGF receptors and high levels of normal p185c-neu lead to transformation of rodent fibroblasts. Anti-EGF receptor and anti-p185neu monoclonal antibodies inhibited tumorigenic growth of these transformants implanted into nude mice. These monoclonal antibodies also suppressed focus formation of the cells transformed by the synergistic action of these receptor proteins in vitro. However, EGF enhanced focus formation and stimulated cell growth when added to cells transfected just with the EGF receptor encoding cDNA. These data suggest that receptor specific effectors may have potentially useful applications in cancer therapy for neoplasms which demonstrate increased receptor densities. In addition the data suggest novel differences in the actions of tyrosine kinases when acting alone or in concert with other receptors.

ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion!

ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.

Growth stimulation of human head and neck squamous cell carcinoma cell lines by interleukin 4.

Interleukin 4 (IL-4) has been reported recently to inhibit growth of acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, melanoma, sarcoma, breast, gastric, colon, and renal tumor cell lines, and treatment of murine tumors with IL-4 gene-transduced cells has been therapeutically successful. Therefore, we sought to determine the effect of IL-4 on the growth of human squamous cell carcinoma of the head and neck (SCCHN) cell lines. Growth of SCCHN cell lines incubated in the presence of various concentrations of IL-4 was measured in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assays and by cell counts. Specific binding of IL-4 to SCCHN cells was demonstrated by flow cytometry with phycoerythrin-labeled IL-4, blocking studies with antibodies to IL-4, and using the radiolabeled ligand 125I-labeled IL-4. Reverse transcription PCR for IL-4 and IL-4 receptor (IL-4R) mRNA was performed. SCCHN tissue biopsies were examined by immunohistology and in situ hybridization for the presence of IL-4 protein and IL-4 mRNA in the tumor, respectively. In contrast to earlier reports, we observed growth stimulatory effects of IL-4 consistently in 6 of 13 SCCHN cell lines tested. Growth stimulation by IL-4 ranged from 20 to 200% of control (P < 0.05) and was IL-4 dose dependent. The growth-promoting effect of IL-4 was inhibited completely by incubation of tumor cells in the presence of antibodies specific for IL-4. Reverse transcription PCR analysis of mRNA obtained from the SCCHN cell lines and ELISA performed with SCCHN cell supernatants respectively indicated that the tumor cells did not transcribe or secrete IL-4 actively. The SCCHN cell lines expressed 260-540 IL-4Rs/cell with a dissociation constant of 100 +/- 8 pM. SCCHN cell lines also contained IL-4R mRNA. Immunostaining of SCCHN tissue biopsies indicated that IL-4 may be produced and secreted within these tumors by tumor-infiltrating lymphocytes. In situ hybridization for IL-4 mRNA indicated the presence of positive cells in the tumor stroma. Our data suggest that IL-4 may regulate the growth of SCCHN cells by a paracrine mechanism. These data also indicate that immunotherapy with exogenous IL-4 or IL-4 gene therapy to treat head and neck cancer may not be effective, given the potential tumor growth-stimulatory effects of this cytokine.

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.

Diltiazem and exercise performance in patients with chronic atrial fibrillation.

To evaluate the influence of calcium entry blockade (diltiazem 60 mg qid) on exercise capacity in patients with chronic atrial fibrillation, nine men (mean age 65 years) with atrial fibrillation underwent maximal treadmill exercise on and off diltiazem therapy. Heart rate, blood pressure, and measured ventilatory parameters were assessed at a standard submaximal workload (3.0 mph/0% grade), the gas exchange anaerobic threshold (ATge), and maximal exercise. Significant reductions in heart rate at all stages of exercise were demonstrated: maximum heart rate decreased from 171 +/- 30 beats/min to 142 +/- 27 beats/min (17 percent, p less than .01) and submaximal exercise heart rate decreased from 123 +/- 22 beats/min to 96 +/- 16 beats/min (22 percent, p less than .01). However, there were no significant changes in blood pressure or gas exchange data, ie, oxygen uptake, minute ventilation, or respiratory exchange ratio at any of the exercise workloads. These data demonstrate that in patients with chronic atrial fibrillation, diltiazem controls the ventricular rate response throughout exercise without attenuating blood pressure or exercise capacity.

Successful use of cyclosporine in a lung transplant recipient with tacrolimus-associated hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS) is a rare, but well-described complication in organ transplant recipients maintained on cyclosporine immunosuppression. Tacrolimus is a newer agent with similar immunosuppressant efficacy. In cases of cyclosporine-related HUS in renal transplant recipients, tacrolimus has been used successfully without recurrence of HUS. Tacrolimus has been reported to cause HUS in renal and more recently in cardiac transplant patients. We report a case of HUS in a lung transplant recipient receiving tacrolimus who was subsequently converted to cyclosporine without recurrence of HUS.

Increased reverse cholesterol transport in athletes.

Proposed mechanisms for the cardioprotective benefits of exercise include decreased lipid deposition and increased reverse cholesterol transport (RCT). RCT involves the efflux of tissue free cholesterol into high-density lipoprotein (HDL) particles, esterification by lecithin:cholesterol acyltransferase (LCAT), transfer to other lipoproteins by cholesterol ester transfer proteins (CETP), and liver excretion. We tested the hypothesis that RCT is enhanced in athletes and that this can occur without large increases in plasma HDL cholesterol (HDL-C) mass levels. Fasting venous blood was drawn from 13 sedentary men and 11 athletes exercising at the rate of 5,185 +/- 501 kcal/wk. Compared with controls, athletes had similar age, body mass index (BMI), HDL-C (P > .1) and apolipoprotein (apo) A-1 (P > .5) levels, and lower low-density lipoprotein cholesterol (LDL-C) (P < .05) and apo B (P < .03) levels. The net mass of free cholesterol transported (NMCT) out of cultured human fibroblasts into the athletes' serum was greater than that for controls (25.5 +/- 8.0 v 7.1 +/- 2.6 micrograms/mL/h, P = .048). The efflux component of this transport correlated with HDL-C and apo A-1 levels and was similar between groups (P = .24), suggesting that athletes' antiatherogenic NMCT findings were due to decreased cholesterol influx into the cells. Athletes had increased plasma LCAT (20.3 +/- 2.1 v 13.9 +/- 1.5 micrograms/mL/h, P = .028) and CETP activities (69.7 +/- 4.5 v 21.5 +/- 4.8%/mL/h, P < .001). The NMCT positively correlated with CETP and LCAT activities and inversely with apo B levels and the cardiac risk ratio apo B/A-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise stress testing. An overview of current guidelines.

Exercise stress testing (ET) is an inexpensive noninvasive tool that provides valuable cardiopulmonary information in healthy and diseased populations. It is most commonly used for diagnosing coronary artery disease (CAD) and developing appropriate exercise prescriptions (EP). With its widespread use and application, it is imperative that safe and appropriate guidelines and procedures are used, as there are a number of risks associated with testing in a population with or suspected of having CAD. The focus should be on the patient's safety: personnel must be properly trained and aware of all emergency procedures, contra-indications for ET and indications for test termination must be strictly adhered to. Three main types of testing are prevalent: submaximal, maximal and maximal utilising gas exchange. The maximal test is most commonly used, and the submaximal is appropriate for hospitalised patients. Gas exchange data is essential when assessing congestive heart failure and timing for heart transplantation. ET is commonly performed using a treadmill or a bicycle ergometer. The treadmill provides a more familiar exercise modality and has been shown to have greater diagnostic sensitivity than the bicycle ergometer; it is, however, more expensive and requires more space in the testing room. The bicycle ergometer is more appropriate for those individuals who are severely obese or have problems with extended periods of walking. Regardless of the modality used, an appropriate exercise protocol should be used. In North America, the Bruce protocol is the most common. However, the Bruce protocol, and others that estimate exercise capacity based on equations, tend to overestimate exercise capacity. They may be too demanding for those with limited exercise capacity, and too long for those with high exercise capacity. For these people, an exercise protocol that reaches maximal capacity in 8 to 12 minutes using smaller increments in workload should be considered. Once completed, the results of ET needs to be correctly interpreted. This includes reviewing the test results while considering the patient's history, medications and indication for the test. ET can also be used to develop an EP for the participant. An EP should take into account the intensity, modality of exercise, frequency and duration, as well as being realistic for the individual and the goals to be achieved. All the information from the test results and the pre-test examination should be presented in a report that also includes the advised EP.

Perception of chest pain during exercise testing in patients with coronary artery disease.

Psychophysical scaling of symptoms or discomfort during exercise testing has evolved as an important adjunct to the study of therapeutic interventions in heart disease. One of the major shortcomings of clinical exercise testing, however, has been the assessment of chest pain. Although the presence and characteristics of chest pain have important diagnostic, prognostic, and therapeutic implications, few studies in the literature adequately address chest pain responses to exercise. Clinical trials using exercise as an efficacy parameter frequently use only a single descriptive testing endpoint, such as "moderate" angina. Methods of scaling chest pain during exercise testing are underutilized. Of the several grading systems that have been used, the 0-10 scale developed by Borg has been the most common. It is preferable for patients to relate chest pain sensations during exercise testing to those experienced during daily activities, and treadmill experience improves the reliability and reproducibility of patient responses. This paper examines the methodology and clinical applications of quantifying chest pain during exercise.

The use of biological therapy in cancer of the head and neck.

Exciting progress, in the molecular and cell biology of head and neck cancer has provided us with new ways to target cancer cells more specifically. The possibility now exists with gene therapy of targeting specific genetic defects found in certain tumor types using any one of a number of possible gene delivery systems. Although specific problems with currently existing gene therapy strategies remain to be addressed, encouraging preclinical and clinical data indicate that this is a very promising area. In addition, the exquisite sensitivity of anti/bodies directed at specific molecular targets should make antibody-conjugated toxins, radioimmunoconjugates, and antibodies alone viable therapeutic options. Finally, increased understanding of the antitumor immune response has yielded more rationally designed cytokine as well as cellular-based immunologic treatments for cancer. During the next several years, physicians and scientists alike will need to critically appraise the results of clinical trials of some of these novel treatment approaches and determine how they will fit in with the existing options for the treatment of patients with head and neck cancer. Given that these tumors arise from multiple molecular aberrations, it is likely that biological therapies will be used in combination with other biological approaches or more conventional treatment modalities.