First nations people's perspectives on barriers and supports for enhancing HPV vaccination: Foundations for sustainable, community-driven strategies.

OBJECTIVE: In Canada, Indigenous people have higher human papillomavirus (HPV) infection rates, lower screening rates for cervical cancer, and higher rates of invasive cancer, leading to worse cervical cancer-related outcomes than observed in non-Indigenous Canadian women. Lingering harms from European colonization drive these health inequities and create public health challenges. Policy guidance is needed to optimize HPV vaccination rates and, thereby, decrease the burden of HPV-related illness, including high-morbidity surgical procedures and chemo-radiotherapy. The Enhancing HPV Vaccination In First Nations Populations in Alberta (EHVINA) project focuses on First Nations, a diverse subset of recognized Indigenous people in Canada, and seeks to increase HPV vaccination among girls and boys living in First Nation communities. METHODS: Developing an effective strategy requires partnership with affected communities to better understand knowledge and perceptions about cancer, healthcare, and the HPV vaccine. A 2017 community gathering was convened to engage First Nations community members, health directors, and health services researchers in dialogue around unique barriers and supports to HPV vaccination in Alberta. Voices of community Elders, parents, health directors, and cancer survivors (n=24) are presented as qualitative evidence to help inform intervention design. RESULTS: Key findings from discussions indicate barriers to HPV vaccination include resource constraints and service infrastructure gaps, historical mistrust in healthcare systems, impacts of changing modes of communication, and community sensitivities regarding sexual health promotion. Supports were identified as strengthened inter-generational relationships in communities. CONCLUSIONS AND FUTURE DIRECTION: Ongoing dialogue and co-development of community-based strategies to increase HPV vaccine uptake are required. The identification of possible barriers to HPV vaccination in a Canadian Indigenous population contributes to limited global literature on this subject and may inform researchers and policy makers who work with Indigenous populations in other regions.

Global patterns of cardia and non-cardia gastric cancer incidence in 2012.

OBJECTIVE: Globally, gastric cancer incidence shows remarkable international variation and demonstrates distinct characteristics by the two major topographical subsites, cardia (CGC) and non-cardia (NCGC). Because global incidence estimates by subsite are lacking, we aimed to describe the worldwide incidence patterns of CGC and NCGC separately. DESIGN: Using Cancer Incidence in Five Continents Volume X (CI5X), we ascertained the proportions of CGC and NCGC by country, sex and age group (<65 and ≥65 years). These derived proportions were applied to GLOBOCAN 2012 data to estimate country-specific age-standardised CGC and NCGC incidence rates (ASR). Regional proportions were used to estimate rates for countries not included in CI5X. RESULTS: According to our estimates, in 2012, there were 260,000 cases of CGC (ASR 3.3 per 100,000) and 691,000 cases of NCGC (ASR 8.8) worldwide. The highest regional rates of both gastric cancer subsites were in Eastern/Southeastern Asia (in men, ASRs: 8.7 and 21.7 for CGC and NCGC, respectively). In most countries NCGC occurred more frequently than CGC with an average ratio of 2:1; however, in some populations where NCGC incidence rates were lower than the global average, CGC rates were similar or higher than NCGC rates. Men had higher rates than women for both subsites but particularly for CGC (male-to-female ratio 3:1). CONCLUSIONS: This study has, for the first time, quantified global incidence patterns of CGC and NCGC providing new insights into the global burden of these cancers. Country-specific estimates are provided; however, these should be interpreted with caution. This work will support future investigations across populations.

An investigation of cancer incidence in a First Nations community in Alberta, Canada, 1995-2006.

OBJECTIVE: To determine colorectal and overall cancer incidence as part of a three-pronged investigation in response to the concerns of a First Nations community in Alberta, Canada, located close to sulfur-rich natural gas installations, and to determine whether the incidence of cancers observed in this reserve was higher than expected. METHODS: A population dataset with information identifying First Nations status and band affiliation was linked to the Alberta Cancer Registry to determine cancer incidence cases between 1995 and 2006 for on- and off-reserve study populations. Using indirect standardized incidence ratios, observed cancer incidence cases for the study populations were compared with cases expected based on three separate reference populations. RESULTS: Observed colorectal and overall cancer incidence cases within the First Nations community were not higher than expected. Cervical cancer incidence cases, however, were higher than expected for on- and off-reserve populations; public health measures designed to address this risk have been implemented and on-going surveillance of cancer incidence in the community will be maintained.

The Success and Evolution of a Urological "Boot Camp" for Newly Appointed UK Urology Registrars: Incorporating Simulation, Nontechnical Skills and Assessment.

BACKGROUND: Urological training has dramatically changed in recent years. Training durations are shorter and a drive toward consultant led care has reduced trainees experience. Within the UK, approximately 50 registrars annually embark on a 5-year Urology training programme, with variable levels of basic urological experience. OBJECTIVE: To describe a simulation programme aimed at delivering the knowledge and skills necessary to safely and effectively start working as a registrar in Urology by intensive training with a 1:1 faculty to delegate ratio. DESIGN, SETTING, AND PARTICIPANTS: Our course content mirrors the UK training syllabus for junior Urology registrars. We delivered 8 modules over a 4-day programme with a fifth day of assessments. Delegates level of urological knowledge, operative competency and confidence pre-, immediately post-training and at 3-months postcourse were assessed. Objective delegate and faculty feedback was also collected. Technical skills modules include; inguinoscrotal surgery, ureteroscopy, transurethral resection, urodynamics, and Botox administration as well as basic reconstructive and laparoscopic operative skills. "Nontechnical" skills included simulated ward round, out-patient, and emergency scenarios. RESULTS: Feedback from delegates and faculty members has been overwhelmingly positive. We have used this feedback to tailor the content of the course for following years. An increased knowledge level (based on mean examination scores [precourse 55.5%, postcourse 70.1%]) and operative competency was observed in all skills assessed (transurethral resection of the prostate, transurethral resection of bladder tumor, Ureteroscopy, laparoscopic skills, and instrument assembly). Operative confidence was increased immediately and at 3-months postcourse. CONCLUSIONS: Our "boot camp" course provides a realistic introduction and foundation to begin Urological practice. Being delivered at the beginning of the training scheme, prior to intensive patient exposure, registrars are in an optimum position to develop their newly acquired knowledge and skills to enhance training and intends to improve patient safety and satisfaction.

Combination treatment with ionising radiation and gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) inhibitor, significantly inhibits bladder cancer cell growth in vitro and in vivo.

PURPOSE: External beam radiotherapy (EBRT) is the principal bladder-preserving monotherapy for muscle-invasive bladder cancer. Seventy percent of muscle-invasive bladder cancers express epidermal growth factor receptor (EGFR), which is associated with poor prognosis. Ionising radiation (IR) stimulates EGFR causing activation of cytoprotective signalling cascades and thus may be an underlying cause of radioresistance in bladder tumours. MATERIALS AND METHODS: We assessed the ability of IR to activate EGFR in bladder cancer cells and the effect of the anti-EGFR therapy, gefitinib on potential radiation-induced activation. Subsequently we assessed the effect of IR on signalling pathways downstream of EGFR. Finally we assessed the activity of gefitinib as a monotherapy, and in combination with IR, using clonogenic assay in vitro, and a murine model in vivo. RESULTS: IR activated EGFR and gefitinib partially inhibited this activation. Radiation-induced activation of EGFR activated the MAPK and Akt pathways. Gefitinib partially inhibited activation of the MAPK pathway but not the Akt pathway. Treatment with combined gefitinib and IR significantly inhibited bladder cancer cell colony formation more than treatment with gefitinib alone (p = 0.001-0.03). J82 xenograft tumours treated with combined gefitinib and IR showed significantly greater growth inhibition than tumours treated with IR alone (p = 0.04). CONCLUSIONS: Combining gefitinib and IR results in significantly greater inhibition of invasive bladder cancer cell colony formation in vitro and significantly greater tumour growth inhibition in vivo. Given the high frequency of EGFR expression by bladder tumours and the low toxicity of gefitinib there is justification to translate this work into a clinical trial.

Carbonic anhydrase IX expression and outcome after radiotherapy for muscle-invasive bladder cancer.

AIMS: Carbonic anhydrase IX (CA IX) expression has been described as an endogenous marker of hypoxia in solid neoplasms. Furthermore, CA IX expression has been associated with an aggressive phenotype and resistance to radiotherapy. We assessed the prognostic significance of CA IX expression in patients with muscle-invasive bladder cancer treated with radiotherapy. MATERIALS AND METHODS: A standard immunohistochemistry technique was used to show CA IX expression in 110 muscle-invasive bladder tumours treated with radiotherapy. Clinicopathological data were obtained from medical case notes. RESULTS: CA IX immunostaining was detected in 89 ( approximately 81%) patients. Staining was predominantly membranous, with areas of concurrent cytoplasmic and nuclear staining and was abundant in luminal and perinecrotic areas. No significant correlation was shown between the overall CA IX status and the initial response to radiotherapy, 5-year bladder cancer-specific survival or the time to local recurrence. CONCLUSIONS: The distribution of CA IX expression in paraffin-embedded tissue sections seen in this series is consistent with previous studies in bladder cancer, but does not provide significant prognostic information with respect to the response to radiotherapy at 3 months and disease-specific survival after radical radiotherapy.

Epidermal growth factor receptor status predicts local response to radical radiotherapy in muscle-invasive bladder cancer.

AIMS: Epidermal growth factor receptor (EGFR) is expressed by over 70% of muscle-invasive bladder tumours and is associated with diminished overall survival. In model tumour systems, ionising radiation has been shown to activate EGFR, leading to cellular proliferation and is therefore a possible mechanism of underlying radioresistance. We carried out an immunohistochemical study relating the clinical outcome of patients receiving radical radiotherapy for muscle-invasive bladder cancer to tumour EGFR status. MATERIALS AND METHODS: Archived paraffin-embedded tumours from 110 consecutive patients receiving radical radiotherapy for muscle-invasive bladder cancer between 1991 and 1997 were immunohistochemically stained for EGFR. Data were collected concerning the tumour stage and grade, the presence of ureteric obstruction, the response to radiotherapy at 3 months, local recurrence rates, metastatic spread and survival. Multivariate analysis of potential independent prognostic factors of impaired bladder cancer-specific survival was carried out using Cox's regression. RESULTS: Of 110 tumours, 79 (72%) stained positively for EGFR. Of 87 patients undergoing the 3-month check cystoscopy, 60 (69%) had a positive response to radiotherapy. A positive response to radiotherapy correlated significantly with a negative EGFR status (chi(2) test, P = 0.05). Kaplan-Meier survival analysis revealed a trend towards improved bladder cancer-specific survival in EGFR-negative patients (Log-rank, P = 0.10). A lack of response to radiotherapy at 3 months, local recurrence, metastatic spread and the presence of ureteric obstruction were all independent prognostic factors for diminished bladder cancer-specific survival (Cox's regression: P = 0.009, P = 0.001, P = 0.04 and P = 0.005, respectively). CONCLUSIONS: EGFR status predicts the local response to radiotherapy but does not provide prognostic utility in relation to overall or bladder cancer-specific survival. As EGFR status seems to be linked to the initial response to radiotherapy, its inhibition may be a means of enhancing the radio-responsiveness of these poor prognosis tumours. Colquhoun, A. J.

High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose.

Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not catalyse the rate-controlling step. Instead, hexokinase activity may assume a more important regulatory role. Hexokinase activities are consistently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., Biochem. J. 265: 503-509, 1990). The present work has focused on the glucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cell lines were found to have an additional glucose-phosphorylating activity, with properties similar to hepatic glucokinase. Maximal activities range from 1.1-20 nmol/min/mg cell protein, and the activity is consistently absent from any untransformed cell line or tissue tested, except rat liver tissue (18 nmol/min/mg cell protein). Tumor cell glucokinase activity has been characterized by its high Km for glucose (8-11.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptulose (I50, 12.5 mM); and lack of inhibition by 10 mM glucose-6-phosphate. Mannoheptulose also causes inhibition of glucose uptake by tumor cells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growth of cultured tumor cell lines (I50, 21.4 mM). Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified from avocados and is assumed to be of low toxicity), as a cancer treatment is discussed.

gamma-Linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells.

The polyunsaturated fatty acids gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) are cytotoxic to tumour cells. GLA inhibits Walker 256 tumour growth in vivo, causing alterations in mitochondrial ultrastructure and cellular metabolism. The objective of the present study was to investigate the mechanisms behind fatty acid inhibition of Walker 256 tumour growth under controlled in vitro conditions. At a concentration of 150 microM, both GLA and EPA caused a decrease in cell proliferation and an increase in apoptotic index. Increases in reactive oxygen species (ROS) and lipid peroxide production were identified, as well as alterations in energy metabolism and the deposition of large amounts of triacylglycerol in the form of lipid droplets. Mitochondrial respiratory chain complexes I+III and IV had significantly decreased activity and mitochondrial membrane potential was greatly diminished. Intracellular ATP concentrations were maintained at 70-80% of control values despite the decreased mitochondrial function, which may be in part due to increased utilisation of glucose for ATP generation. Cytochrome c release from mitochondria was found, as was caspase-3-like activation. DNA fragmentation in situ revealed many apoptotic events within the cell population. The mechanism(s) by which ROS and lipid peroxides induce apoptosis remains unclear, but the effects of GLA and EPA appear to involve the mitochondrial pathway of apoptosis induction leading to cytochrome c release, caspase activation, loss of mitochondrial membrane potential and DNA fragmentation.

Effects of in-vivo administration of insulin-like growth factor-I on the rate of glucose utilization in the soleus muscle of the rat.

This study investigated the effects of insulin-like growth factor-I (IGF-I) administered to rats in vivo on the soleus muscle isolated from these rats. In order to study the interactions between IGF-I and insulin, the soleus muscles were incubated in the presence of various concentrations of insulin. IGF-I (190-200 micrograms) was given twice daily; the rats were killed 1 h after one injection of IGF-I (acute administration) or after treatment with IGF-I for 10 days (prolonged administration). The level of IGF-I in plasma was increased by approximately 100% after acute administration and by around 30% after 10 days of treatment with IGF-I. Acute administration of IGF-I to the rats increased the flux of glucose to hexose monophosphate and the rates of lactate formation and glycogen synthesis in the soleus muscles; however, the responsiveness of these muscles to insulin was lost: the increase in the rate of glucose utilization by IGF-I at physiological concentrations of insulin (10 or 100 mU/l) was similar to that observed at maximal concentrations of insulin (1000 mU/l). Similar results were obtained after prolonged treatment of the rats with IGF-I; however, the increase in the rate of glucose utilization was less pronounced than when IGF-I was given acutely and the muscles were still capable of responding to insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Right ventricular function and high-frequency positive-pressure ventilation during coronary artery bypass grafting.

The hemodynamic and respiratory consequences of two modes of ventilation, conventional intermittent positive-pressure ventilation with a frequency of 10 cycles/min and high-frequency positive-pressure ventilation at 70 cycles/min were investigated before and after cardiopulmonary bypass in 6 patients having coronary artery bypass grafting. All patients were adequately ventilated with each mode. During prebypass and postbypass periods, the group with high-frequency ventilation had significantly lower peak airway pressures (p = 0.0001) and mean airway pressure (p less than 0.05). There were, however, no significant differences in right ventricular performance or pulmonary vascular resistance between the two modes of ventilation. No significant differences in other cardiovascular and respiratory variables were noted. High-frequency positive-pressure ventilation, with the advantage of quieter operating conditions and improved surgical access, can be safely applied when meticulous operation or hemostasis is required or during dissection of the internal mammary artery.

Hemifacial atrophy with bilateral short roots.

We present a case in which the patient had both bilateral shortening of the roots, and hemifacial atrophy. As far as we know, this combination has not been described before.

Leukaemia in children. Part I: Orofacial complications and side-effects of treatment.

Significant orofacial complications of leukaemia in children include lymphadenopathy, spontaneous gingival bleeding, labial and lingual ecchymoses and mucosal petechiae, ulceration, gingival swelling, and infections. The dentist may be the first to notice signs of the illness. Treatment of leukaemia can result in serious orofacial problems which include oral mucositis and ulceration, infections, spontaneous gingival bleeding, neuropathy, xerostomia, and gingival hypertrophy. A prompt diagnosis leading to early intervention can decrease the morbidity and mortality of the disease and its treatment.

Leukaemia in children. Part II--Dental care of the leukaemic child, including management of oral side effects of cancer treatment.

The treatment of a leukaemic child requires a multidisciplinary approach. The dental team should provide interceptive and preventive measures prior to the commencement of therapy whenever possible. During therapy, preventive and palliative measures are essential. Once remission is achieved, the child continues to have increased dental needs due to the effects of treatment. These needs may include an increased caries rate, dental maldevelopment, and secondary malignancy.

Halitosis: causes, diagnosis, and treatment.

Halitosis is a major concern to the general public and the source of a multimillion-dollar industry world wide. Although the aetiology may be localised to the oral cavity in up to 90 percent of instances, halitosis may indicate a serious underlying medical condition necessitating medical referral. In general, halitosis of an oral cause can be safely and easily diagnosed and treated by the general dental practitioner.

Mitochondrial swelling and incipient outer membrane rupture in preapoptotic and apoptotic cells.

Outer mitochondrial membrane (OMM) rupture was first noted in isolated mitochondria in which the inner mitochondrial membrane (IMM) had lost its selective permeability. This phenomenon referred to as mitochondrial permeability transition (MPT) refers to a permeabilized inner membrane that originates a large swelling in the mitochondrial matrix, which distends the outer membrane until it ruptures. Here, we have expanded previous electron microscopic observations that in apoptotic cells, OMM rupture is not caused by a membrane stretching promoted by a markedly swollen matrix. It is shown that the widths of the ruptured regions of the OMM vary from 6 to 250 nm. Independent of the perforation size, herniation of the mitochondrial matrix appeared to have resulted in pushing the IMM through the perforation. A large, long focal herniation of the mitochondrial matrix, covered with the IMM, was associated with a rupture of the OMM that was as small as 6 nm. Contextually, the collapse of the selective permeability of the IMM may precede or follow the release of the mitochondrial proteins of the intermembrane space into the cytoplasm. When the MPT is a late event, exit of the intermembrane space proteins to the cytoplasm is unimpeded and occurs through channels that transverse the outer membrane, because so far, the inner membrane is impermeable. No channel within the outer membrane can expose to the cytoplasm a permeable inner membrane, because it would serve as a conduit for local herniation of the mitochondrial matrix.

Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer.

BACKGROUND: Prostate cancer incidence and mortality vary dramatically by geographical location. Both are higher in developed countries. Some attribute this to westernized lifestyles of high-energy diets and limited physical activity with consequent obesity. Obesity and obesity-related diseases like diabetes cause hyperinsulinaemia, which upregulates pro-survival cell signalling. Previous work revealed diet-induced hyperinsulinaemia enhances prostate cancer xenograft growth in vivo. Metformin, an antidiabetic medication, reduces hyperinsulinaemia and also exhibits antineoplastic properties. Herein, we assess the potential additive benefit of combining bicalutamide antiandrogen therapy with metformin, in vitro and in vivo. METHODS: Using clonogenic assays, we assessed the effect of bicalutamide and/or metformin on clonogenicity in prostate cancer cell lines. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs in androgen receptor (AR)-positive (LNCaP) and AR-negative (PC3) cell lines. The combination treatment regimen was assessed in vivo using an LNCaP murine xenograft model. RESULTS: Micromolar bicalutamide or millimolar metformin caused a significant dose-dependent reduction in clonogenicity (P<0.001). Combination treatment further significantly reduced clonogenicity (P<0.005) with greater effects in AR-positive cells. Western blot and cell cycle analyses suggested differing mechanisms of interaction in AR-positive and -negative cell lines. Following combination treatment, LNCaP cells exhibited an altered cell proliferation (decreased phospho mammalian target of rapamycin expression) and perturbed cell cycle kinetics (G1/S cell cycle arrest). PC3 cells showed evidence of enhanced apoptosis (increased Bcl-2-associated X protein and decreased total caspase 3 expression). Markedly diminished tumour growth occurred following combination treatment in vivo (P<0.001). CONCLUSIONS: Combining bicalutamide and metformin significantly reduces prostate cancer cell growth further than either monotherapy. In AR-positive cells, this effect appeared to be mediated by reducing proliferation rates, whereas in AR-negative cells the combination treatment appeared to promote apoptosis. This combination drug regimen may improve prostate-cancer-specific survival by the direct antineoplastic properties outlined.

Invasive oral aspergillosis in a patient with acute myeloid leukaemia.

Aspergillosis (a fungal infection by an organism of the Aspergillus species) of the oral cavity is an uncommon condition which most frequently occurs in immunocompromised patients, such as those with haematological malignancies. In such patients, prolonged neutropenia secondary to chemotherapeutic agents enables the spread of invasive aspergillosis, which is unaffected by anatomical barriers. Early detection and treatment of the condition is essential to avoid more serious complications, such as disseminated infection, which results in increased morbidity and mortality. This case report describes a patient with acute myeloid leukaemia who developed localized invasive Aspergillus flavus of the palate. High-dose antifungal therapy was instituted along with surgical removal of the involved tissues. Aspergillosis of the palate was successfully eradicated with no long-term ill effects from the treatment. Management of invasive aspergillosis includes early aggressive antifungal medication combined with surgical removal of the involved tissues.

An unusual presentation of oropharyngeal mucosal plasmacytosis related to toothpaste.

OBJECTIVE: We present the case of a 59-year-old Chinese patient with an unusual presentation of mucosal plasmacytosis involving the oropharynx, related to the use of toothpaste. METHOD: Case presentation and review of English medical literature involving mucosal plasmacytosis. RESULTS: Mucosal plasmacytosis is an uncommon disease process and has been associated with hypersensitivity reactions. Most cases involve the gingival mucosa, although there have been reports of cases involving other oral mucosal sites and the upper aerodigestive tract. Our case provides an example of oropharyngeal plasmacytosis related to toothpaste. A resolution of signs and symptoms followed withdrawal of the suspected allergens. CONCLUSION: Mucosal plasmacytosis is a benign inflammatory process that may appear to be more sinister on clinical examination. Skin patch testing is a useful adjunct in confirming the diagnosis.