Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their ...treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival.
Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma.
Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival.
Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.
Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression ...of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.
To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with ...measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck.
Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined.
Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02).
Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.
Hand hygiene is the cornerstone of infection prevention and control practices, and reduces healthcare-associated infections significantly. However, international evidence suggests that medical ...doctors demonstrate poor compliance.
To explore and compare practices and attitudes towards hand hygiene, particularly hand rubbing using alcohol-based hand rub (ABHR), among hospital-based physicians in Ireland between 2007 and 2015.
In 2007, a random sample of doctors in a large teaching hospital was invited to complete a postal survey using a validated questionnaire. In 2015, the study was replicated among all doctors employed in a university hospital group, including the setting of the original study, using an online survey. Data were analysed using SPSS and Survey Monkey.
Predominately positive and improving attitudes and practices were found, with 86% of doctors compliant with hand hygiene before patient contact in 2015, compared with 58% in 2007. Ninety-one percent of doctors were compliant after patient contact in 2015, compared with 76% in 2007. In 2015, only 39% of respondents reported that they ‘almost always’ used ABHR for hand hygiene. However, this represents 13.5% more than in 2007. Stated barriers to use of ABHR included dermatological issues, poor acceptance, tolerance and poor availability of ABHR products.
Greater awareness of hand hygiene guidelines and greater governance appear to have had a positive impact on practice. However, despite this, practice remains suboptimal and there is scope for substantial improvement. Continued and sustained efforts are required in order to build on progress achieved since the World Health Organization hand hygiene guidelines were published in 2009.
Abstract Aims There is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry ...is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. Materials and methods Formalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. Results Ninety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger ( P < 0.0001), with lower alcohol ( P = 0.0002) and tobacco ( P = 0.0001) exposure. The tumours were less differentiated ( P = 0.0069), had a lower T stage ( P = 0.0027), higher nodal status ( P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group ( P = 0.0036). AJCC prognostic group was significant for RFS ( P = 0.0096) and CSS ( P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours ( P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin ( P < 0.0001 and <0.0001), chemoradiotherapy ( P = 0.005 and 0.03) and P16 status ( P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC ( P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43–7.08), ( P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57–10.61) and ( P = 0.001, hazard ratio 3.74; confidence interval 1.76–7.95). Conclusion This study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.
Objectives/Hypothesis
To determine the prognostic value of hypoxia‐associated markers carbonic anhydrase‐9 (CA‐9) and hypoxia‐inducible factor‐1α (HIF‐1α) in advanced larynx and hypopharynx squamous ...cell carcinoma (SCCa) treated by organ preservation strategies.
Study Design
Retrospective cohort study.
Methods
Pretreatment CA‐9 and HIF‐1α expression, clinicopathologic data, and tumor volume were analyzed in a series of 114 patients with T3–4 SCCa larynx or hypopharynx treated by (chemo)radiation.
Results
Adverse prognostic factors for locoregional control were T4 classification (P = 0.008), and for disease‐specific survival were CA‐9 positivity (P = 0.039), T4 classification (P = 0.001), larger tumor volume (P = 0.004), N1–3 classification (P = 0.002), and pretreatment hemoglobin < 13.0 g/dl (P = 0.014). With increasing CA‐9 expression, there was a trend to increasing tumor recurrence (Ptrend = 0.009) and decreasing survival (Ptrend = 0.002). On multivariate analysis, independent variables were T4 classification (hazard ratio HR 13.54, P = 0.01) for locoregional failure, and CA‐9 positivity (HR = 8.02, P = 0.042) and higher tumor volume (HR = 3.33, P = 0.007) for disease‐specific mortality.
Conclusion
This is the first study to look specifically at T3 and T4 SCCa larynx and hypopharynx for a relationship between hypoxia‐associated marker expression and clinical outcome. Pretreatment immunohistochemical CA‐9 expression is an adverse prognostic factor for disease‐specific survival, indicating that CA‐9 expression may confer a more aggressive tumor phenotype.
Level of Evidence
4. Laryngoscope, 125:E8–E15, 2015
Background
Morphine‐6‐glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity. Morphine‐3‐glucuronide (M3G), the most prevalent metabolite, has minimal affinity for ...opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G.
Methods
We performed a double‐blind placebo‐controlled trial with 10 healthy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphine, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg/70 kg of M6G; all were give by slow intravenous bolus. Analgesia was assessed with the use of the submaximal ischemic pain model. The effects were quantified on numerical and visual analogue scales. Respiratory parameters and response to steady state 5% carbon dioxide challenge were assessed with spirometry, mass spectroscopy, and earlobe blood gas analysis.
Results
Morphine and M6G produced significant pain relief compared with placebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26). Pain relief with morphine and M6G were not significantly altered by M3G (P = .59 and P = .28, respectively). Significant and similar dysphoria and sedation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo (morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively).
Conclusions
M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine. (Clin Pharmacol Ther 2000;68:667‐76.)
Clinical Pharmacology & Therapeutics (2000) 68, 667–676; doi: 10.1067/mcp.2000.111934
Hypoxia in head and neck cancer Isa, A Y; Ward, T H; West, C M L ...
British journal of radiology,
10/2006, Letnik:
79, Številka:
946
Journal Article
Recenzirano
A high level of hypoxia in solid tumours is an adverse prognostic factor for the poor outcome of cancer patients following treatment. This review describes the status of research into finding a ...practical method for measuring hypoxia and treating hypoxic tumours. The application of such methodology would enable the selection of head and neck cancer treatment based on an individual's tumour oxygenation status. This individualization would include the selection not only of surgery or radiotherapy, but also of novel hypoxia-modification strategies.
Abstract Aims To evaluate the prognostic significance of potential tumour markers of hypoxia and apoptosis in early squamous cell carcinoma of the glottic larynx managed with radiotherapy. Materials ...and methods In total, 382 patients with T1 and T2 squamous cell carcinoma of the glottic larynx (vocal cords) received radical radiotherapy (50–55 Gy, in 16 fractions in 98% of cases). Pre-treatment haemoglobin was available for 328 patients; biopsy samples were available for 286. Immunohistochemistry was carried out for carbonic anhydrase-9 (CA-9), hypoxia inducible factor-1α (HIF-1α) and Bcl-2. Results At 5 years, locoregional control was achieved in 88.2%, cancer-specific survival in 95.0% and overall survival in 78.7%. Adverse prognostic factors for locoregional tumour recurrence were pre-treatment haemoglobin <13.0 g/dl ( P = 0.035, Log rank test; sensitivity 0.28, specificity 0.84) and stage T2 rather than T1 ( P = 0.002). The effect of haemoglobin level on locoregional control was not significant when stratified by the median of 14.2 g/dl ( P = 0.43) or as a continuous variable ( P = 0.59). High CA-9 ( P = 0.11), HIF-1α ( P = 0.67) and Bcl-2 ( P = 0.77) expression had no prognostic significance. Conclusions High CA-9, HIF-1α and Bcl-2 do not add to the prognostic significance of tumour stage and lower haemoglobin in predicting failure of local control in early glottic larynx squamous cell carcinoma managed with radiotherapy. The effect of haemoglobin was not strong enough to be useful as a prognostic biomarker.
The frequency and severity of fatty infiltration of the liver in patients receiving 5-fluorouracil (5-FU) and folinic acid has not been documented systematically. Its development can result in ...difficulty assessing disease progression, and treatment may be altered inappropriately. Twenty-seven patients with colon cancer and liver metastases receiving 5-FU and folinic acid were studied with computerized tomography (CT) before treatment and after six or 12 cycles of chemotherapy. Forty-seven per cent of patients developed hepatic steatosis during treatment. There was no correlation between development of hepatic steatosis and the dose of chemotherapy or the liver function tests. Hepatic steatosis occurs commonly in patients receiving 5-FU and folinic acid and can be severe. Its development can make hepatic metastases difficult to assess and if its benign nature is not appreciated treatment may be inappropriately altered.
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