Analysis of the EGFR mutation status in head and neck squamous cell carcinoma before treatment with Gefitinib

BACKGROUND: The efficacy of chemotherapy in metastatic and recurrent squamous cell carcinomas of the head and neck (HNSCC) remains unsatisfactory. Gefitinib offers a new therapeutic option with comparable results and better tolerability than chemotherapy. We conducted this study to see if mutations in the epidermal growth factor receptor (EGFR) might predict the therapeutic benefit in HNSCC patients. PATIENTS AND METHODS: In a pilot trial, 8 patients with metastatic or recurrent HNSCC were treated palliatively with gefitinib (500 mg/day orally). Forceps biopsies were taken to confirm tumor recurrence and to perform an EGFR mutation analysis. RESULTS: The EGFR status could be determined in 6 of the 8 patients. 5 patients had no EGFR gene mutation, and 1 patient showed a silent guanine-to-adenosine mutation in position 2607. Even without any relevant mutation in the EGFR, we observed partial remission in 3 of 6 patients treated with gefitinib. We also observed that an additional 4 patients had stable disease for at least 10 weeks. The median progression-free survival was 6.25 months, and the median overall survival was 7.39 months. CONCLUSION: In HNSCC, there are tumor responses to gefitinib without protein-altering mutations in the EGFR gene

Scope and significance of non-uniform classification practices in breast cancer with non-inflammatory skin involvement: a clinicopathologic study and an international survey

Background: The study evaluates the scope of non-uniform classification practices concerning breast carcinomas with non-inflammatory skin involvement. Patients and methods: We compared the clinical course of patients with histologically proven non-inflammatory skin involvement: 119 (65.4%) with clinically obvious ‘classical' skin changes (Group A) and 63 (34.6%) with no or only discreet changes (Group B). A questionnaire was circulated to pathology departments in 24 countries to assess the practice concerning the placement of skin- involved breast carcinomas in the TNM classification. Results: Patients in Group B showed a significantly better disease specific survival (P = 0.0002). Eighty-six respondents (70.5%) of the survey preferred the ‘histological view' and classified tumors with only histological proven skin involvement as T4b/stage IIIB. The opposing classification principle (‘clinical view'), which dictates that T4b breast cancer is a clinical diagnosis and the classical signs must be present, was supported by 31 respondents (25.4%). Conclusions: A large number of breast cancer patients with non-inflammatory skin involvement are only histologically proven and show, compared with cases exhibiting the classical clinical signs, significant differences in clinical course and prognosis. In general, both subsets were aggregated in one T category/stage (T4b/IIIB). This results in a considerable distortion of the reported statistical dat

Geophysical analysis of an area affected by subsurface dissolution - case study of an inland salt marsh in northern Thuringia, Germany

The subsurface dissolution of soluble rocks can affect areas over a long period of time and pose a severe hazard. We show the benefits of a combined approach using P-wave and SH-wave reflection seismics, electrical resistivity tomography, transient electromagnetics, and gravimetry for a better understanding of the dissolution process. The study area, "Esperstedter Ried"in northern Thuringia, Germany, located south of the Kyffhäuser hills, is a large inland salt marsh that developed due to dissolution of soluble rocks at approximately 300 m depth. We were able to locate buried dissolution structures and zones, faults and fractures, and potential fluid pathways, aquifers, and aquitards based on seismic and electromagnetic surveys. Further improvement of the model was accomplished by analyzing gravimetry data that indicates dissolution-induced mass movement, as shown by local minima of the Bouguer anomaly for the Esperstedter Ried. Forward modeling of the gravimetry data, in combination with the seismic results, delivered a cross section through the inland salt marsh from north to south. We conclude that tectonic movements during the Tertiary, which led to the uplift of the Kyffhäuser hills and the formation of faults parallel and perpendicular to the low mountain range, were the initial trigger for subsurface dissolution. The faults and the fractured Triassic and lower Tertiary deposits serve as fluid pathways for groundwater to leach the deep Permian Zechstein deposits, since dissolution and erosional processes are more intense near faults. The artesian-confined saltwater rises towards the surface along the faults and fracture networks, and it formed the inland salt marsh over time. In the past, dissolution of the Zechstein formations formed several, now buried, sagging and collapse structures, and, since the entire region is affected by recent sinkhole development, dissolution is still ongoing. From the results of this study, we suggest that the combined geophysical investigation of areas prone to subsurface dissolution can improve the knowledge of control factors, hazardous areas, and thus local dissolution processes

Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings

Various studies have emphasized an immunodepression state observed at the tumour site. To reverse this defect and based upon animal studies, we initiated a phase I clinical trial of gene therapy in which various doses of xenogeneic monkey fibroblasts (Vero cells) genetically engineered to produce human IL-2 were administered intratumorally in 8 patients with metastatic solid tumours. No severe adverse effect was observed in the 8 patients analysed during this clinical trial even in the highest dose (5 ¥ 107 cells) group. This absence of toxicity seems to be associated with rapid elimination of Vero-IL-2 cells from the organism. Indeed, exogenous IL-2 mRNA could no longer be detected in the peripheral whole blood 48 hours after Vero-IL-2 cell administration. In addition, we did not find any expression of exogenous IL-2 mRNA in post-therapeutic lesions removed 29 days after the start of therapy. A major finding of this trial concerns the two histological responses of two treated subcutaneous nodules not associated with an apparent clinical response. The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg …) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration. Gene therapy using xenogeneic cells as vehicle may therefore present certain advantages over other vectors, such as its complete absence of toxicity. Furthermore, the in vivo biological effect of immunostimulatory genes, i.e IL-2-, may be potentiated by the xenogeneic rejection reaction. © 2000 Cancer Research Campaign http://www.bjcancer.co

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

Purpose: Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90Y or 177Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. Methods: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [90Y-DOTA]-TOC or [177Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Results: Overall, 910 patients underwent 1,804cycles of [90Y-DOTA]-TOC and 141 patients underwent 259cycles of [177Lu-DOTA]-TOC. The median survival after [177Lu-DOTA]-TOC and after [90Y-DOTA]-TOC was comparable (45.5months versus 35.9months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [177Lu-DOTA]-TOC over [90Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [177Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). Conclusion: The present results revealed no difference in median overall survival after [177Lu-DOTA]-TOC and [90Y-DOTA]-TOC. Furthermore, [177Lu-DOTA]-TOC was less haematotoxic than [90Y-DOTA]-TOC

Can sleep and resting behaviours be used as indicators of welfare in shelter dogs (Canis lupusfamiliaris)?

Previous research on humans and animals suggests that the analysis of sleep patterns may reliably inform us about welfare status, but little research of this kind has been carried out for non-human animals in an applied context. This study explored the use of sleep and resting behaviour as indicators of welfare by describing the activity patterns of dogs (Canis lupus familiaris) housed in rescue shelters, and comparing their sleep patterns to other behavioural and cognitive measures of welfare. Sleep and activity patterns were observed over five non-consecutive days in a population of 15 dogs. Subsequently, the characteristics of sleep and resting behaviour were described and the impact of activity on patterns of sleep and resting behaviour analysed. Shelter dogs slept for 2.8% of the day, 14.3% less than previously reported and experienced less sleep fragmentation at night (32 sleep bouts). There were no statistically significant relationships between behaviours exhibited during the day and sleep behaviour. A higher proportion of daytime resting behaviour was significantly associated with a positive judgement bias, less repetitive behaviour and increased time spent coded as ‘relaxed’ across days by shelter staff. These results suggest that, in the context of a busy shelter environment, the ability to rest more during the day could be a sign of improved welfare. Considering the non-linear relationship between sleep and welfare in humans, the relationship between sleep and behavioural indicators of welfare, including judgement bias, in shelter dogs may be more complex than this study could detect

Remarks on the Concept of Critique in Habermasian Thought

The main purpose of this paper is to examine the concept of critique in Habermasian thought. Given that the concept of critique is a central theoretical category in the work of the Frankfurt School, it comes as a surprise that little in the way of a systematic account which sheds light on the multifaceted meanings of the concept of critique in Habermas’s oeuvre can be found in the literature. This paper aims to fill this gap by exploring the various meanings that Habermas attributes to the concept of critique in 10 key thematic areas of his writings: (1) the public sphere, (2) knowledge, (3) language, (4) morality, (5) ethics, (6) evolution, (7) legitimation, (8) democracy, (9) religion, and (10) modernity. On the basis of a detailed analysis of Habermas’s multifaceted concerns with the nature and function of critique, the study seeks to demonstrate that the concept of critique can be considered not only as a constitutive element but also as a normative cornerstone of Habermasian thought. The paper draws to a close by reflecting on some of the limitations of Habermas’s conception of critique, arguing that in order to be truly critical in the Habermasian sense we need to turn the subject of critique into an object of critique

Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Interleukin-2 (IL-2) induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s) responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity.</p> <p>Methods</p> <p>25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses.</p> <p>Results</p> <p>There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12%) were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48%) had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261). All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs.</p> <p>Conclusion</p> <p><b>V</b>accination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients.</p> <p>Trial registration number</p> <p>ISRCTN83977250</p

Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma

Background: Renal cancer patients respond poorly to conventional chemotherapy, this unresponsiveness may be attributable to multidrug resistance (MDR). The mechanisms of MDR in renal cancer are not fully understood and the specific contribution of ABC transporter proteins which have been implicated in the chemoresistance of various cancers has not been fully defined in this disease. Methods: The aim of this prospective study was to analyse by immunohistochemistry the expression of two of these transporter efflux pumps, namely MDR-1/P-gp (ABCB1) and MRP-1 (ABCC1) in archival material from 113 renal carcinoma patients. Results: In the largest study of its kind, results presented here show 100% of cases stained positively for P-gp and MRP-1 protein expression. Conclusion: However, although these findings do not prove a causal role, the high frequency of tumours expressing these efflux pumps suggests that they may be important contributors to the chemoresistance of this tumour type