Dexmedetomidine target controlled infusion for awake craniotomy†.

A 73-year-old woman underwent an awake craniotomy for the resection of a supratentorial brain tumour. We provided sedation for the surgery using a dexmedetomidine target controlled infusion using the Dyck pharmacokinetic model. Using a target controlled infusion allowed more rapid titration to the desired plasma level compared with a manual infusion, without any unexpected cardiovascular, respiratory or other complications. Rapid titration of sedation during awake craniotomy is desirable, allowing deeper sedation during stimulating parts of the surgery, followed by lighter sedation - or absence of sedation - during cortical mapping. While this can be performed manually, we found utilising the Dyck model in this case simple and quick to use, avoiding the need to manually calculate infusion rates. We believe this is the first report of using a target controlled infusion model to administer dexmedetomidine for awake craniotomy, and suggest it could be considered as an alternative to administering a manual infusion.

High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival.

AIM: The primary aim was to determine the prognostic significance of apoptosis in colorectal tumour cells and tumour-associated stroma. A secondary aim was to determine whether apoptosis was related to immune surveillance. METHODS: Immunohistochemistry was performed using monoclonal antibodies recognising cleaved caspase-3 (CC3), cleaved poly (ADP-ribose) polymerase (PARP), p53, Bcl2, MHC-II, B cells (CD16), macrophages (CD68) and T cells (CD3), on a tissue microarray of 462 colorectal tumours. RESULTS: Kaplan-Meier analysis demonstrated that patients with high expression of CC3 in the tumour or CC3 or cleaved PARP in tumour-associated stroma have a good prognosis. This suggests that tumour stroma is promoting tumourigenesis and that high levels of death within the stroma breaks this link. CC3 levels in the tumour correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. CC3 levels on tumour-associated stroma also correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. Tumour cells express MHC-II in response to IFN-γ, suggesting that this may be one of the initiators of apoptosis within the good prognosis tumours. Although 73% of the MHC-II-positive tumour had high levels of apoptosis, many tumours had high levels of apoptosis in the absence of MHC-II, implying that this is only one of many causes of apoptosis within tumours. On multivariate analysis, using Cox's proportional hazards model, tumour stage, vascular invasion and expression of CC3 in tumour-associated stroma were shown to be independent markers of prognosis. CONCLUSION: This study shows that a high level of apoptosis within colorectal tumour-associated stroma is an independent marker of good prognosis.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P=0.006), optimal debulking (P=0.009), and overall survival (P=0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P=0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P=0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P=0.007), vascular invasion (P=0.05), and poorly differentiated tumours (P=0.068). A trend was noticed with advanced stage (P=0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

CD24 shows early upregulation and nuclear expression but is not a prognostic marker in colorectal cancer.

BACKGROUND AND AIMS: The putative stem cell marker CD24 is a small, heavily glycosylated, cell surface molecule which was originally associated with tumour metastasis. Recently it has been reported to be upregulated and of prognostic importance in colorectal tumours. The study aims to study the prognostic value of CD24 in a large series of colorectal cancer (CRC). METHODS: CD24 protein expression was examined by immunohistochemistry. A total of 10 whole tissue sections (WTS) of adenoma and 345 CRCs arranged as tissue microarrays (TMAs) were evaluated. For comparison with non-neoplastic tissue, 10 WTS containing tumour with associated non-neoplastic tissue were also studied. RESULTS: None of the samples of normal tissue (adjacent to tumour) showed CD24 expression. In the tumours, CD24 expression was seen on the luminal surface of the cells, within the cytoplasm and, unexpectedly, also within the nucleus. Positive immunostaining was seen in 9/10 (90%) adenomas and 313/345 (91%) of CRCs. Weak statistical associations were found between CD24 expression and some clinicopathological features. In contrast to other published studies, however, the analysis did not show any association between CD24 expression and poor prognosis-if anything it was found that loss of CD24 expression appeared to be more related to poor outcome. CONCLUSION: Upregulation of CD24 is an early and common event during the development of CRC and it may be expressed in any cellular compartment, including the nucleus. CD24 is not, however, a good prognostic marker in CRC.

Human leukocyte antigen class I expression is an independent prognostic factor in advanced ovarian cancer resistant to first-line platinum chemotherapy.

BACKGROUND: Loss of HLA class I is important in ovarian cancer prognosis but its role as a prognostic indicator in relation to therapy remains unproven. We studied the prognostic potential of this antigen and its significance in relation to platinum therapy. METHODS: A total of 157 primary ovarian cancers were assessed for HLA class I immunohistochemically and linked to a comprehensive database of clinicopathological variables, treatment details, and platinum sensitivity. RESULTS: Tumours expressing high levels of HLA class I had significantly improved survival (P=0.044). There was a 19-month difference in the median overall survival between tumours with high and low antigen expression. HLA class I antigen expression, stage, and platinum sensitivity were independently predictive of prognosis on multivariate analysis. HLA class I antigen was shown to be expressed at higher levels in patients with good overall survival in platinum-resistant patients (P=0.042). HLA class I significantly correlated with overall survival on multivariate analyses (P=0.034). CONCLUSION: Low-level HLA class I expression is an independent prognostic indicator of poor clinical outcome in ovarian cancer. The survival advantage of patients with platinum-resistant tumours expressing high levels of HLA class I suggests that immunotherapy may be of use in these ovarian cancers resistant to standard chemotherapy.

Factors associated with severe caries among adults in Kuwait.

AIM: To investigate the relationship between caries etiological factors and occurrence of severe caries among adults in Kuwait. METHODS: Forty-two adult patients with severe caries, attending Kuwait polyclinics, were compared with 36 caries-free subjects in a cross-sectional study. The patients with severe caries were aged 16 years or older and had a minimum of eight open coronal carious cavities, with the involvement of at least one anterior tooth. In addition, their salivary glands had not been compromised by disease or medication. The caries-free subjects had at least 24 standing teeth, and no carious cavities. Salivary flow rates, buffering capacity, frequency of sugar consumption, and oral hygiene index were measured. Mutans streptococci and Lactobacillus counts were determined by the dip-slide method. RESULTS: Fisher's exact test or chi(2) test showed that the patients with severe caries had a significantly higher frequency of sugar consumption, plaque index, Lactobacillus and mutans streptococci counts, as compared with those who were caries-free. In contrast, no significant difference was observed in salivary flow rates or buffering capacity between the two groups of patients. In the multiple logistic regression analysis, only frequency of sugar consumption, oral hygiene, and mutans streptococci count were found to be significantly associated with the occurrence of severe caries. CONCLUSION: Severe caries may occur in Kuwait even among adults whose salivary gland functions have not been compromised.

Perceived effectiveness and side effects of intermaxillary fixation for diet control.

Weight loss is one of the major side effects associated with intermaxillary fixation (IMF) following orthognathic surgery or jaw fractures. The aim of this study was to retrospectively interview patients treated with intermaxillary fixation for diet control (IMFDC) to collect base-line information regarding: (1) perceived effectiveness, patients' compliance and patients' satisfaction with the treatment; (2) the frequency of side effects associated with IMFDC. The results show that IMFDC significantly reduced weight by a mean of 6.8 kg during treatment, and a mean of 4.1 kg at a minimum of 1 month following IMFDC removal (P<0.0001). Only 32.5% of the patients complied with the planned period of IMFDC treatment while 70% were satisfied with the treatment results. The most common side effects were speech problems and oral-facial pain with a prevalence of 52.5 and 32.5%, respectively. IMFDC treatment is not effective for long-term weight reduction and may only be used for a very short period of time to initiate weight loss. Exercise and/or special diet programs are healthier and better means to treat obesity and maintain weight loss.

Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein.

Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typically stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a chaperone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is up-regulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we focused on FGF-1 and -2 and investigated interactions with recombinant human FGF-BP1 protein as well as effects on signal transduction, cell proliferation, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FGF-2 and that this binding is inhibited by FGF-1, heparan sulfate, and heparinoids. Furthermore, FGF-BP1 enhances FGF-1- and FGF-2-dependent proliferation of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We conclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modulates the biological activities of these growth factors.

'Debulking' surgery is unnecessary in advanced abdominal Burkitt lymphoma in Iraq.

In a previous study (Burkitt lymphoma study I, BL I) between 1982 and 1984, we used a multidrug rotating chemotherapy schedule, now known as 'GRAB', to treat 24 Iraqi children with non-localised BL (Murphy stages II, III and IV). At the time of reporting, actuarial survival was 50% (current actual survival 42%) and the major morbidity and mortality was not from resistant or relapsed lymphoma, but from complications of the tumour lysis syndrome, sepsis and early abdominal surgery. The study (BL II) reported here was carried out between 1984 and 1986; we used GRAB to treat 24 newly and consecutively diagnosed children with advanced Burkitt lymphoma but discouraged early 'debulking' surgery and paid special attention to supportive care during the first two weeks of treatment. As in BL I, no radiotherapy was used. Twenty patients (83.8%) attained complete remission: 17 (71%), including three of the seven stage IV patients, survive continuously disease-free at a median of 26 months (range 18-36 months) from diagnosis. We have previously pointed out that GRAB, without radiotherapy, may be especially suited for use in some developing countries. From this study we conclude that, with appropriate supportive care and minimal surgery, survival rates over 50% may be achieved. Our next studies are aimed at defining a 'good risk' group of patients, who may be curable without alkylating agents and a 'poor risk' group, who need more intensive therapy.

Intensive chemotherapy for non-localised Burkitt's lymphoma.

Between 1982 and 1984, 24 consecutively diagnosed children from Iraq with non-localised Burkitt lymphoma (Murphy stages II, III, and IV) were eligible for treatment with a multi-drug rotating chemotherapy schedule. This schedule was intensive and included early treatment directed at the central nervous system but was of only six months' duration and fairly inexpensive compared with schedules recently advocated for use in the developed world. Some patients had 'debulking' abdominal surgery, but no radiation treatment was used. There were a number of complications related to early treatment, some of them fatal, but of 13 patients entering complete remission 12 are long term survivors who are free of disease and, hopefully, cured. These results represent a substantial improvement over our experience before 1982 (6.9% survival). A similar treatment approach might be adopted by other centres, especially those in developing countries where cancer accounts for a rising proportion of childhood death but whose resources are limited.

Familial erythrophagocytic reticulosis. Complete response to combination chemotherapy.

Two infants with familial erythrophagocytic reticulosis attained a durable complete remission after combination chemotherapy including intrathecal methotrexate. Though both later died, neither child had definitive evidence of tumour at necropsy.

Burkitt's lymphoma in Iraq. Clinical and pathological study of forty-seven patients.

The clinical and pathological features of 47 patients with Burkitt's lymphoma seen at the University of Baghdad Teaching Hospital over the years 1969-1977 are described. There were 30 males and 17 females with a mean age of 7.5 years. All patients presented with advanced disease; 44 were in Stage III and 3 in Stage IV, (1 with central nervous system involvement; 1 with bone-marrow involvement; 1 presented as acute leukaemia). The abdomen, with or without other sites, was involved in 42 patients. Thirty-four patients died within 18 months, 11 in the immediate post-operative period. Cyclophosphamide in variable dosages was administered to 29 patients with a good response in 15. The 3 patients with Stage IV disease died with poor response to therapy. Thus, in Iraq, a non-endemic area for the disease, Burkitt's lymphoma seems to have somewhat different clinical and pathological features from the endemic (African), or the rare, sporadic disease reported elsewhere.