Involved Node, Site, Field and Residual Volume Radiotherapy for Lymphoma: A Comparison of Organ at Risk Dosimetry and Second Malignancy Risks.

AIMS: Recent radiotherapy guidelines for lymphoma have included involved site radiotherapy (ISRT), involved node radiotherapy (INRT) and irradiation of residual volume after full-course chemotherapy. In the absence of late toxicity data, we aim to compare organ at risk (OAR) dose-metrics and calculated second malignancy risks. MATERIALS AND METHODS: Fifteen consecutive patients who had received mediastinal radiotherapy were included. Four radiotherapy plans were generated for each patient using a parallel pair photon technique: (i) involved field radiotherapy (IFRT), (ii) ISRT, (iii) INRT, (iv) residual post-chemotherapy volume. The radiotherapy dose was 30 Gy in 15 fractions. The OARs evaluated were: breasts, lungs, thyroid, heart, oesophagus. Relative and absolute second malignancy rates were estimated using the concept of organ equivalent dose. Significance was defined as P < 0.005. RESULTS: Compared with ISRT, IFRT significantly increased doses to lung, thyroid, heart and oesophagus, whereas INRT and residual volume techniques significantly reduced doses to all OARs. The relative risks of second cancers were significantly higher with IFRT compared with ISRT for lung, breast and thyroid; INRT and residual volume resulted in significantly lower relative risks compared with ISRT for lung, breast and thyroid. The median excess absolute risks of second cancers were consistently lowest for the residual technique and highest for IFRT in terms of thyroid, lung and breast cancers. The risk of oesophageal cancer was similar for all four techniques. Overall, the absolute risk of second cancers was very similar for ISRT and INRT. CONCLUSIONS: Decreasing treatment volumes from IFRT to ISRT, INRT or residual volume reduces radiation exposure to OARs. Second malignancy modelling suggests that this reduction in treatment volumes will lead to a reduction in absolute excess second malignancy. Little difference was observed in second malignancy risks between ISRT and INRT, supporting the use of ISRT in the absence of a pre-chemotherapy positron emission tomography scan in the radiotherapy treatment position.

Clostridium difficile-associated disease acquired in the neurocritical care unit.

BACKGROUND: Clostridium difficile is an important cause of nosocomial infection on the intensive care unit. Little is known about infection rates on the neurocritical care unit (NICU). The purpose of this study was to determine the prevalence, severity, and outcome associated with Clostridium difficile-associated disease (CDAD) acquired on the NICU. METHODS: Patients on NICU with a positive stool Clostridium difficile toxin assay, from August 2004 to February 2008, were identified by the Department of Microbiology. Each patient's medical notes and charts were reviewed in turn. Patients with a positive assay within 48 h of NICU admission were excluded. RESULTS: Twenty-one (0.6%) NICU patients developed CDAD. All were emergency admissions, 18 (86.0%) were neurosurgical. Subarachnoid hemorrhage was the most common diagnosis, 5 (23.8%) patients. Median age and APACHE II score on admission were 55 (IQR 40-66) and 21 (IQR 16-24), respectively. Thirteen (61.9%) patients were female. Median interval between NICU admission and diarrhea onset and CDAD diagnosis were 5 (3-8) days and 7 (4-12) days, respectively. At the time of diagnosis most, 11 (52.4%) patients, had moderate CDAD. Previously identified risk factors for ICU-acquired CDAD comprised: age > 65 (6), antibiotics (21), and medical device requirements (21). Five (23.8%) patients deteriorated clinically as a result of CDAD. The overall in-hospital mortality for those with NICU acquired CDAD was 19%. CONCLUSIONS: Although CDAD is rarely acquired on the NICU, up to one quarter of affected patients may experience complications. Prospective validation of severity definitions and treatment guidelines may help to reduce the complication rates.

Diabetes mellitus: anaesthetic management.

As the incidence of diabetes mellitus continues to increase in the United Kingdom, more diabetic patients will present for both elective and emergency surgery. Whilst the underlying pathophysiology of type 1 and type 2 diabetes differs, there is much good evidence that controlling the blood glucose to < or = [corrected] 10 mmol.l(-1) in the peri-operative period for both types of diabetic patients improves outcome. This should be achieved with a glucose-insulin-potassium regimen in all type 1 diabetics and in type 2 diabetics undergoing moderate or major surgical procedures. After surgery, a decrease in the catabolic hormone response resulting from good analgesia and the avoidance of nausea and vomiting should allow early re-establishment of normal glycaemic control.

Cutaneous infection with Alternaria tenuissima in an immunocompromised patient.

A 28-year-old man, on immunosuppressive therapy for a recent kidney-pancreas transplant, presented to our department with an unusual violaceous nodule on his right knee. A biopsy specimen showed a granulomatous response in the dermis, surrounding numerous fungal cells and septate hyphae. Fungal cultures yielded dark grey colonies, which were identified as Alternaria tenuissima. To our knowledge this is the first report of A. tenuissima infection reported in the U.K.

Release of tumour necrosis factor alpha (TNFalpha) by TNFalpha cleaving enzyme (TACE) in response to septic stimuli in vitro.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha), in its soluble form (solTNF), has been well described as an important cytokine in inflammatory states including sepsis. The transmembrane precursor of solTNF, membrane-bound TNFalpha (memTNF), is cleaved by TNFalpha cleaving enzyme (TACE), the regulation of which is poorly understood. We hypothesized that the diversity of clinical features seen with sepsis caused by different organisms may be a result of differential regulation of TACE. Therefore, we measured these proteins in models of sepsis using flow cytometric methods that we have developed. METHODS: Surface protein expression of memTNF and TACE, and TACE catalytic activity were measured in human monocytes by flow cytometry following cell stimulation by lipopolysaccharide (LPS), zymosan (a yeast cell wall product) or heat-inactivated Neisseria meninigitidis. RESULTS: Unstimulated human monocytes express memTNF on the cell surface (mean fluorescence intensity, MFI 131) and this is down-regulated initially in response to LPS (MFI 57) but then recovers to exceed the resting protein expression (MFI 614). TACE protein is also present on the surface of resting cells (MFI 389) but is catalytically inactive until cell stimulation. Stimulation of monocytes with LPS, zymosan and Neisseria meningitidis produced different patterns of TACE activation with time. CONCLUSIONS: The regulation of memTNF by TACE on monocytes is an important regulatory event in the pro-inflammatory cytokine cascade. As monocytes are important in the inflammatory cascade, we suggest that the control of memTNF and TACE activity on monocytes may play a role in the pathophysiology of sepsis.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer.

PURPOSE: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 micrograms/ml for five days (5d) or 1 microgram/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. PATIENTS AND METHODS: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. RESULTS: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 10(9)/1 after 5d and 5.0 x 10(9)/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. CONCLUSIONS: Although the number of patients entered into this trial was small, the low activity seen at 1 microgram/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.

Ambient oxygen concentrations during simulated cardiopulmonary resuscitation.

Oxygen concentrations were measured at 12 points around a cardiopulmonary resuscitation practice mannequin following simulated ventilation with a self-inflating bag, a 'Waters' bag and a ventilator to determine whether increased oxygen concentrations may contribute to the risk of combustion from arcing defibrillator paddles. Ventilation was simulated using either a mask or via a tracheal tube fitted to the airway. The head of the mannequin rested upon a 10-cm-high pillow. Gas sampling took place after 5 min of ventilation with subsequent removal of the ventilatory device and placement on the pillow to the left of the mouth, with the tubing of the device removed to a point 1 m behind the mouth and with the device left connected to the tracheal tube. Gas was sampled after using all devices at oxygen flows of 10l.min-1 and 15l.min-1. Slightly increased oxygen concentrations were noted over the anterior chest after placement of all devices on the pillow at the higher flow. Concentrations of greater than 30% were measured in the left axilla after placement of all devices on the pillow at both flows. No increase in oxygen concentration was seen when the devices were either left connected to the tracheal tube or removed to a distance of 1 m. It would appear that leaving a patient connected to a ventilator poses no increase in risk of fire from ignition of combustible material in an oxygen-enriched atmosphere during defibrillation. Disconnecting any device which continues to discharge oxygen and leaving it on the pillow before defibrillation is dangerous.

Nasotracheal intubation in the presence of frontobasal skull fracture.

PURPOSE: To present a case of maxillofacial trauma and basal skull fracture (BSF) in whom nasotracheal intubation (NTI) was successfully used, without complication, to facilitate surgical fixation. To present alternative methods of airway management in this situation and to review the evidence supporting the notion that NTI is contraindicated in the presence of basal skull fracture. CLINICAL FEATURES: A 17-yr-old man was referred for surgical fixation of bilateral mandibular fractures. Cranial computed tomography revealed intracranial air and blood in all four sinuses and distortion of the nasal passage on the right. There was no cerebral injury and the left nasal passage appeared patent. In order to facilitate intraoperative intermaxillary fixation fibreoptic NTI was undertaken in preference to tracheostomy. The patient made an uneventful recovery without evidence of meningitis or direct cerebral injury. CONCLUSION: In selected patients NTI may be performed in the presence of BSF. Available evidence suggests that BSF-should not be regarded as an absolute contraindication to NTI.

High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer.

PURPOSE: To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS: Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS: Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION: Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.

Clinical and endocrine effects of the oral aromatase inhibitor vorozole in postmenopausal patients with advanced breast cancer.

Vorozole is an orally active, nonsteroidal aromatase inhibitor. Twenty-four postmenopausal patients with advanced breast cancer who had relapsed after treatment with tamoxifen received three separate daily doses of vorozole (1, 2.5, and 5 mg) each for 1 month in a randomized, double-blind, phase II study. There was significant suppression (P < 0.001) of serum estradiol at all three doses (median reduction, 91, 90, and 89%, respectively). There was a significant trend (P = 0.02) for estradiol to be suppressed below the detection limit of the assay (3 pmol/liter) more frequently with an increasing dose of vorozole; 13, 31, and 40% respectively. Estrone and estrone-sulfate levels were likewise reduced at each dose by 52-55% and 64-69%, respectively. There was no significant effect at any dose on aldosterone, testosterone, androstenedione, 17 alpha-hydroxyprogesterone, or thyroid-stimulating hormone levels. A small reduction in cortisol was seen at the 5 mg dose, although the relevance is unclear given that 17 alpha-hydroxyprogesterone levels did not rise. Eight patients (33%) achieved an objective response (2 complete remission, 6 partial remission) with a median response duration of 13 months. Four patients (17%) achieved disease stabilization for more than 6 months. Patients who had responded previously to tamoxifen were more likely to respond to vorozole. There were no significant clinical side effects and the drug was well tolerated. These data suggest that vorozole is a potent and selective oral aromatase inhibitor for use in postmenopausal breast cancer.

Phase II study of continuous infusion fluorouracil with epirubicin and cisplatin in patients with metastatic and locally advanced breast cancer: an active new regimen.

PURPOSE: To investigate the efficacy and toxicity of continuous infusion fluorouracil (5-FU) with every-3-weeks epirubicin and cisplatin (ECF) in advanced breast cancer in a phase II study. PATIENTS AND METHODS: Forty-three patients with metastatic (n = 29) or locally advanced/inflammatory (n = 14) breast cancer were treated with 5-FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks, for eight courses. RESULTS: The overall response rate (complete plus partial) was 84% (95% confidence interval [Cl], 76% to 96%), with a complete response rate of 24% (95% Cl, 9% to 40%) in patients with metastatic disease and 36% (95% Cl, 11% to 61%) in patients with locally advanced disease. The main World Health Organization [WHO] grade 3 or 4 toxicities included leukopenia, emesis, and alopecia. CONCLUSION: Infusional ECF is a highly active regimen in advanced breast cancer and warrants evaluation in high-risk early breast cancer.

Ultrastructural quantification of collagen in the articular disc of the temporomandibular joint of the rabbit.

Collagen fibril diameters were quantified in two regions of the articular disc of this joint. One region was the thinner, translucent central part of the disc; the other was from the thicker, opaque peripheral part more anteriorly. Mean collagen fibril diameters in the thicker zone were small and had a unimodal distribution. In contrast, mean collagen fibril diameters in the thinner central region were larger and with a much wider range of values, as indicated by the larger standard deviations. It was concluded that regional variations exist in the collagen of the rabbit articular disc and may reflect the mechanical loads to which the disc is subjected.