Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2).

BACKGROUND: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. METHODS: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). RESULTS: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. CONCLUSION: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

Mutational Signatures in Mandibular Ameloblastoma Correlate with Smoking.

Ameloblastoma is a rare tumor of odontogenic epithelium, the low incidence rate of which precludes statistical determination of its molecular characterizations. Despite recent genomic and transcriptomic profiling, the etiology of ameloblastomas remains poorly understood. Risk factors of ameloblastoma development are also largely unknown. Whole exome sequencing was performed on 11 mandibular ameloblastoma samples. We identified 2 convergent mutational signatures in ameloblastoma: 1) a signature found in multiple types of lung cancers with probable etiology of tobacco carcinogens (COSMIC signature 4) and 2) a signature present in gingivobuccal oral squamous cell carcinoma and correlated with tobacco-chewing habits (COSMIC signature 29). These mutational signatures highlight tobacco usage or related mutagens as one possible risk factor of ameloblastoma, since the association of BRAF mutations and smoking was demonstrated in multiple studies. In addition to BRAF hotspot mutations (V600E), we observed clear inter- and intratumor heterogeneities. Interestingly, prior to BRAF mutation, important genes regulating odontogenesis mutated (e.g., corepressor BCOR), possibly playing important roles in tumorigenesis. Furthermore, recurrent mutations in the CDC73 gene, the germline mutations of which predispose patients to the development of jaw tumors, were found in 2 patients, which may lead to recurrence if not targeted by therapeutic drugs. Our unbiased profiling of coding regions of ameloblastoma genomes provides insights to the possible etiology of mandibular ameloblastoma and highlights potential disease risk factors for screening and prevention, especially for Asian patients. Because of the limited sample size and incomplete habitual, dietary, and occupational data, a causal link between tobacco usage and ameloblastoma still requires further investigations.

An evaluation of information dissemination during the severe acute respiratory syndrome (SARS) outbreak among selected rural communities in Kuala Kangsar.

To assess the level of knowledge, attitude and practice (KAP) on SARS and its preventive measures among the rural population of Kuala Kangsar district. This KAP study was also done to identify the expectation and preference of rural population upon obtaining health information. This is a cross-sectional study of 201 households from four villages in Kuala Kangsar. Face-to-face interview was done regarding knowledge, attitude and practice on SARS and its preventive measures. Statistical analyses were performed with SPSS (Version 10.0). A scoring system was used to assess the level of knowledge, attitude and practice towards SARS. Ninety one percent of the study population was aware of SARS. Majority of them have good attitude towards SARS based on the formulated scoring system. Television was found to be the first hand information about SARS and most preferred source of information by the rural population. Knowledge and attitude of respondents concerning SARS were good. Television was found to be the preference among the rural population in obtaining health information.

Sequence variation in the early genes E1E4, E6 and E7 of human papilloma virus type 6.

The majority of condylomata acuminata (anogenital warts) are caused by infection with Human Papilloma Virus type 6 (HPV-6). We have sequenced the HPV-6 early genes, E1-E4, E6 and E7 from wart biopsy DNA samples sourced from the UK and USA and derived a consensus sequence for these genes and the proteins they encode. When compared to the prototype HPV-6b sequence, published over 12 years ago, the E1-E4 consensus sequence showed 3/91 (3.3%) amino acid changes, the E6 consensus sequence showed 1/150 (0.7%) changes and the E7 consensus sequence showed 1/98 (1.0%) changes. Since many of the early gene sequences from biopsy material were more similar to the HPV-6a subtype than HPV-6b, this data supports the use of HPV-6a as the HPV-6 prototype.

Influence of substrate carbon on the metabolism of Clostridium thermohydrosulfuricum.

The concentration of carbon sources has a significant influence on the growth, carbohydrate uptake and metabolite distribution in Clostridium thermohydrosulfuricum. The growing concentrations of glucose or starch increase the production of ethanol and lactate, the intracellular fructose-1,6-diphosphate (FDP) and the specific activity of lactate dehydrogenase (LDH), but decrease the ethanol/lactate ratio.

PCR sequencing of the spike genes of geographically and chronologically distinct human coronaviruses 229E.

A reverse transcription nested PCR (RT-PCR) sequencing methodology was developed and used to generate sequence data from the spike genes of three geographically and chronologically distinct human coronaviruses 229E. These three coronaviruses were isolated originally from the USA in the 1960s (human coronavirus 229E strain ATCC VR-74), the UK in the 1990s (human coronavirus 229E LRI 281) and Ghana (human coronavirus 229E A162). Upon translation and alignment with the published spike protein sequence of human coronavirus 229E 'LP' (isolated in the UK in the 1970s), it was found that variation within the translated protein sequences was rather limited. In particular, minimal variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and ATCC VR-74 (1/1012 amino acid differences), whilst most variation was observed between the translated spike protein sequence of human coronaviruses 229E LP and A162 (47/1012 amino acid changes). Further, the translated spike protein sequence of human coronavirus 229E A162 showed three clusters of amino acid changes, situated within the 5' half of the translated spike protein sequence.

The presence of Epstein-Barr virus in multiple organs in a fatal case of virus-associated haemophagocytic syndrome.

We describe a case report of a 21-year-old male with fatal Epstein-Barr virus-associated haemophagocytic syndrome. Virus is detected in multiple organs by polymerase chain reaction and in the tissue-specific cells of those organs by in situ hybridisation. It is suggested that organ failure may be a direct response to infection.

Effects of rhinovirus-induced common colds on granulocyte activity in allergic rhinitis.

OBJECTIVE: To explore the activities of mast cells, eosinophils, and neutrophils in patients with allergic rhinitis developing common colds and increased responsiveness to allergen following nasal rhinovirus inoculation. METHODS: We have revisited a nasal lavage material obtained from 17 patients who were successfully inoculated with rhinovirus outside the pollen season and received nasal allergen challenges before and after inoculation. We have examined indices of mast cell activity (tryptase), eosinophil degranulation (eosinophil peroxidase; EPO), and neutrophil activation (myeloperoxidase; MPO). RESULTS: Allergen challenges performed before rhinovirus inoculation increased the nasal output of EPO. Notably, this response was significantly greater after rhinovirus inoculation (cf. before inoculation). The output of MPO was also increased following allergen challenge after, but not before, rhinovirus inoculation. Nasal lavage fluid levels of tryptase were increased following allergen challenge similarly before and after rhinovirus inoculation. Also, the viral infection did not affect the baseline levels of tryptase. CONCLUSIONS: The present data demonstrate that rhinovirus infections activate both eosinophils and neutrophils, but that they may not affect mast cell activity. We suggest that common colds in part through stimulation of granulocyte activity potentiate the airway inflammation in allergic diseases.

Non-uniform dwell times in line source high dose rate brachytherapy: physical and radiobiological considerations.

The ability to vary source dwell times in high dose rate (HDR) brachytherapy allows for the use of non-uniform dwell times along a line source. This may have advantages in the radical treatment of tumours depending on individual tumour geometry. This study investigates the potential improvements in local tumour control relative to adjacent normal tissue isoeffects when intratumour source dwell times are increased along the central portion of a line source (technique A) in radiotherapy schedules which include a relatively small component of HDR brachytherapy. Such a technique is predicted to increase the local control for tumours of diameters ranging between 2 cm and 4 cm by up to 11% compared with a technique in which there are uniform dwell times along the line source (technique B). There is no difference in the local control rates for the two techniques when used to treat smaller tumours. Normal tissue doses are also modified by the technique used. Technique A produces higher normal tissue doses at points perpendicular to the centre of the line source and lower doses at points nearer the ends of the line source if the prescription point is not in the central plane of the line source. Alternatively, if the dose is prescribed at a point in the central plane of the line source, the dose at all the normal tissue points are lower when technique A is used.

Accelerated fast neutron therapy: a pilot study.

The clinical role of fast neutron therapy has been limited by excessive late normal tissue damage. A pilot study of accelerated fractionation of fast neutron therapy was performed, based on the rationale that this should result in an increase in the response in acute reacting tissues (normal and malignant), with no change in late damage and a consequent increase in the therapeutic ratio. Further accelerated fractionation should improve the local control of rapidly proliferating tumour, without the potential problem of inadequate reoxygenation inherent in accelerated photon schedules. 6 or 12 fractions of 62 MeV (p-Be) neutrons were given over 12 days to 27 sites in 23 patients with locally advanced tumours. With a dose reduction of 12% (18 Gy), acceptable skin and oral mucosa early reactions were obtained. A larger dose reduction (15%) was required at pelvic sites. The incidence of late EORTC/RTOG grade 4 toxicity was 46%. The overall response rate was 76% with a complete response rate of 16%. For locally advanced breast cancer, the complete response rate was 9%, which compares unfavourably with previous results with conventional neutron fractionation schedules. The combination of a low overall complete response rate and excessive late normal tissue toxicity suggests that accelerated fractionation of fast neutrons does not lead to an improvement in the therapeutic ratio, and that late normal tissue damage will continue to be dose limiting.

Antiviral activity of some Nigerian medicinal plant extracts.

Plants from Northern Nigeria with a history of use in both human and veterinary traditional medicine have been investigated for their antiviral activity and their cytotoxicity determined. Extracts were tested against poliovirus, astrovirus, herpes simplex viruses and parvovirus, using the microtitre plate inhibition tests. Most of the extracts have activity against more than one virus at a dose rate of between 100 and 400 microg/100 microl.

Aetiology of gastroenteritis at a major referral centre in Saudi Arabia.

To determine the causes of gastroenteritis at a major referral centre in Saudi Arabia, retrospective study was carried out on 58,110 fresh stools from 42,035 patients. Examination of stool specimens for pathogens was based on the clinical judgement of the physician responsible, so that all specimens were not tested for the presence of all pathogen groups. Bacterial enteropathogens were found in 7.7% of patients; Salmonella species (51.7%) were found to be the most frequent pathogens followed by Campylobacter jejuni (28%) and Shigella species (14.9%). Protozoan or metazoan parasites were detected in 27.8% of patients examined, the most common being Giardia lamblia and Hymenolepsis nana. Of the patients tested for viruses in stool, 14.1% had rotavirus, 5.3% adenovirus, 1.2% small round viruses and 0.3% coronavirus. Clostridium difficile toxin was also found in 9.5% of patients examined.

The incidence and detection of HPV in the upper aerodigestive tract using brush and biopsy techniques.

The association between human papillomavirus (HPV) and squamous carcinoma is well established. In the polymerase chain reaction (PCR) we have an effective technique for detecting small quantities of viral DNA, but the assay requires tissue taken at endoscopy to reveal the presence or absence of HPV. Brushings have been used effectively elsewhere in the body to obtain cytological material. This study set out to ascertain if sufficient viral DNA could be obtained, using a laryngeal brushing and the PCR, to detect the presence or absence of HPV. Six patients with squamous carcinoma of the larynx and seven controls who were having laryngoscopy for other reasons underwent laryngeal biopsy. In addition, in the patients with carcinoma, biopsies were taken at the tumour margins and brushings from both sites. The samples were tested for the presence of HPV types 6, 11, 16, 18 and 31 by means of the PCR. The distribution of HPV types was as expected in the biopsy specimens, but only one brushing detected any HPV type at all. We conclude that laryngeal brushing is an inadequate technique for assessing the presence of HPV in the larynx.

Human papilloma virus and carcinoma of the laryngopharynx.

The presence of human papillomavirus (HPV) genomes 6, 11, 16 and 33 in 16 patients with laryngopharyngeal carcinomas was examined by means of a polymerase chain reaction. HPV genomes were detected in 75 per cent of cases. In hypopharyngeal carcinoma, HPV 6 and 11 were present in adjacent tissue but absent from the tumour. HPV 16 and 33 were present in 40 per cent of laryngeal tumours and adjacent tissue. These results suggest that HPV 16 and 33 may be closely associated with the development of some laryngopharyngeal carcinomas.

Some characteristics of hospitalized HIV seropositive patients in Myanmar.

Twenty-two hospitalized HIV seropositive patients were studied prospectively between July 1991 and January 1992. The majority of the patients were intravenous drug users (IVDUs). Their age ranged from 20 to 38 years with a male preponderance of 12 to 1. Anemia, lymphopenia and thrombocytopenia were observed in 100%, 36% and 41%, respectively. The common pathogens like malaria parasites, Mycobacterium tuberculosis, Entamoeba histolytica, Streptococcus and Salmonella were isolated/identified rather than opportunistic organisms.

Prospective case-control study of role of infection in patients who reconsult after initial antibiotic treatment for lower respiratory tract infection in primary care.

OBJECTIVE: To assess direct and indirect evidence of active infection which may benefit from further antibiotics in adults who reconsult within 4 weeks of initial antibiotic management of acute lower respiratory tract infection in primary care. DESIGN: Observational study with a nested case-control group. SETTING: Two suburban general practices in Arnold, Nottingham, over 7 winter months. SUBJECTS: 367 adults aged 16 years and over fulfilling a definition of lower respiratory tract infection and treated with antibiotics. 74 (20%) patients who reconsulted within 4 weeks for the same symptoms and 82 "control" patients who did not were investigated in detail at fallow up. MAIN OUTCOME MEASURES: Direct and indirect evidence of active infection at the time of the reconsultation or the follow up visit with the research nurse for the controls. Investigations performed included sputum culture, pneumococcal antigen detection, serial serology for viral and atypical pathogens and C reactive protein, throat swabs for detecting viral and atypical pathogens by culture and polymerase chain reaction, and chest radiographs. RESULTS: Demographic and clinical features of the groups were similar. Two thirds of the 74 patients who reconsulted received another antibiotic because the general practitioner suspected continuing infection. Any evidence of infection warranting antibiotic treatment was uncommon at reconsultation. The findings for the two groups were similar for the occurrence of identified pathogens; chest x ray changes of infection (present in 13%); and C reactive protein concentrations, which had nearly all fallen towards normal. Only three patients in the reconsultation group had concentrations > or = 40 mg/l. Pathogens identified at follow up in the 156 patients in both groups included ampicillin sensitive bacteria in six. Atypical infections diagnosed in 27 (Chlamydia pneumoniae in 22) and viral infections in 54 had probably been present at the initial presentation. CONCLUSION: Our study suggests that active infection, which may benefit from further antibiotics, is uncommon in patients who reconsult after a lower respiratory tract infection, and a repeat antibiotic prescription should be the exception rather than the rule. Other factors, such as patients' perception of their illness, may be more important than disease and infection in their decision to reconsult.

High energy neutron treatment for pelvic cancers: study stopped because of increased mortality.

OBJECTIVE: To compare high energy fast neutron treatment with conventional megavoltage x ray treatment in the management of locally advanced pelvic carcinomas (of the cervix, bladder, prostate, and rectum). DESIGN: Randomised study from February 1986; randomisation to neutron treatment or photon treatment was unstratified and in the ratio of 3 to 1 until January 1988, when randomisation was in the ratio 1 to 1 and stratified by site of tumour. SETTING: Mersey regional radiotherapy centre at Clatterbridge Hospital, Wirral. PATIENTS: 151 patients with locally advanced, non-metastatic pelvic cancer (27 cervical, 69 of the bladder, seven prostatic, and 48 of the rectum). INTERVENTION: Randomisation to neutron treatment was stopped in February 1990. MAIN OUTCOME MEASURES: Patient survival and causes of death in relation to the development of metastatic disease and treatment related morbidity. RESULTS: In the first phase of the trial 42 patients were randomised to neutron treatment and 14 to photon treatment, and in the second phase 48 to neutron treatment and 47 to photon treatment. The relative risk of mortality for photons compared with neutrons was 0.66 (95% confidence interval 0.40 to 1.10) after adjustment for site of tumour and other important prognostic factors. Short term and long term complications were similar in both groups. CONCLUSIONS: The trial was stopped because of the increased mortality in patients with cancer of the cervix, bladder, or rectum treated with neutrons.

Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.

OBJECTIVE: To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. DESIGN: Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. SUBJECTS: 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. SETTING: Southampton and surrounding community. MAIN OUTCOME MEASURES: Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. RESULTS: Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus. CONCLUSIONS: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.