Follow-up after curative treatment for colorectal cancer: longitudinal evaluation of patient initiated follow-up in the first 12 months.

PURPOSE: To compare patient-triggered follow-up (PTFU) for curatively treated colorectal cancer against traditional outpatient follow-up (OPFU). METHODS: Questionnaires were mailed at four time points over one-year post-treatment to two prospectively-recruited cohorts: A, patients entering follow-up and receiving OPFU pre-implementation of PTFU; B, patients entering follow-up (FU) and receiving either OPFU (B1) or PTFU (B2) post-implementation of PTFU. Bi-variate tests were used to compare patient characteristics and outcomes eight months after entering follow-up (generic and cancer-specific quality of life (QoL), satisfaction). Regression analysis explored associations between follow-up model and outcomes. Resource implications and costs of models were compared. RESULTS: Patients in Cohort B1 were significantly more likely to have received chemotherapy (p < 0.001), radiotherapy (p < 0.05), and reported poorer QoL (p = 0.001). Having a longstanding co-morbid condition was the most important determinant of QoL (p < 0.001); model of care was not significant. Patients were satisfied with their follow-up care regardless of model. Health service costs were higher in PTFU over the first year CONCLUSIONS: PTFU is acceptable to patients with colorectal cancer and can be considered to be a realistic alternative to OPFU for clinically suitable patients. The initial costs are higher due to provision of a self-management (SM) programme and remote surveillance. Further research is needed to establish long-term outcomes and costs.

Family history and outcome of young patients with breast cancer in the UK (POSH study).

BACKGROUND: Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer. METHODS: Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large prospective cohort study of women aged less than 41 years with breast cancer diagnosed and treated in the UK using modern oncological management. Personal characteristics, tumour pathology, treatment and family history of breast/ovarian cancer were recorded. Follow-up data were collected annually. RESULTS: Family history data were available for 2850 patients. No family history was reported by 65·9 per cent, and 34·1 per cent reported breast/ovarian cancer in at least one first- or second-degree relative. Patients with a family history were more likely to have grade 3 tumours (63·3 versus 58·9 per cent) and less likely to have human epidermal growth factor receptor 2-positive tumours (24·7 versus 28·8 per cent) than those with no family history. In multivariable analyses, there were no significant differences in distant disease-free intervals for patients with versus those without a family history, either for the whole cohort (hazard ratio (HR) 0·89, 95 per cent c.i. 0·76 to 1·03; P = 0·120) or when stratified by oestrogen receptor (ER) status (ER-negative: HR 0·80, 0·62 to 1·04, P = 0·101; ER-positive: HR 0·95, 0·78 to 1·15, P = 0·589). CONCLUSION: Young British patients presenting to breast surgical clinics with a positive family history can be reassured that this is not a significant independent risk factor for breast cancer outcome.

Obesity and the outcome of young breast cancer patients in the UK: the POSH study.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m(2)), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26 mm versus U/H 20 mm, P < 0.001; Ov 24 mm versus U/H 20 mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS: Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.

Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study.

BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

UK guidance document: treatment of metastatic breast cancer.

Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.

Adjuvant chemotherapy in older women (ACTION) study - what did we learn from the pilot phase?

BACKGROUND: The ACTION trial was initiated to provide evidence from a randomised trial on the effects of chemotherapy in women aged over 70 years where evidence for risk and benefit are lacking. METHODS: This was a randomised, phase III clinical trial for high risk, oestrogen receptor (ER) negative/ER weakly positive early breast cancer. The trial planned to recruit 1000 women aged 70 years and older, randomised to receive 4 cycles of anthracycline chemotherapy or observation. The primary endpoint was relapse-free interval. The trial included a pilot phase to assess the acceptability and feasibility of recruitment. RESULTS: The trial opened at 43 UK centres. Information on number of patients approached was available from 38 centres. Of the 43 eligible patients that were approached, 39 were not randomised due to patients declining entry. After 10 months only 4 patients had been randomised and after discussion with the research funder, the trial was closed and funding terminated. CONCLUSION: Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.

Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model.

BACKGROUND: The most common acute infections occur in the respiratory tract. Recent discoveries of several novel viruses have markedly increased the repertoire of agents understood to cause presentations of acute respiratory disease. OBJECTIVES: Further understanding is needed of the relative importance of newly discovered pathogens in the clinical setting to provide clinicians with an indication of appropriate diagnostic and therapeutic targets. To address this, quantification of the disease burden of respiratory viruses in hospitalized patients was undertaken. STUDY DESIGN: Disease burden caused by respiratory viruses in hospitalized patients was quantified using the World Health Organization endorsed DALY model. Diagnostic testing results from samples collected over three years for adenovirus (AdV), influenzas A and B, parainfluenza viruses 1, 2 and 3 (PIV-1, -2 and -3), respiratory syncytial virus (HRSV), and previously published retrospective screening for human metapneumovirus, rhinoviruses, and four respiratory coronaviruses were applied to the DALY model. Disability weights were calculated per 1000 hospitalized patients in age banded groups. RESULTS: Strikingly different disease burden profiles were observed in children and adults. Adenoviruses were among the leading cause of respiratory presentations in children but not adults. HRSV and influenza A were consistently one of the greatest causes of disease regardless of sampled population. Rhinoviruses and PIV-3 were significant pathogens in all groups except those aged 16-64 years. In immunocompromised patients rhinoviruses were the leading viral cause of disease. CONCLUSIONS: These analyses provide a framework which can be used to identify where finite resources should be directed in respiratory therapeutics and vaccine development.

Use of nucleotide composition analysis to infer hosts for three novel picorna-like viruses.

Nearly complete genome sequences of three novel RNA viruses were acquired from the stool of an Afghan child. Phylogenetic analysis indicated that these viruses belong to the picorna-like virus superfamily. Because of their unique genomic organization and deep phylogenetic roots, we propose these viruses, provisionally named calhevirus, tetnovirus-1, and tetnovirus-2, as prototypes of new viral families. A newly developed nucleotide composition analysis (NCA) method was used to compare mononucleotide and dinucleotide frequencies for RNA viruses infecting mammals, plants, or insects. Using a large training data set of 284 representative picornavirus-like genomic sequences with defined host origins, NCA correctly identified the kingdom or phylum of the viral host for >95% of picorna-like viruses. NCA predicted an insect host origin for the 3 novel picorna-like viruses. Their presence in human stool therefore likely reflects ingestion of insect-contaminated food. As metagenomic analyses of different environments and organisms continue to yield highly divergent viral genomes NCA provides a rapid and robust method to identify their likely cellular hosts.

Screening respiratory samples for detection of human rhinoviruses (HRVs) and enteroviruses: comprehensive VP4-VP2 typing reveals high incidence and genetic diversity of HRV species C.

Rhinovirus infections are the most common cause of viral illness in humans, and there is increasing evidence of their etiological role in severe acute respiratory tract infections (ARTIs). Human rhinoviruses (HRVs) are classified into two species, species A and B, which contain over 100 serotypes, and a recently discovered genetically heterogeneous third species (HRV species C). To investigate their diversity and population turnover, screening for the detection and the genetic characterization of HRV variants in diagnostic respiratory samples was performed by using nested primers for the efficient amplification of the VP4-VP2 region of HRV (and enterovirus) species and serotype identification. HRV species A, B, and C variants were detected in 14%, 1.8%, and 6.8%, respectively, of 456 diagnostic respiratory samples from 345 subjects (6 samples also contained enteroviruses), predominantly among children under age 10 years. HRV species A and B variants were remarkably heterogeneous, with 22 and 6 different serotypes, respectively, detected among 73 positive samples. Similarly, by using a pairwise distance threshold of 0.1, species C variants occurring worldwide were provisionally assigned to 47 different types, of which 15 were present among samples from Edinburgh, United Kingdom. There was a rapid turnover of variants, with only 5 of 43 serotypes detected during both sampling periods. By using divergence thresholds and phylogenetic analysis, several species A and C variants could provisionally be assigned to new types. An initial investigation of the clinical differences between rhinovirus species found HRV species C to be nearly twice as frequently associated with ARTIs than other rhinovirus species, which matches the frequencies of detection of respiratory syncytial virus. The study demonstrates the extraordinary genetic diversity of HRVs, their rapid population turnover, and their extensive involvement in childhood respiratory disease.

Sex cord stromal testicular tumors: a clinical series--uniformly stage I disease.

PURPOSE: Sex cord stromal testicular tumors are rare. Historically 10% of lesions are said to be malignant but to our knowledge there are no clinical or histological features that can accurately predict potential malignant behavior. Because of this, groups at some centers have advocated prophylactic retroperitoneal lymph node dissection in patients with clinical stage I disease. We reviewed our experience with these tumors to determine whether this policy is justified. MATERIALS AND METHODS: We retrospectively reviewed the records of all 38 men older than 18 years with sex cord stromal testicular tumors who were referred to the Wessex regional cancer center for treatment or pathological review during the 25-year period of 1982 to 2006. We then compared our series with a malignant sex cord stromal testicular tumor database generated from the world literature. RESULTS: All Wessex patients were treated with excision of the primary tumor alone and metastatic disease developed in none. All remained disease-free with an overall median survival of 6.8 years (range 1.4 to 25). Features in the literature favoring malignant behavior, ie metastatic disease, included larger tumors (mean 6.43 vs 1.71 cm), a high mitotic rate, tumor necrosis, angiolymphatic invasion, infiltrative margins and extratesticular extension (each p <0.0001). The malignant group had an overall median survival of 2.3 years (range 0.02 to 17.3). CONCLUSIONS: No patient had disease progression in our study, which is to our knowledge the largest reported United Kingdom series of sex cord stromal testicular tumors. Our data suggest that malignancy is uncommon and prophylactic retroperitoneal lymph node dissection is unjustified for clinical stage I disease.

Transmission networks and population turnover of echovirus 30.

Globally, echovirus 30 (E30) is one of the most frequently identified enteroviruses and a major cause of meningitis. Despite its wide distribution, little is known about its transmission networks or the dynamics of its recombination and geographical spread. To address this, we have conducted an extensive molecular epidemiology and evolutionary study of E30 isolates collected over 8 years from a geographically wide sample base (11 European countries, Asia, and Australia). 3Dpol sequences fell into several distinct phylogenetic groups, interspersed with other species B serotypes, enabling E30 isolates to be classified into 38 recombinant forms (RFs). Substitutions in VP1 and 3Dpol regions occurred predominantly at synonymous sites (ratio of nonsynonymous to synonymous substitutions, 0.05) with VP1 showing a rapid substitution rate of 8.3 x 10(-3) substitutions per site per year. Recombination frequency was tightly correlated with VP1 divergence; viruses differing by evolutionary distances of >0.1 (or 6 years divergent evolution) almost invariably (>97%) had different 3Dpol groups. Frequencies of shared 3Dpol groups additionally correlated with geographical distances, with Europe and South Asia showing turnover of entirely distinct virus populations. Population turnover of E30 was characterized by repeated cycles of emergence, dominance, and disappearance of individual RFs over periods of 3 to 5 years, although the existence and nature of evolutionary selection underlying these population replacements remain unclear. The occurrence of frequent "sporadic" recombinants embedded within VP1 groupings of other RFs and the much greater number of 3Dpol groups than separately identifiable VP1 lineages suggest frequent recombination with an external diverse reservoir of non-E30 viruses.

Epidemiology and clinical associations of human parechovirus respiratory infections.

Infections with human parechoviruses (HPeVs) are prevalent in young children and have been associated with mild gastroenteritis and, less frequently, with meningitis and neonatal sepsis. To investigate the involvement of these viruses in respiratory disease, a highly sensitive nested PCR was used to screen a large archive of respiratory specimens, collected between January and December 2007. Respiratory samples had previously been tested for eight respiratory viruses, including respiratory syncytial virus and adenovirus, by PCR. HPeV was detected in 34 of 3,844 specimens, representing 27 of 2,220 study subjects (1.2%). HPeV types were identified by sequencing the VP3/VP1 junction amplified by PCR directly from clinical specimens. The assay could amplify all HPeV types examined with high sensitivity (types 1 and 3 to 6) and also identified HPeV types in all but one of the screen-positive study specimens (25 HPeV1 and eight HPeV6 specimens). Infections with both HPeV1 and HPeV6 were seasonal, with highest frequencies in July and August, and restricted to children aged between 6 months and 5 years. Other respiratory viruses were frequently codetected in HPeV-positive specimens, with significant overrepresentation of adenovirus coinfections (37%). Most HPeV-positive specimens were referred from emergency departments, although no association with specific respiratory symptoms or disease was found. In summary, the low frequency of detection and lack of clear disease associations indicate that HPeV1 and -6 are not major pathogens in individuals presenting with respiratory disease. However, the screening and typing methods developed will be of value in further HPeV testing, including testing for meningitis cases and other suspected HPeV-associated disease presentations.

Widespread recombination within human parechoviruses: analysis of temporal dynamics and constraints.

Human parechoviruses (HPeVs), members of the family Picornaviridae, are classified into six types. To investigate the dynamics and likelihood of recombination among HPeVs, we compared phylogenies of two distant regions (VP1 and 3Dpol) of 37 HPeV isolates (types 1 and 3-5) and prototype sequences (types 1-6). Evidence for frequent recombination between HPeV1, 4, 5 and 6 was found. The likelihood of recombination was correlated with the degree of VP1 divergence and differences in isolation dates, both indicative of evolutionary times of divergence. These temporal dynamics were found to be most similar to those of human enterovirus species B variants. In contrast, HPeV3 remained phylogenetically distinct from other types throughout the genome. As HPeV3 is equally divergent in nucleotide sequence from the other HPeV types, its genetic isolation may reflect different biology and changed cellular tropisms, arising from the deletion of the RGD motif, and likely use of a non-integrin receptor.

A highly divergent picornavirus in a marine mammal.

Nucleic acids from an unidentified virus from ringed seals (Phoca hispida) were amplified using sequence-independent PCR, subcloned, and then sequenced. The full genome of a novel RNA virus was derived, identifying the first sequence-confirmed picornavirus in a marine mammal. The phylogenetic position of the tentatively named seal picornavirus 1 (SePV-1) as an outlier to the grouping of parechoviruses was found consistently in alignable regions of the genome. A mean protein sequence identity of only 19.3 to 30.0% was found between the 3D polymerase gene sequence of SePV-1 and those of other picornaviruses. The predicted secondary structure of the short 506-base 5'-untranslated region showed some attributes of a type IVB internal ribosome entry site, and the polyprotein lacked an apparent L peptide, both properties associated with the Parechovirus genus. The presence of two SePV-1 2A genes and of the canonical sequence required for cotranslational cleavage resembled the genetic organization of Ljungan virus. Minor genetic variants were detected in culture supernatants derived from 8 of 108 (7.4%) seals collected in 2000 to 2002, indicating a high prevalence of SePV-1 in this hunted seal population. The high level of genetic divergence of SePV-1 compared to other picornaviruses and its mix of characteristics relative to its closest relatives support the provisional classification of SePV-1 as the prototype for a new genus in the family Picornaviridae.

No evidence for an association between infections with WU and KI polyomaviruses and respiratory disease.

BACKGROUND: WU virus (WUV) and KI polyomavirus (KIPyV) are newly discovered related human polyomaviruses detected in respiratory samples. To investigate their potential role in respiratory disease, we determined their frequencies of detection, clinical presentations and epidemiological characteristics among samples referred for diagnostic respiratory virus testing. METHODS: Anonymised samples and accompanying study subject information were obtained from the Edinburgh respiratory specimen archive. Samples were screened by nested PCR using two sets of primers conserved between WUV and KIPyV, as well for other respiratory viruses (respiratory syncytial virus [RSV], adenoviruses [AdV], influenza A/B and parainfluenza viruses 1-3, human bocavirus, B19). RESULTS AND CONCLUSIONS: WUV and KIPyV were detected in 10 and 14 samples, respectively from 983 specimens (from 9 to 10 different individuals from 612 study subjects). Infections occurred in two types of study subject; those who were young (<2 years) with lower respiratory tract infections (n=8), and almost invariably co-infected with other respiratory viruses (RSV, AdV), and a second, generally older group either without respiratory disease (n=6) or with mild upper respiratory tract infections (n=5) but who were generally clinically severely immunosuppressed from leukaemia or transplant therapy. Findings from either group do not support an aetiological link between infection with WUV or KIPyV and respiratory disease.

RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells.

Numerous studies have demonstrated a central role of renal tubular epithelial cells in the etiology of kidney injury and disease through the elaboration of inflammatory mediators. However, little is known about the cellular signaling mechanisms involved in this process. In this study we employed normal rat kidney epithelial (NRK52E) cells to identify a novel LPS-induced signaling pathway in which RhoA-mediated AP-1 activity promotes expression of cyclooxygenase-2 (COX-2) with consequent feedback inhibition of NF-kappaB activation through IKKbeta. Inhibition of RhoA signaling using either the RhoA kinase inhibitor Y-27632 or a dominant negative mutant of RhoA (RhoA-DN) dramatically extended the duration of p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity following LPS treatment. Prolongation of events associated with NF-kappaB activation was also observed in cells pretreated and/or cotransfected with the JNK inhibitor SP600125 or deletion mutants of MEKK1 (MEKK1-KD) or Jun (Jun-DN). Conversely, constitutive expression of RhoA prevented NF-kappaB activation by LPS, and this effect was reversed by cotransfection with MEKK1-KD. In addition, we found that the RhoA/AP-1 signaling axis plays a necessary role in COX-2 expression by LPS and that this effect is independent of NF-kappaB activation. Moreover, inhibition of COX-2 activity results in persistent p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity, similar to that observed after prevention of RhoA/AP-1 axis signaling. These findings suggest that COX-2 links the RhoA/AP-1 signaling cascade to NF-kappaB activation, thereby defining a novel integrated model for regulation of the inflammatory response of kidney epithelial cells to LPS and potentially other external stimuli.

Epidemiological profile and clinical associations of human bocavirus and other human parvoviruses.

BACKGROUND: Human bocavirus (HBoV) and PARV4 are newly discovered human parvoviruses. HBoV, which was first detected in respiratory samples, has a potential role in the development of human respiratory disease. The present study compared the frequencies, epidemiological profiles, and clinical backgrounds of HBoV and PARV4 infections with those of other respiratory virus infections, by evaluating diagnostic samples referred to the Specialist Virology Laboratory (SVL) at the Royal Infirmary of Edinburgh (Edinburgh, United Kingdom). METHODS: Anonymized samples and study subject information were obtained from the respiratory sample archive of the SVL. Samples were screened for HBoV, PARV4, B19, respiratory syncytial virus (RSV), adenoviruses, influenza viruses, and parainfluenza viruses by use of nested polymerase chain reaction. RESULTS: HBoV infection was detected in 47 (8.2%) of 574 study subjects, ranking third in prevalence behind RSV infection (15.7%) and adenovirus infection (10.3%). Peak incidences of HBoV were noted among infants and young children (age, 6-24 months) during the midwinter months (December and January) and were specifically associated with lower respiratory tract infections. HBoV infections were frequently accompanied by other respiratory viruses (frequency, 43%), and they were more prevalent among individuals infected with other respiratory viruses (17%), frequently adenovirus or RSV. All respiratory samples were negative for PARV4. CONCLUSIONS: In the present study, HBoV was a frequently detected, potential respiratory pathogen, with a prevalence and an epidemiological profile comparable to those of RSV. Identification of HBoV infections may be clinically important in the future.

Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies.

No consensus on the indications for surgical resection of colorectal liver metastases exists. This systematic review has been undertaken to assess the published evidence for its efficacy and safety and to identify prognostic factors. Studies were identified by computerised and hand searches of the literature, scanning references and contacting investigators. The outcome measures were overall survival, disease-free survival, postoperative morbidity and mortality, quality of life and cost effectiveness, and a qualitative summary of the trends across all studies was produced. Only 30 of 529 independent studies met all the eligibility criteria for the review, and data on 30-day mortality and morbidity only were included from a further nine studies. The best available evidence came from prospective case series, but only two studies reported outcomes for all patients undergoing surgery. The remainder reported outcomes for selected groups of patients: those undergoing hepatic resection or those undergoing curative resection. Postoperative mortality rates were generally low (median 2.8%). The majority of studies described only serious postoperative morbidity, the most common being bile leak and associated perihepatic abscess. Approximately 30% of patients remained alive 5 years after resection and around two-thirds of these are disease free. The quality of the majority of published papers was poor and ascertaining the benefits of surgical resection of colorectal hepatic metastases is difficult in the absence of randomised trials. However, it is clear that there is group of patients with liver metastases who may become long-term disease-free survivors following hepatic resection. Such survival is rare in apparently comparable patients who do not have surgical treatment. Further work is needed to more accurately define this group of patients and to determine whether the addition of adjuvant treatments results in improved survival.