Relationship between tumour size and outcome in pancreatic ductal adenocarcinoma.

BACKGROUND: The size of pancreatic ductal adenocarcinoma (PDAC) at diagnosis is an indicator of outcome. Previous studies have focused mostly on patients with resectable disease. The aim of this study was to investigate the relationship between tumour size and risk of metastasis and death in a large PDAC cohort, including all stages. METHODS: Patients diagnosed with PDAC between 1988 and 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Tumour size was defined as the maximum dimension of the tumour as provided by the registry. Metastatic spread was assessed, and survival was calculated according to size of the primary tumour using the Kaplan-Meier method. Cox proportional regression modelling was used to adjust for known confounders. RESULTS: Some 58 728 patients were included. There were 187 patients (0·3 per cent) with a tumour size of 0·5 cm or less, in whom the rate of distant metastasis was 30·6 per cent. The probability of tumour dissemination was associated with tumour size at the time of diagnosis. The association between survival and tumour size was linear for patients with localized tumours, but stochastic in patients with regional and distant stages. In patients with resected tumours, increasing tumour size was associated with worse tumour-specific survival, whereas size was not associated with survival in patients with unresected tumours. In the adjusted Cox regression analysis, the death rate increased by 4·1 per cent for each additional 1-cm increase in tumour size. CONCLUSION: Pancreatic cancer has a high metastatic capacity even in small tumours. The prognostic impact of tumour size is restricted to patients with localized disease.

The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy.

Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting.

Testicular damage by microcirculatory disruption and colonization of an immune-privileged site during Borrelia crocidurae infection.

The agent of African relapsing fever, Borrelia crocidurae, causes reversible multiple organ damage. We hypothesize that this damage is caused when the spirochete forms aggregate with erythrocytes in vivo, creating rosettes that plug the microcirculatory system. To test this hypothesis, we compared testicular microcirculation over an extended time period in two groups of rats: one experimentally inoculated with B. crocidurae, the other with the nonerythrocyte rosette-forming Borrelia hermsii. In the B. crocidurae group, erythrocyte rosettes formed during spiro-chetemia blocked precapillary blood vessels and reduced the normal pattern of microcirculatory blood flow. After spirochetemia, erythrocyte rosettes disappeared and flow was normalized. Decreased blood flow and focal vascular damage with increased permeability and interstitial bleeding adjacent to the erythrocyte microemboli induced cell death in seminiferous tubules. Interestingly, we found that B. crocidurae could penetrate the tubules and remain in the testis long after the end of spirochetemia, suggesting that the testis can serve as a reservoir for this bacteria in subsequent relapses. The group infected with B. hermsii displayed normal testicular blood flow and vasomotion at all selected time points, and suffered no testicular damage. These results confirmed our hypothesis that the erythrocyte rosettes produce vascular obstruction and are the main cause of histopathology seen in model animal and human infections.

Pilus- gonococcal variants. Evidence for multiple forms of piliation control.

Pilus+ to pilus- transitions of gonococci (Gc) that involve rearrangement of pilin gene DNA yield the P-n phenotype, which is incapable of reversion (to pilus+). Reversion to pilus+ is found for nonpiliated Gc that have undergone no apparent pilin gene rearrangement. Among the reverting, nonpiliated Gc, two distinct phenotypes (P-rp- and P-rp+) occur and are differentiated according to their synthesis (or lack) of pilin subunits; both P-rp- and P-rp+ Gc contain pilin-specific mRNA. The occurrence of these different pilus- phenotypes strongly suggests that several mechanisms can account for changes in the piliation status of Gc; one of these involves pilin gene rearrangement but the others apparently operate at posttranscriptional levels. Reverting pilus- Gc may have a pathogenic advantage in being able to reversibly alter their host cell adherence-promoting surface properties through high frequency transitions in piliation status.

Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever.

Multilocus sequence analysis (MLSA) was used to clarify the taxonomic status of a virulent Borrelia organism previously isolated from patients with relapsing fever and from ticks in Spain that is designated the Spanish relapsing fever (SRF) Borrelia. This species has been used extensively in experimental infection models because of its continued virulence. Seven genes were amplified to analyze the phylogenetic relationships among several Spanish isolates of SRF Borrelia and other relapsing fever Borrelia species. The genes targeted in this study included rrs and flaB, which have commonly been used in phylogenetic studies; the rrf-rrl intergenic spacer (IGS), which is highly discriminatory; and four additional genes, p66, groEL, glpQ, and recC, which are located on the chromosome and which have therefore evolved in a clonal way. The species included in this study were Borrelia duttonii, B. recurrentis, B. crocidurae, and B. hispanica as Old World Borrelia species and B. turicatae and B. hermsii as New World Borrelia species. The results obtained by MLSA of the SRF Borrelia on the basis of 1% of the genomic sequence data analyzed confirmed that the SRF Borrelia isolates are B. hispanica. However, the prototype isolates of B. hispanica used in this study have an uncertain history and display unique phenotypic characteristics that are not shared with the SRF Borrelia. Therefore, we propose to use strain SP1, isolated from a relapsing fever patient in 1994 in southern Spain, as the type strain for B. hispanica.

Audit of cases with uterine rupture: a process indicator of quality of obstetric care in Angola.

Audit of uterine rupture (UR) used as a process indicator, can identify factors considered avoidable to improve future quality of obstetric care. Records of UR cases at a referral maternity in Luanda were studied retrospectively (n=43) and prospectively (n=67) including basic obstetric information, maternal and foetal outcome, duration of labour, time interval between diagnosis and intervention, drugs used, type of delivery and intervention, surgical procedures and complications. A clinical estimation of avoidability was based on this information. Prevalence of UR was 4.9%. Maternal case fatality rate was 14% and early perinatal mortality 71%. Women with previous Caesarean Section (CS) constituted 28%, grand multiparous women 44% and primiparous women 6%. Uterotonic treatment was given in 36%. Avoidability was estimated to 65%. Regular morbidity-oriented audits with analysis of clinical management reveal weaknesses in obstetric care and may serve as an instrument for future improvement.

Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin.

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for gamma-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growth factor-1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

T-cell epitope mapping of the Borrelia garinii outer surface protein A in lyme neuroborreliosis.

We studied the T-cell reactivity to overlapping peptides of B. garinii OspA, in order to locate possible immunodominant T-cell epitopes in neuroborreliosis. Cells from cerebrospinal fluid (CSF) and blood from 39 patients with neuroborreliosis and 31 controls were stimulated with 31 overlapping peptides, and interferon-gamma secreting cells were detected by ELISPOT. The peptides OspA(17-36), OspA(49-68), OspA(105-124), OspA(137-156), OspA(193-212) and OspA(233-252) showed the highest frequency of positive responses, being positive in CSF from 38% to 50% of patients with neuroborreliosis. These peptides also elicited higher responses in CSF compared with controls (P = 0.004). CSF cells more often showed positive responses to these peptides than blood cells (P = 0.001), in line with a compartmentalization to the central nervous system. Thus, a set of potential T-cell epitopes were identified in CSF cells from patients with neuroborreliosis. Further studies may reveal whether these epitopes can be used diagnostically and studies involving HLA interactions may show their possible pathogenetic importance.

Pathogen burden and cortisol profiles over the day.

Hypothalamic-pituitary-adrenocortical (HPA) regulation in adults is influenced by early psychosocial adversity, but the role of infectious disease history is poorly understood. We studied the association between cumulative pathogen burden and cortisol profile over the day in a sample of 317 healthy men and women aged 51-72 years. Cumulative pathogen burden was defined as positive serostatus for Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1). Salivary cortisol was sampled repeatedly over the day. The cortisol slope was defined as the decrease across the day and evening. Age, gender, grade of employment, body mass index, smoking status, self-rated health, cardiovascular medication, depressed mood and time of waking were included as covariates. The pathogen burden averaged 1.76 (s.d.=0.92). The cortisol slope was inversely associated with pathogen burden after controlling for covariates. When individual pathogens were studied, only CMV was associated with flatter cortisol rhythms in isolation. We conclude that pathogen burden is independently associated with flatter cortisol slopes over the day, and may contribute to disturbed neuroendocrine regulation.

Risk indicators for the tick Ixodes ricinus and Borrelia burgdorferi sensu lato in Sweden.

The distributional area of the tick Ixodes ricinus (L.), the primary European vector to humans of Lyme borreliosis spirochaetes (Borrelia burgdorferi sensu lato) and tick-borne encephalitis virus, appears to be increasing in Sweden. It is therefore important to determine which environmental factors are most useful to assess risk of human exposure to this tick and its associated pathogens. The geographical distribution of I. ricinus in Sweden was analysed with respect to vegetation zones and climate. The northern limit of I. ricinus and B. burgdorferi s.l. in Sweden corresponds roughly to the northern limit of the southern boreal vegetation zone, and is characterized climatically by snow cover for a mean duration of 150 days and a vegetation period averaging 170 days. The zoogeographical distribution of I. ricinus in Sweden can be classified as southerly-central, with the centre of the distribution south of the Limes Norrlandicus. Ixodes ricinus nymphs from 13 localities in different parts of Sweden were examined for the presence of B. burgdorferi s.l. and found to be infected with Borrelia afzelii and Borrelia garinii. Tick sampling localities were characterized on the basis of the density of Borrelia-infected I. ricinus nymphs, presence of specific mammals, dominant vegetation and climate. Densities of I. ricinus nymphs and Borrelia-infected nymphs were significantly correlated, and nymphal density can thus serve as a general indicator of risk for exposure to Lyme borreliosis spirochaetes. Analysis of data from this and other studies suggests that high densities of Borrelia-infected nymphs typically occur in coastal, broadleaf vegetation and in mixed deciduous/spruce vegetation in southern Sweden. Ixodes ricinus populations consistently infected with B. burgdorferi s.l. can occur in: (a) biotopes with shrews, rodents, hares and birds; (b) biotopes with shrews, rodents, hares, deer and birds, and (c) island locations where the varying hare (Lepus timidus) is the only mammalian tick host.

Audit of referral of obstetric emergencies in Angola: a tool for assessing quality of care.

By auditing various aspects of referrals of obstetric emergencies, we wanted to study the effectiveness over time of a recently established network of peripheral birth units and two central hospitals in Luanda. 157 women referred for obstetric emergencies were studied regarding clinical outcome and process indicators like waiting time, partogramme quality and Caesarean section rate (CSR). After a change in routines at hospital admission and further partogramme education 92 referred women were compared with the former. Maternal mortality decreased from 17.8% to nil in the second. Total mean waiting time was reduced from 13.7 hours to 1.2 hours. Partogramme quality was significantly improved. CSR increased from 13 to 30%. Prolonged labour was the most common diagnosis.This study demonstrates the importance of clinic-based audit to enhance quality of care regarding referrals of patients with obstetric emergencies.

Economic evaluation of surgically trained assistant medical officers in performing major obstetric surgery in Mozambique.

OBJECTIVE: To compare the training and deployment costs and surgical productivity of surgically trained assistant medical officers (técnicos de cirurgia) and specialist physicians (surgeons and obstetrician/gynaecologists) in Mozambique in order to inform health human resource planning in a developing country with low availability of obstetric care and severe physician shortages. Técnicos de cirurgia have been previously shown to have quality of care outcomes comparable to physicians. DESIGN: Economic evaluation of costs and productivity of surgically trained assistant medical officers and specialist physicians. SETTING: Hospitals and health science training institutions in Mozambique. POPULATION: Surgically trained assistants, medical officers, surgeons and obstetrician/gynaecologists in Mozambique. METHODS: The costs of training and deploying the two cadres of health workers were derived from a review of budgets, annual expenditure reports, enrolment registers, and accounting statements from training institutions and interviews with directors and administrators. Productivity estimates were based on a hospital survey of physicians and técnicos de cirurgia. MAIN OUTCOME MEASURES: Cost per major obstetric surgical procedure over 30 years in 2006 US dollars. RESULTS: The 30-year cost per major obstetric surgery was $38.9 for técnicos de cirurgia and $144.1 for surgeons and obstetrician/gynaecologists. Doubling the salaries of técnicos de cirurgia resulted in a smaller but still substantial difference in cost per surgery between the groups ($60.3 versus $144.1 per procedure). One-way sensitivity analysis to test the impact of varying other inputs did not substantially change the magnitude of the cost advantage of técnicos de cirurgia. CONCLUSION: Training more mid-level health workers in surgery can be part of the response to the health worker shortage, which today threatens the achievement of the health Millennium Development Goals in developing countries.

Meeting the need for emergency obstetric care in Mozambique: work performance and histories of medical doctors and assistant medical officers trained for surgery.

OBJECTIVE: Nonphysicians in Mozambique have been performing major surgery for more than 20 years, with documented outcomes equivalent to those of specialists. The purpose of this study was to make an inventory of all government hospitals so as to document obstetric surgery performed by 'técnicos de cirurgia' (TCs) and to elucidate their retention at district level. DESIGN: Cross-sectional study of surgical procedures during 2002; longitudinal study of TCs and doctors graduating in 1987, 1988 and 1996. SETTING: All 34 hospitals with an operating theatre in Mozambique. POPULATION: Records of 12,178 major surgical obstetric operations were examined, and 59 medical officers and 34 TCs were interviewed. METHODS: Analysis of all surgical registers during 2002 in all government rural, provincial, general and central hospitals in Mozambique. TCs and doctors who had graduated in the specified years were traced and interviewed; health ministry records were reviewed to confirm assignments. MAIN OUTCOME MEASURES: Proportion of major obstetric surgeries performed by TCs. Proportion of TCs and medical doctors still at rural/district level at 7 years after graduation. RESULTS: Major obstetric surgery is conducted by nonphysicians in 57% of the 12,178 operations scrutinised. In district hospitals, they conducted 92% of 3246 operations. Retention of TCs and medical doctors at district hospital level differed markedly: after 7 years, 88% of the TCs remained in post compared with none of the medical doctors. CONCLUSION: Nonphysicians, trained in surgery, do most of the emergency obstetric surgery in Mozambique, and almost all of that performed in district hospitals. Nonphysicians, compared with physicians, stay longer in rural areas. After 7 years, around 90% of nonphysicians are still working in district hospitals, while almost no physicians remain there.

Unexpected low prevalence of HIV among fertile women in Luanda, Angola. Does war prevent the spread of HIV?

We studied HIV prevalence and risk factors for HIV infection among fertile women in Luanda for the purposes of obtaining background data for planning of interventions as well as to look into the association of armed conflicts and HIV prevalence in sub-Saharan Africa. The HIV-1 prevalence was 1.7% in an antenatal care group (n = 517) and 1.9% in a family planning group (n = 518). Socioeconomic and sexual background factors did not significantly differ HIV-positive from HIV-negative women. Data on armed conflict factors were matched with HIV prevalence figures among pregnant women in sub-Saharan Africa. The level of armed conflicts was found to be inversely related to HIV prevalence. The low HIV seroprevalence in Luanda is in sharp contrast to the capitals of neighbouring countries. While the spread of HIV may have been hampered by the long armed conflict in the country, it is feared to increase rapidly with the return of soldiers and refugees in a post-war situation. The challenge for preventive actions is urgent. This example may be relevant to other areas with a recent end-of-war situation.

Increased postpartum blood loss in pregnancies associated with placental malaria.

OBJECTIVE: To determine the relationship of placental malaria and parity with postpartum blood loss in a malarious area of Tanzania. METHODS: A total of 706 uncomplicated vaginal deliveries were studied at Muhimbili University Hospital, Dar es Salaam, Tanzania. Maternal age, parity, date of delivery, birth weight, presence of placental malaria, stillbirths, and delivery complications were noted. Collection and measurement of vaginal blood loss commenced immediately following birth using a plastic vinyl sheet placed underneath the mother. The bed was divided in the middle to allow the blood to drain into a bucket. Blood loss was measured for a period of 2 h following delivery. RESULTS: In singleton births the mean postpartum blood loss was 170 mL in nulliparas and 187 mL in multiparas (p=0.017). Blood loss was 400 mL or greater in 23 women (3.4%) and 500 mL or greater in 10 women (1.5%). Mean postpartum bleeding tended to increase with maternal age, parity, and birth weight. In logistic regression the odds ratio for a blood loss of 400 mL or greater was significantly increased for women with placental malaria (3.2; 95% confidence interval, 1.1-9.0; p=0.028), after adjusting for a birth weight greater than 4000 g. Placental malaria showed a marked seasonal pattern, which corresponded to the months of peak prevalence for a postpartum blood loss of 400 mL or greater (p=0.007). CONCLUSION: A postpartum blood loss of 400 mL or greater should be considered a possible complication of placental malaria.

Role of circulating cytokeratin fragments and angiogenic factors in NSCLC patients stage IIIa-IIIb receiving curatively intended treatment.

Non-small cell lung cancer (NSCLC) is derived from epithelial cells and accounts for approximately 80% of all lung cancers. Cytokeratins are specific for epithelial cells and during malignant transformation the cytokeratin profile usually remains constant. Angiogenesis is the formation of new blood vessels out of the existing vascular bed. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent circulating angiogenic factors. The aim of the present study was to determine if increased levels of a new cytokeratin assay (MonoTotal, which in comparison with TPAcyk detects not only fragments of cytokeratins 8 and 18 but also of cytokeratin 19) is correlated with circulating angiogenic factors (VEGF and bFGF) and the secondary aim was to investigate if increased levels of these circulating markers are associated with survival. In the present study, a total of 45 NSCLC patients (26 patients stage IIIa and 19 patients stage IIIb) receiving only curatively intended treatment for advanced NSCLC were included. These patients donated a total of 291 serum samples during follow-up which was investigated for the presence of MonoTotal, VEGF and bFGF. MonoTotal was statistically significantly correlated with bFGF (R=0.26, p=0.00049) and VEGF (R=0.26, p=0.00007). From the time of histological diagnosis until time of death, MonoTotal increased by 603 U/l (p<0.0001). VEGF increased by 430 pg/ml (p=0.0004) whereas the corresponding value for bFGF was 5.93 pg/ml (p=0.018). MonoTotal, a newly developed commercial cytokeratin assay, seems to be a potentially very interesting serum marker that, in conjunction with other clinical data, might be used for monitoring of patients with NSCLC.

Borrelia pathogenesis research in the post-genomic and post-vaccine era.

In the two years after publication of the genome sequence of Borrelia burgdorferi and reports on human field trials of a vaccine against Lyme borreliosis, there has been further progress in understanding of host-parasite interactions during Lyme borreliosis and relapsing fever. Some mechanisms that Borrelia spirochetes use to avoid elimination and to persist in the host are novel. In addition, the recent discovery of antigenic variation in the Lyme disease agent B. burgdorferi adds to the complexity of the possible virulence properties of this human pathogen.

Maternal mortality among Palestinian women in the West Bank.

OBJECTIVE: To assess maternal mortality and determine the most common causes of maternal death among Palestinian women. METHODS: Available data on the 431 women who died between the ages of 15 and 49 years in the West Bank in 2000 and 2001 were reviewed. The data were collected from official agencies and, using the verbal autopsy approach, interviews of the deceased women's relatives. The interviews were conducted in all 10 districts of the West Bank over 30 months. RESULTS: Maternal mortality ratios for 2000 and 2001 were 29.2 and 36.5 per 100,000 live births, respectively. Cardiovascular diseases and hemorrhage were the most common causes of death. Misclassification was found in 38% of the deaths. A tentative analysis of avoidability indicated that 69% of maternal deaths could be classified as avoidable. CONCLUSION: A majority of the maternal deaths identified were avoidable. Substandard classification of maternal deaths is hampering efforts to reduce maternal mortality.

Effects of recA mutations on pilus antigenic variation and phase transitions in Neisseria gonorrhoeae.

Intragenic recombination between the single complete pilin gene (expression locus) and multiple, distinct, partial pilin gene copies (silent, storage loci) is thought to account for the generation of pilus antigenic diversity and piliation phase (on-off) changes exhibited by Neisseria gonorrhoeae. The mechanisms operating in the genomic rearrangements associated with these forms of pilus variation were investigated through the study of isogenic strains of gonococci bearing either wild-type or altered recA alleles. Examination of the rates of pilus phase variation and the genetic basis for changes in piliation status displayed by these strains show that recA mediated homologous recombination is required for these high frequency events and confirm that the nonpiliated state results from mutations in the expressed pilin gene. In a strain that is deficient in recA mediated homologous recombination, pilus phase variation occurs at a 100-1000-fold reduced rate and results predominantly from one class of spontaneous frameshift mutations within the pilin structural gene.