Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys.

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg-1) or as single oral doses (0, 10, 50, and 100 mg kg-1). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was < 2%; steady-state volume of distribution was 0.67 L kg-1; clearance was 10.4 mL min-1 kg-1. Following oral administration, tmax generally occurred 6-9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg-1, but did not change appreciably from 50 to 100 mg kg-1. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL-1. Following the 10 mg kg-1 oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration.

Brucellosis in childhood in the Western Cape.

Human brucellosis, a multisystem disease which may mimic other conditions, has a low incidence in childhood and the diagnosis may easily be missed. Over a 7-month period 9 children with brucellosis presented to the Department of Paediatrics and Child Health, Tygerberg Hospital. Six of the children had consumed unpasteurized milk. The main presenting symptoms were fever, fatigue, headache, myalgia and haematuria. Clinical signs included lymphadenopathy (3), nasopharyngitis (2), features of lower respiratory tract infection (2), splenomegaly (2) and pyrexia (1). The diagnosis was made on the basis of a positive serological titre (> 1:160) for Brucella abortus. The prozone phenomenon was encountered in 6 cases; however, the Coombs test confirmed the diagnosis in these cases. Children under 7 years were treated with co-trimoxazole and rifampicin and those over 7 years with tetracycline and rifampicin, for at least 6 weeks. No relapses were detected on follow-up.

Bacteraemia in children in the south-western Cape. A hospital-based survey.

During 1989, of the 8,524 children admitted to the paediatric wards of Tygerberg Hospital, 165 (1.96%) had bacteraemia. The incidence of community-acquired bacteraemias was 1.6% and that of nosocomial bacteraemias 0.5%. The most important community-acquired isolates were Streptococcus pneumoniae, Staphylococcus aureus and Neisseria meningitidis. The most important nosocomial isolates were Klebsiella and Salmonella spp. Both bacteraemia (relative risk (RR) = 2.08) and severe malnutrition (RR = 3.01) were more common in black patients. Overall, severe malnutrition was more common than mild malnutrition or a normal nutritional status in bacteraemic patients (odds radio (OR) = 3.17). Nineteen patients with bacteraemia died, there was a significantly higher case-fatality rate in patients with extreme malnutrition (P = 0.03; OR = 3.7). Gram-negative bacilli were found more commonly in patients with extreme malnutrition (OR = 5.4) and patients with nosocomial bacteraemia (OR = 4.6). Three of 39 patients (7.6%) with nosocomial bacteraemia had suppurative thrombophlebitis.

Ventriculoperitoneal shunt infections in children. A 6-year study.

In a study of ventriculoperitoneal shunt infections conducted retrospectively between 1983 and 1987 and prospectively in 1988 39 infections from 372 shunt procedures (incidence 10.5%) were identified. The most common organism isolated was Staphylococcus aureus (18; 47%) followed by S. epidermidis (10; 26%). Forty-two per cent of staphylococci were methicillin-resistant. Gram-negative infections were associated with myelomeningoceles and Gram-positive infections with other forms of hydrocephalus (P = 0.048). Lymphocyte predominance was found more frequently than polymorphonuclear predominance in cerebrospinal fluid.

Detection of bacterial antigens in cerebrospinal fluid by a latex agglutination test in 'septic unknown' meningitis and serogroup B meningococcal meningitis.

The latex agglutination test (Wellcogen) was evaluated specifically in cases of 'septic unknown' meningitis, with CSF findings characteristic of bacterial meningitis but with no bacterial organisms grown on CSF culture or seen on microscopy after Gram staining. In only 4 (12%) of 33 cases of 'septic unknown' meningitis were antigens identified in the CSF. This kit contains for the first time reagents for the detection of serogroup B Neisseria meningitidis antigens and was also evaluated for this bacteria. Only 6 (27%) of 22 serogroup B N. meningitidis cases were identified.

Methicillin-resistant Staphylococcus aureus at Tygerberg Hospital.

During 1985 Staphylococcus aureus was isolated from blood cultures of 74 patients at Tygerberg Hospital who were suffering from serious illness compatible with systemic spread of the organism. Twenty-six isolates (35%) were community-acquired and none were methicillin-resistant, while 48 were hospital-acquired of which 23 (48%) were methicillin-resistant. Methicillin resistance appears to be a problem confined to hospital isolates of S. aureus.

Shigellosis in the south-western Cape of Good Hope 1968-85.

During the period 1968-85 shigella organisms were isolated from stool specimens of 1562 patients attending Tygerberg Hospital, situated in the south-western province of the Cape of Good Hope of the Republic of South Africa. Shigella flexneri (72% of patients) was the commonest subgroup identified. Sh. sonnei was the second-commonest isolate (20%), with smaller numbers of Sh. boydii (5%) and Sh. dysenteriae (3%). Sh. dysenteriae has not been isolated since 1979. In 1985 30% of isolates were resistant to ampicillin and 52% to trimethoprim-sulphamethoxazole. During this period 12 cases of shigellaemia were seen, 11 in young infants less than 13 months of age who were malnourished in 6 cases. The single adult had had a previous gastrectomy and splenectomy.

Mumps meningo-encephalitis.

Between July 1981 and June 1985, 49 cases (36 boys (73%) and 13 girls (27%] of mumps meningo-encephalitis confirmed by culture of the virus from the cerebrospinal fluid (CSF) were seen. Patients presented particularly in the late spring and early summer. A CSF cell count greater than 500 X 10(6)/l was obtained in 14 cases (28%), a total CSF protein greater than 0.8 g/l in 6 cases (12%) and a CSF glucose of less than 2.2 mmol/l in 2 cases (4%). Two cases are reported to illustrate the diagnostic problems which the infection may cause, particularly when the CSF changes resemble those of tuberculous meningitis. In 1 case neurogenic pulmonary oedema developed after a convulsion; this caused further diagnostic uncertainty.

Paediatric meningitis in the western Cape. A 3-year hospital-based prospective survey.

Between July 1981 and June 1984 1223 cases of meningitis were seen in the Department of Paediatrics, Tygerberg Hospital. The commonest form in each population group was aseptic meningitis. Positive viral cultures were obtained from the CSF in 108 cases. The median age of white children with aseptic meningitis, 64 months, was significantly greater than that of coloured children, 45 months (P greater than 0.0001), and black children, 26 months (P greater than 0.014). The commonest cause of confirmed bacterial meningitis was Neisseria meningitidis (140 cases; 11.5%), which continues to affect mainly young coloured children (median age 16.9 months). Resistance to sulphonamides was found among 21% of 114 N. meningitidis isolates. Among white children Haemophilus influenzae was responsible for 9 of the 18 cases of confirmed bacterial meningitis. Tuberculosis was responsible for 62 cases of meningitis (5%) and was a commoner cause of meningitis than either H. influenzae (47 cases) or Streptococcus pneumoniae (34 cases). Thirty-four confirmed cases of bacterial meningitis were seen in children less than 1 month old. Klebsiella species were responsible for 8 cases (24%), Escherichia coli for 6 cases (12%), group B beta-haemolytic Streptococcus for 5 cases (15%) while 4 cases each were due to N. meningitidis and Strept. pneumoniae.

Bacteriologically confirmed pulmonary tuberculosis in childhood. Clinical and radiological features.

Over a 4-year period 185 cases of pulmonary tuberculosis in children were confirmed by culture of Mycobacterium tuberculosis, usually from gastric aspirate. The majority of cases occurred in boys (62%) and the younger age groups were more commonly affected--26% of patients were less than 1 year old and 65% less than 3 years of age. At the time of presentation 40% of the 151 children tested had a negative tuberculin test. A chest radiograph was available in 136 cases. The commonest changes seen were lymphadenopathy (63%) and segmental lesions (56%). The latter affected mainly the right lung and in particular the right middle lobe. Cavitating tuberculous disease was present in 19 children, including 5 aged less than 1 year.

Meningococcal disease at Tygerberg Hospital.

From June 1978 to November 1979, 298 patients with meningococcal disease were seen at Tygerberg Hospital, Parowvallei, CP. The manner of presentation, the diagnosis and some of the clinical features of these patients are reviewed and certain aspects discussed.