Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human-melanoma brain metastases

Neurotrophins (NT), such as nerve growth factor (NGF), stimulate the growth and differentiation of several neuronal subpopulations in a distinct yet overlapping manner. Brain-metastatic human melanoma cells overexpress p75(NTR), the low-affinity neurotrophin receptor, and treatment of brain-metastatic cells with NGF stimulates extracellular matrix invasion and production of degradative enzymes in relation to the cellular expression of p75(NTR) Although human melanoma cells express high affinity neurotrophin receptors, such as TrkC (the putative receptor for NT-3), they do not express TrkA, the high-affinity NGF receptor. Using digoxigenin-labeled sense/antisense riboprobes against human p75(NTR) and NGF for in situ hybridization, we determined whether the expression of p75(NTR) and NGF mRNAs are related to brain metastasis of human melanoma. We detected p75(NTR) mRNA at the invasion front of human melanoma brain metastases, whereas p75(NTR) expression was not found in adjacent tissues. In contrast, human NGF mRNA levels were increased in tissues surrounding the melanoma lesions, supporting the notion that NGF and NT are important in determining melanoma brain-metastatic microenvironment. Using antibodies specific to p75(NTR), TrkC, NGF and related NT we found high but heterogeneous levels of p75(NTR) and TrkC expression in malignant melanomas metastatic to the brain. Lower levels of expression were found in primary melanomas or in metastatic melanomas to sites other than brain. Additionally, we found elevated levels of synthesis of NGF and NT-3 but not brain-derived neurotrophic factor (BDNF) or NT-4/5 in the brain tissues surrounding melanoma lesions. These studies support a role for NT and their receptors in the progression of melanomas to the brain-metastatic phenotype.     

Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae type b-CRM197 conjugate vaccine

OBJECTIVE: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4). METHODS: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. RESULTS: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05). CONCLUSIONS: The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.     

Correlation between Extreme Drug Resistance Assay and Response to Primary Paclitaxel and Cisplatin in Patients with Epithelial Ovarian Cancer

Objective.The extreme drug resistance (EDR) assay has been correlated with failure of response to chemotherapy in greater than 99% of patients. The goal of this study is to correlate the results of the EDR assay to response to first-line paclitaxel/cisplatin among patients with epithelial ovarian cancer.Methods.Seventy-five of 100 patients with epithelial ovarian cancer for whom EDR assay was performed were treated with weekly induction cisplatin (1 mg/kg body wt) × 4, followed by monthly paclitaxel (135 mg/m²) and cisplatin (75 mg/m²) × 6 and were evaluable for correlation of response to chemotherapy and EDR assay. Specimens for EDR assay were obtained at primary surgery and the EDR assay was performed by Oncotech, Inc. Response to chemotherapy was correlated to EDR assay results regarding paclitaxel and cisplatin.Results.Among 75 evaluable patients, the prevalence of EDR to paclitaxel was 20.0% (n= 15) and to cisplatin it was 2.7% (n= 2). Only 1 patient (1.3%) exhibited EDR to both paclitaxel and cisplatin. Surgical assessment of response was performed in 42 patients; 33 patients were clinically evaluable. The overall response rate was 85.3%. The overall response rate for patients whose tumors demonstrated no EDR to either paclitaxel or cisplatin did not differ significantly from that for patients whose tumors demonstrated EDR to at least one of these two drugs (86.4% versus 81.3%, respectively,P= 0.692). Similarly, the complete surgical response rate for both groups did not differ significantly (25.4% versus 12.5%, respectively,P= 0.34). A single patient whose tumor exhibited EDR to both paclitaxel and cisplatin had tumor progression. The sensitivity, specificity, positive predictive value, and negative predictive value of the EDR assay were 79.6, 27.0, 86.0, and 19.0%, respectively.Conclusions.EDR to paclitaxel does not preclude response to the combination of paclitaxel and cisplatin as primary therapy for patients with epithelial ovarian cancer. The role of the EDR assay in the primary management of patients with epithelial ovarian cancer remains to be determined.     

Risk for obstetric complications and schizophrenia

The goal of this study was to determine whether cases with schizophrenia or related disorders show a history of obstetric complications significantly more often than control subjects and, if so, whether the enhanced risk of a negative pregnancy outcome also extends to the non-schizophrenic offspring of cases. Data based on the obstetric birth case-notes of patients with diagnosed schizophrenia or related disorders were compared to those of normal 'healthy' control subjects; each case/control pair was individually matched by gender, time and parity of birth, maternal age and marital status. Forty-four case/control pairs born in Padova (Italy) between 1964 and 1978 were assessed for prenatal and perinatal complications, including abnormal gestational age or birthweight. No significant differences were observed between cases and control subjects in the general characteristics of birth; gestational age and birthweight in particular were strictly comparable between cases and control subjects. The schizophrenia spectrum patients (75%) were more likely than control subjects (59%) to have experienced at least one definite obstetric complication: odds ratio=2.07 (95% CI: 0.83-5. 15). Cases also suffered more complications per birth than control subjects (average 2:1). In particular, obstetric complications involving a clear damaging potential were seen significantly more often among cases than control subjects: 34% vs. 9%, Fisher's exact test, P=0.008 (odds ratio=5.17, 95% CI: 1.55-17.21). Moreover, severe obstetric complications were noted more often among males (n=13, 41%) than females (n=2, 15%). When any previous pregnancies of the mothers of patients were compared with those of the mothers of control subjects, mothers of cases were seen to have suffered unfavorable pregnancy outcomes significantly more often. In particular mothers of cases were seen to have had more miscarriages (OR=4.66), and pre-term births (OR=2.58) than control subects' mothers. Severe, brain-damaging obstetric complications would seem to be a possible antecedent to a diagnosis of schizophrenia or a related disorder in adulthood. Indeed, some early onset cases may be accounted for by prenatal brain lesions. This enhanced risk of negative pregnancy outcome may be under genetic control, contributing to the persistence of schizophrenia in the general population. The 'healthy' status of control subjects was ascertained indirectly, not by individual assessment of the subjects. The sample size limits the statistical power of calculations.     

Are preoperative parameters of unilateral pyelo-ureteric junction obstruction in children predictive of postoperative function improvement?

OBJECTIVES: Surgery on the pyelo-ureteric junction obstruction (PUJO) has long been thought to affect postoperative renal function. However, preoperative assessment of which kidneys will benefit from such surgery remains unreliable. MATERIAL AND METHODS: Pre- and postoperative data relating to renal function were obtained by renal scan for 69 patients who were operated upon for PUJO. These patients were divided into two groups: group A (improved differential renal function) and group B (unimproved or decreased differential renal function). The two groups were then compared with regard to age at operation and presence or absence of clinical symptoms. Ultrasound (anteroposterior diameter of the pelvis, parenchymal thickness) and renal scan (glomerular filtration rate, differential renal function of the affected kidney, obstructive pattern) parameters were also taken into consideration. Some variables were also made dichotomous (pelvic diameter < or > 15 mm, parenchymal thickness < or > 5 mm, differential renal function < or > 40%). Statistical correlation was sought with parametric and non-parametric tests. RESULTS: No correlation whatsoever was found between the two groups for any of the parameters under consideration, so that any attempt at logistical regression analysis failed. CONCLUSIONS: None of the currently adopted diagnostic tests can be used to indicate which renal units will benefit from surgery through an improved renal function. The presence or absence of clinical symptoms does not appear to affect renal function either. There is evidence that parents should be provided with such information when giving their informed consent to pyeloplasty.