Ro 13-9904, a long-acting broad-spectrum cephalosporin: in vitro and in vivo studies.

Ro 13-9904, a new parenteral cephalosporin, was found to have high in vitro activity against Enterobacteriaceae and other gram-negative bacteria, including various isolates resistant to cefuroxime, cefamandole, cefoxitin, and cefazolin. It showed promising activity against Pseudomonas aeruginosa. Although inhibitory against Staphylococcus aureus at concentrations readily achievable in plasma, it was less potent against this pathogen than cefamandole, cefazolin, or cefuroxime. Isolates of Streptococcus faecalis were uniformly resistant to all the cephalosporins tested. Ro 13-9904 was more active than cefotaxime against Proteus mirabilis, Neisseria gonorrhoeae, Neisseria meningitidis, and Haemophilus influenzae, but less active against S. aureus. Ro 13-9904 was stable to various types of beta-lactamases. Its therapeutic efficacy against experimental septicemias in mice was equal to or slightly superior to that of cefotaxime and SCE-1365 when the antibiotics were administered in repeated subcutaneous doses after bacterial challenge. Cefoperazone, and particularly cefamandole nafate, cefazolin, and mezlocillin were less effective. Although structurally related to cefotaxime and SCE-1365, Ro 13-9904 was found to differ from them in one important respect, namely, in having a long duration of action; this was observed with single-dose treatment given before bacterial challenge. Its broad spectrum of activity coupled with favorable pharmacokinetic properties make Ro 13-9904 a promising compound for clinical studies.     

Tinnitus before and 6 months after cochlear implantation

In this prospective multicenter study, tinnitus loudness and tinnitus-related distress were investigated in 174 cochlear implant (CI) candidates who underwent CI surgery at a Swiss cochlear implant center. All subjects participated in two session, one preoperatively and one 6 months after device activation. In both sessions, tinnitus loudness was assessed using a visual analogue scale and tinnitus distress using a standardized tinnitus questionnaire. The data were compared with unaided pre- and postoperative pure tone thresholds, and postoperative speech reception scores. 71.8% of the subjects reported tinnitus preoperatively. Six months after CI surgery 20.0% of these reported abolition of their tinnitus, 51.2% a subjective improvement, 21.6% no change and 7.2% a deterioration. Of the 49 (28.2%) subjects with no tinnitus preoperatively, 5 developed tinnitus 6 months after CI. These 5 had poorer speech understanding after CI surgery with their device than the group who remained tinnitus free. We found no correlation between tinnitus improvement, age, duration of tinnitus, or change in unaided hearing thresholds between the two sessions.     

Codon optimization of the human papillomavirus 11 (HPV 11) L1 gene leads to increased gene expression and formation of virus-like particles in mammalian epithelial cells

The 505 amino acid L1 protein of the human papillomavirus type 11 (HPV 11) is the major capsid polypeptide that has been shown to self-assemble into virus-like particles (VLPs) in vivo and in vitro. While L1 is essential for viral infection, expression studies in mammalian cells have been hampered by different codon preference between the virus and its host. To optimize L1 gene expression in mammalian cells, we converted wild-type HPV 11 L1 (11 L1wt) codons to those more common in human genes. The modified HPV 11 L1 gene (11 L1h) generated protein levels that were at least 100-fold higher than those of wild-type HPV 11 L1, while no obvious differences were seen in the level of mRNA. HPV 11 L1 protein was detected in mammalian epithelial and fibroblast cells, by immunoblotting and indirect immunofluorescence (IIF) techniques. Unlike the situation in situ, IIF revealed the presence of L1 mainly at perinuclear sites. Virus-like particles assembled intranuclearly only to a low extent, as indicated by transmission electron microscopy. DNA vaccination using the HPV 11 L1h gene yielded a drastic increase in L1-specific antibody production in mice as compared to immunization with the wild-type gene.     

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

BackgroundHigh-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.MethodsAll children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m²) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).ResultsFifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.ConclusionsThis treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.     

Serotonin receptors in the human brain. II. Characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites

The presence, pharmacological properties and anatomical distribution of serotonin-1C and serotonin-2 receptor subtypes were studied in the human brain by both radioligand binding and autoradiographic procedures. Frontal cortex, hippocampus and choroid plexus from human brains obtained at autopsy without history of neurological diseases were used in this study. [3H]5-HT and [3H]mesulergine were used to label 5-HT1C recognition sites while [3H]ketanserin was used to label 5-HT2 receptors. The pharmacological profile of 5-HT1C sites which are very concentrated in the choroid plexus, was extremely similar to that of pig and rat 5-HT1C sites. These receptors were also detected in the hippocampus and the cortex from human brain. The general distribution of 5-HT1C sites in human and rat brain was similar although slight differences were observed. Human 5-HT2 receptors were concentrated in cortical areas but also found in the hippocampus. The pharmacological profile of these receptors was extremely similar in human and pig brain tissue, but differed in certain respects to that found in rat brain 5-HT2 receptors. The anatomical distribution of 5-HT2 receptors is similar in human and rat brain with some differences at the microscopic level. The importance of species differences in the development of 5-HT2 compounds is discussed.     

Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA,RTOG/EORTC,and NCI-CTC scoring systems

PURPOSE: To prospectively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales. METHODS AND MATERIALS: A total of 226 patients were entered in a Phase III multicenter, randomized trial comparing radiotherapy alone (70 Gy in 35 fractions: Arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil: Arm B). Five living patients, free of local or distant recurrences, could not be evaluated for late toxicity. Forty-four patients were eligible for late toxicity with a median follow-up of 5 years. Late toxicity was evaluated by the radiation oncologist using a large questionnaire containing 120 mixed items of three scales (NCI-CTC, LENT/SOMA, and RTOG). The data were then transposed on separate scales using corresponding grades. RESULTS: The 5-year overall survival rate was 22% in Arm B and 16% in Arm A (p = 0.05). The 5-year locoregional control rate was 48% in Arm B and 25% in Arm A (p = 0.002). The spinal cord was not affected by the concomitant adjunct of chemotherapy, and no deaths were caused by late toxicity. Using the three late toxicity scales, 100% of the patients treated with the combined modality (Arm B) developed one or more late complications vs. 94% in the radiotherapy-alone arm (Arm A). The difference was not statistically significant. The most commonly damaged organs (all Grade 1-4) were the salivary glands (100% in Arm B vs. 82% in Arm A, p <0.05), skin (78% vs. 47%, p <0.05), teeth (67% vs. 18%, p <0.05), mucosa (59% vs. 63% p = not significant), and mandible (44% vs. 12%, p <0.05). One or more Grade 3-4 complications occurred in 82% of the patients in Arm B vs. 47% in Arm A (p = 0.02) but concerned only the teeth. The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1-4 toxicity (near 30%). The transposability of a patient's symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system. CONCLUSION: Concomitant radiochemotherapy increased overall survival and locoregional control rates. The difference between the two treatment groups for Grade 3-4 complications was only significant for the teeth. The late toxicity assessment of a treatment may depend on the toxicity scale used. The LENT/SOMA scale seems to be the most accurate scale, but most of the score results were not concordant with those obtained with other scales. The results of this study confirm the necessity of using a common late toxicity scale in clinical trials.