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.     

All currently used measurements of recirculation in blood access by chemical methods are flawed due to intradialytic disequilibrium or recirculation at low flow

Blood flows and recirculations with standard and reversed direction of lines were measured by chemical (urea and creatinine) and ultrasound dilution (saline) methods in 47 chronic hemodialysis patients. Thirty-seven patients had 47 dual-lumen, central vein (CV) catheters: 32 were PermCath (Quinton Instruments Company, Seattle, WA), 6 were Access Cath (MEDCOMP, Harleysville, PA), 3 were Soft Cell PC (Vas Cath, Mississauga, Ontario, Canada) and 6 were SNIJ (experimental catheters). Three of these last catheters had the tip staggered 7 mm, and three had flush tips; PermCath, Access Cath, and Soft Cell PC catheters have the tips staggered 23 to 25 mm. Forty-six catheters were implanted into the superior vena cava/right atrium, and one catheter was implanted through the left saphenous vein into the left iliac vein. The catheters were studied 1 to 31 months after implantation (median, 3.0 months). Ten patients with arteriovenous (AV) graft access were also studied. The stop-flow method was used in catheter dialysis, and the slow-flow method was used to calculate recirculations in AV access dialysis with samples for systemic blood concentrations taken from arterial line both before and after samples from the arterial and venous lines. At 500 mL/min pump speed, actual blood flow was 436+/-18 mL/min (mean+/-SD; range, 407 to 464 mL/min) with standard direction of catheter lines. At 500 mL/min pump speed, the arterial chamber pressure was -330+/-48 mm Hg (mean+/-SD; range, -380 to -225 mm Hg, and the venous chamber pressure was 259+/-48 mm Hg (mean+/-SD; range, 140 to 310 mm Hg). Arterial chamber pressure was less negative, and venous chamber pressure was less positive with SNIJ catheters, which had larger internal diameter (2.1 mm) compared with the other catheters (2.0 mm). Recirculation varied with the catheter design and the location of the catheter tip. In the catheters with tip staggered more than 20 mm and with standard line connection at pump speeds of 50 mL/min and 500 mL/min, recirculations were approximately 1 % and 5%, respectively, when measured by the chemical method. In the same catheters with reversed lines, the recirculations were approximately 5% and 27%, respectively. Inflow failure catheters with reversed lines had similar recirculation values to those of well-functioning catheters with reversed lines. In catheters with tips staggered 7 mm, and with standard connection of lines, recirculations were approximately 3% and 8%, respectively, at pump speeds of 50 and 500 mL/min. With reversed lines, at the same pump speeds, the values were 7% and 12%, respectively. In flush-tip catheters, the recirculation was higher at a 50 mL/min pump speed (approximately 17%) than at a pump speed of 500 mL/min (approximately 13%). The ultrasound dilution method usually gave lower values than the chemical methods, most likely because of overestimation of recirculation by chemical methods. At least triplicate measurements are needed because single measurements by the ultrasound dilution method are associated with substantial variation. We conclude that both currently used methods (stop flow and slow flow) of taking systemic samples for measurements of recirculation by chemical methods are flawed because of disequilibrium and recirculation at low flow.     

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.     

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.