Hyperfractionated radiation therapy and concurrent 5-fluorouracil, cisplatin and mitomycin-C in head and neck carcinoma. A pilot study.

Seventeen patients were entered into a Phase I/II trial of concurrent hyperfractionated radiation therapy (7,440 cGy total dose; 120 cGy b.i.d.) combined with constant infusion of 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours for 72 hours) and cisplatin (DDP) (50 mg/m2) for a total of three cycles. Thirteen patients had Stage IV disease; three, Stage III disease; and one, Stage II hypopharyngeal disease. Thirteen of 17 patients had positive cervical lymph nodes, and the mean size of the largest lymph node was 5.5 x 5.1 cm. The patients were not treated with planned adjunctive surgery except for one patient who had a radical neck dissection for massive, rapidly growing cervical adenopathy, which recurred promptly within 1 month before the initiation of protocol therapy. After the initial six patients were entered, mitomycin-C (Mito 8 mg/m2) was added during the second cycle. All the patients completed the planned course of radiotherapy with a median dose of 7,440 cGy and a mean dose of 7,248 cGy except for two patients who died--one from toxicity and the other, suicide. The predominant toxicity was mucositis, which was grade 3/4 in 11 of 15 patients, resulting in an average interruption of radiation therapy of 12 days. Weight loss was significant and was on the average 12% of baseline weight. Hematological toxicity was mild in the 5-FU/DDP group (only one grade 3 toxicity of six) and severe in the 5-FU/DDP/Mito-treated patients (five of eight patients having grade 3/4 toxicity including one leukopenic pneumonitis death). Additional toxicity included one parapharyngeal cellulitis, which responded to antibiotics. Noncompliance with the complex regimen was only seen in three patients. One patient refused b.i.d. radiation therapy, and one patient refused further chemotherapy after the first cycle. Additionally, one patient who had a severe ethanol withdrawal reaction during the first cycle of 5-FU/DDP did not receive further chemotherapy. The complete response rate of both primary site and neck by the protocol regimen alone was 71%. However, two patients, one from each group, did undergo salvage neck dissection, and the locoregional control is currently 73%, with a mean follow-up time of 18.4 months. The feasibility of combining hyperfractionated radiation therapy with aggressive concurrent chemotherapy was demonstrated. The response and local control rate justifies the added toxicity of concurrent chemotherapy and radiation therapy.     

Stereotactic radiosurgery: dose-volume analysis of linear accelerator techniques.

Stereotactic radiosurgery of the brain may be accomplished with a linear accelerator by performing several noncoplanar arcs of a highly collimated beam focused at a point. The shape of the radiation distribution produced by this technique is affected by the beam energy, field size, and the number and size of the arcs. The influence of these parameters on the resulting radiation distributions was analyzed by computing dose volume histograms for a typical brain. Dose volume functions were computed for: (a) the energy range of 4-24 MV x rays; (b) target sizes of 1-4 cm; and (c) 1-11 arcs and dynamic rotation. The dose volume histograms were found to be dependent on the number of arcs for target sizes of 1-4 cm. However, these differences were minimal for techniques with 4 arcs or more. The influence of beam energy on the dose volume histogram was also found to be minimal.     

Can burst fractures be predicted from plain radiographs?

Plain radiographs of 67 acute spinal compression fractures in 49 patients were analysed by subjective and objective criteria, using CT scans as the diagnostic standard for the diagnosis of burst fracture. Discriminant analysis correctly predicted the type of fracture in 88% of cases. Burst fractures, however, were almost as frequently misdiagnosed as being wedge compression fractures using this technique, compared with the reading of 25 films from patients without previous information. A quarter of the injuries would have been misdiagnosed had reliance been placed solely on the plain radiographs. CT scans of all patients with acute spinal compression fractures should be considered to decrease this potentially serious diagnostic error.     

Development and results of the Spanish registry of patients with alpha-1-antitrypsin deficiency

The Spanish registry of alpha-1 antitrypsin deficiency was founded in 1993 and became a member of the International Registry (AIR) in 1999. We describe the updating process following its incorporation into AIR and compare the data collected in the first period (1993–1999) and the second period (1999–2005), during which time patients were included exclusively by internet.The registry included 301 patients during period 1, 69% males and 46% had a history of smoking. Their mean age was 46 years (SD = 13) and 284 (94%) had the ZZ phenotype, 49% received augmentation therapy. During period 2, 161 new cases were included, 63% of whom were males with a mean age of 44 years (SD = 16). A total of 126 (78%) had the ZZ phenotype. Only 12% received augmentation therapy. A total of 462 different patients were included in both periods. Significant differences were observed in the number of cases with the SZ phenotype and the severity of FEV₁ impairment between the two periods.Implementation of an internet-based collection of data did not result in a lower rate of reporting to the registry. However, data from a significant number of patient included in period 1 could not be actualized in the new data base.     

The usefulness of mouse breast tumor models for testing and optimization of breast cancer vaccines at old age

Cancer is an age-related disease and with the graying of the society, there is an increasing need to optimize cancer management and therapy for application in elderly patients. Cancer vaccines that can be applied in both prevention and therapy are potentially less toxic than chemotherapy or radiation and could, therefore, be especially suitable for older more frail cancer patients. In this study, we used syngeneic metastatic (4TO7) and non-metastatic (64pT) breast tumor models to obtain valuable information on the potential usefulness of MAGE-encoding cancer vaccines in metastatic and non-metastatic breast cancer at old age. First, we tested a mouse Mage-b DNA vaccine in young mice and found a significant preventive effect on the development of metastases. However, little effect was observed on primary breast tumors. Second, we studied tumor progression in relation to aging and found significant smaller tumors in old compared to young mice. This was associated with an increase in the percentage of CD8(+) T cells in the inguinal lymph nodes at the site of the tumor at old age. These findings suggest that breast cancer immunotherapeutic approaches could be a valid strategy even in elderly patients.     

Major role of BAX in apoptosis during retinal development and in establishment of a functional postnatal retina.

Apoptosis plays a major role in the development of the central nervous system. Previous studies of apoptosis induction during retinal development are difficult to interpret, however, because they explored different mouse strains, different developmental periods, and used different assays. Here, we first established a comprehensive sequential pattern of cell death during the whole development of the C57BL/6J mouse retina, from E10.5 to postnatal day (P) 21 by using the terminal deoxynucleotidyl transferase (TdT) -mediated deoxyuridine triphosphate (dUTP)-biotinylated nick end labeling (TUNEL) assay. We confirmed the existence of three previously described apoptotic peaks and identified another, later peak at P15, in both the outer nuclear layer, in which the photoreceptors differentiate, and the ganglion cell layer. Comparison of wild-type C57BL/6 mice, gld mice, defective in the death ligand fasL, and bax-/- mice, defective in the pro-apoptotic BAX protein, revealed a minor role for FAS ligand but a crucial role for BAX in both apoptosis and normal retinal development. The lack of BAX resulted in thicker than normal inner neuroblastic and ganglion cell layers in adults, with larger numbers of cells and an impaired electroretinogram response related to a decreased number of responsive cells. Our findings indicate that cell death during normal retinal development is important for the modeling of a functional vision organ and showed that the pro-apoptotic BAX protein plays a crucial role in this process.     

Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy

ABSTRACT We report five novel VMD2 mutations in Best's macular dystrophy patients (S16F, I73N, R92H, V235L, and N296S). An SSCP analysis of the VMD2 11 exons revealed electrophoretic mobility shifts exclusively in exons 2, 3, 4, 6 and 8. Direct sequencing indicated that these shifts are caused by mono-allelic transition in exons 2, 4, 6, 8 and transversion in exons 3 and 6. Five novel "silent" polymorphisms are also reported: 213T>C, 323C>A, 1514A>G, 1661C>T, and 1712T>C. Hum Mutat 17:235, 2001.