Quantification of tumour response to radiotherapy

In 1979, the World Health Organization (WHO) established criteria based on tumour volume change for classifying response to therapy as (i) progressive disease (PD), (ii) partial recovery (PR), and (iii) no change (NC). Typically, the tumour volume is reported from diameter measurements, using the calliper method. Alternatively, the Cavalieri method provides unbiased volume estimates of any structure without assumptions about its shape. In this study, we applied the Cavalieri method in combination with point counting to investigate the changes in tumour volume in four patients with high grade glioma, using 3D MRI. In particular, the volume of tumour within the enhancement boundary, the enhancing abnormality (EA), was estimated from T(1) weighted images, and the volume of the non-enhancing abnormality, (NEA) enhancing abnormality, was estimated from T(2) relaxation time and magnetic transfer ratio tissue characterization maps. We compared changes in tumour volume estimated by the Cavalieri method with those obtained using the calliper method. Absolute tumour volume differed significantly between the two methods. Analysis of relative change in tumour volume, based on the WHO criteria, provided a different classification using the calliper and Cavalieri methods. The benefit of the Cavalieri method over the calliper method in the estimation of tumour volume is justified by the following factors. First, Cavalieri volume estimates are mathematically unbiased. Second, the Cavalieri method is highly efficient under an appropriate sampling density (i.e. EA volume estimates can be obtained with a coefficient of error no higher than 5% in 2-3 min). Third, the source of variation of the volume estimates due to disagreements between observers, and within observer, is much greater in the positioning of the calliper diameters than in the identification of the tumour boundaries when applying the Cavalieri method. Additionally, the error prediction formula, available to estimate the coefficient of error of Cavalieri volume estimates from the data, allows us to establish more precise classification criteria against which to identify potentially clinical significant changes in tumour volume.     

Firing rates and dynamic correlated activities of ganglion cells both contribute to retinal information processing

In the present study, the electrical activities of paired retinal ganglion cells, under full field light stimuli with a variety of chromatic configurations, were recorded from a small functioning piece of retina using multi-electrode array (MEA). Neurons that had increased firings at light-ON and -OFF transients and did not show color-opponent properties were investigated. Single neuronal analysis showed that firing rate of each individual neuron was dependent on the intensity of illumination. Multi-unit analyses revealed that adjacent neurons often fired in synchrony in response to light stimulation. However, in some cases, the strength of correlation between the paired neurons was higher when the retina was exposed to red or green light, and the correlation was attenuated when yellow or white light was given. This seems to suggest that the ensemble activity of non-color-opponent ganglion cells might partly participate in color-information processing, with the red- and green-pathway inputs influencing each other. Such arrangement reflects principle of parsimony: the firing rates of single neuron represent the luminance intensity, and the correlated activities may tell the brain about the color information.     

Neuroprotective effect of inosine on axotomized retinal ganglion cells in adult rats

PURPOSE: To explore the potential survival-promoting effect of inosine on axotomized retinal ganglion cells (RGCs) of adult rats in vivo. METHODS: The left optic nerves (ON) in the subject rats were transected at 1.5 mm from the optic disc. Repeated intraperitoneal injections or single intraocular injection of inosine were administered. The RGCs were retrogradely labeled with a gold fluorescent dye and the density of surviving RGCs in number per square millimeter of retina was calculated in wholemounted retinas. The functional integrity of the blood-retinal barrier (BRB) after ON transection was evaluated with an intravenous injection of Evans blue. RESULTS: In control animals, the mean density of surviving RGCs (number per square millimeter) of the whole retina was 2007 +/- 68 at 2 days (taken as the normal value), 927 +/- 156 at 7 days, and 384 +/- 33 at 14 days after surgery. Repeated intraperitoneal injections (75 mg/kg for each injection) of inosine significantly enhanced RGC survival at 14 days after ON transection (500 +/- 38), whereas no significant difference in the densities was detected at 7 days (974 +/- 101), even when the dosage of inosine was doubled (1039 +/- 61). At this time point, however, a single intraocular injection of inosine significantly increased the density of surviving RGCs (1184 +/- 156). Moreover, more RGCs around the optic disc were rescued when inosine, administered either intraperitoneally or intraocularly, showed a beneficial effect on RGC survival. No breakdown of the BRB after ON transection was detected with the method used in the study. CONCLUSIONS: These findings demonstrate that inosine could protect axotomized RGCs in vivo after ON transection.     

Local hyperthermia combined with external irradiation for regional recurrent breast carcinoma

Backgrounds The purpose of this study was to evaluate the therapeutic effects of hyperthermia in combination with radiotherapy for locoregional recurrence of breast cancer, and to assess the factors related to subsequent local tumor control.Methods Between March 1981 and February 2001, 85 lesions in 73 patients were treated with local hyperthermia combined with external irradiation. Of 75 evaluable lesions, 41 were previously irradiated. Mean radiation dose to the previously unirradiated area was 59.5 ± 6.8Gy (range, 40–70Gy), while a total dose of 43.0 ± 12.4Gy (range, 12–74.4Gy) was administered to previously irradiated tumors. Hyperthermia was administered once or twice per week. The average number of hyperthermia sessions was 4.5 (2–9).Results Complete responses (CRs) were achieved in 56% (23/41) of previously irradiated and 47% (16/34) of unirradiated tumors. There was no significant difference in the CR rate between the two groups. Compared with the response of bulky/nodular tumors, diffuse/multiple small nodular tumors showed a higher CR rate at 4 weeks after treatment. However, at 6 months after treatment, they showed a significantly lower local control rate.Conclusions The present findings suggested a significant benefit of local hyperthermia combined with radiotherapy in the treatment of locally recurrent breast cancer, especially for previously irradiated recurrence, by reducing the total irradiation dose. Diffuse/multiple small nodular tumors respond earlier than bulky/large nodular tumors; however, they tend to recur within the treatment field.     

Renal cell carcinoma,chromophobe type,with collecting duct carcinoma and sarcomatoid components

We report a case of a 72-year-old man with a chromophobe renal cell carcinoma that had both sarcomatoid and collecting duct carcinoma components. The 7-cm tumor occupied the entire lower pole of the kidney and infiltrated the renal parenchyma and the pelvic-calyceal system. Histologically, it had an area of classic chromophobe renal cell carcinoma that merged into a sarcomatoid component. Closely intermixed with the sarcomatoid component was a collecting duct carcinoma component characterized by highly pleomorphic, epithelioid cells arranged in cords, nests, and tubulomicrocystic structures. The cords, nests, and tubules were associated with a florid desmoplastic stromal response and numerous inflammatory cells. In addition, dysplastic changes were noted in adjacent nonneoplastic collecting duct epithelium. Immunohistochemical studies confirmed the presence of 3 distinct components in this patient's tumor. To the best of our knowledge, this is the first reported case of a chromophobe renal cell carcinoma with sarcomatoid and collecting duct carcinoma components.     

Involvement of actin cytoskeleton in modulation of Ca(2+)-activated K(+) channels from rat hippocampal CA1 pyramidal neurons

Anterograde tracing techniques combined with postembedding immunocytochemical staining were used to determine the gamma amino butyric acid (GABA) content of pretectogeniculate (PT-LGN) terminals and their postsynaptic targets. The results provide evidence that PT-LGN terminals are GABAergic and that they contact GABAergic interneurons. These results corroborate previous anatomical studies and support the idea that the PT-LGN projection functions to disinhibit thalamocortical cells in the dorsal lateral geniculate nucleus.     

IPNV VP5, a novel anti-apoptosis gene of the Bcl-2 family,regulates Mcl-1 and viral protein expression

VP5, a 5'-terminal, small open reading frame in segment A of the aquatic birnavirus (infectious pancreatic necrosis virus, IPNV) genome, encodes a 17-kDa nonstructural protein. We previously reported apoptosis induced by IPNV in a fish cell line. In the present study, we cloned and identified VP5 and tested its function. Comparisons of the amino acid sequence of VP5 with well-known Bcl-2 family member proteins showed that the VP5 protein contains Bcl-2 homology (BH) domains BH1, BH2, BH3, and BH4 but without the transmembrane region. VP5-stable clones enhanced viability, prevented membrane blebbing, delayed DNA internucleosomal cleavage, and decreased virus titer during IPNV infection but, when deleted, BH domains 1 and 2 could lose the preventable ability. In addition, VP5 was demonstrated to be able to enhance or assist in maintaining the functional half-life of survival factor Mcl-1 and regulate specific viral protein expression during the early replication cycle. Finally, we found that VP5 was capable of enhancing cell viability when cells were exposed to UV irradiation. In summary, these results suggest that the aquatic birnavirus may utilize a notable strategy via VP5 to regulate the host apoptosis-off system for enhancing progeny production.