High dose rate brachytherapy for early stage oral tongue cancer

BACKGROUND: High dose rate (HDR) interstitial brachytherapy of the oral tongue is a new treatment modality. Our study evaluates the outcomes of patients with early stage oral tongue cancer as treated by HDR interstitial implant. METHODS: We reviewed the records of 19 patients who were seen between 1994 and 2000 with carcinoma of the oral tongue and whose primary tumors were treated solely with interstitial implant using HDR remote afterloading technique. Ten patients had T1 N0 disease, and the remaining 9 had T2 N0 disease. Elective neck treatment was withheld for 12 patients. The remaining seven patients had ipsilateral elective neck dissection. The male-female ratio was 1:0.9, and the median age was 60 years (range, 32-81 years). The median follow-up time was 43 months (range, 6-78 months). The afterloading catheters were positioned by the submandibular approach with the assistance of a template set. Fifteen patients had single planar implants, and the remaining four had double planar implants. The median number of catheters inserted was 5 (range, 4-9). The median dose given was 55 Gy in 10 fractions over 6 days. The minimal interfraction interval was 7 hours for the first 7 patients and was extended to 8 hours for the other 12. Mandibular shields were inserted before treatment. RESULTS: The mucositis lasted for 6 to 20 weeks (median, 9 weeks). One patient had local failure, and the 4-year local failure-free survival rate was 94.7%. Three of the 12 patients without elective neck treatment had ipsilateral regional failure develop. They were salvaged by neck node dissection and regionally remained in control. One patient with multiple nodal metastases and extracapsular spread had biopsy-proven liver metastases and died 6 months after implant. One of the seven patients who were treated with elective neck dissection had multiple nodal metastases and extracapsular spread. She was treated with postoperative radiotherapy to the neck. She died 30 months after implant with evidence of regional and distant failure. One patient treated with double planar implant had grade II necrosis of the soft tissue and bone develop. The necrosis resolved with conservative treatment. Another four patients had small area of soft tissue deficit of the tongue attributed to aggressive debulking or biopsy before brachytherapy. CONCLUSIONS: Our experience in treating early stage tongue cancer with HDR remote afterloading technique is encouraging, because it gives a local control rate of 94.7% at 4 years with acceptable morbidity. Further studies are eagerly awaited to delineate the optimum schedule for this new treatment modality.     

Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy

OBJECT: To determine the acute and long-term effects of a therapeutic dose of brain radiation in a primate model, the authors studied the clinical, laboratory, neuroimaging, molecular, and histological outcomes in rhesus monkeys that had received fractionated whole-brain radiation therapy (WBRT). METHODS: Twelve 3-year-old male primates (Macaca mulatta) underwent fractionated WBRT (350 cGy for 5 days/week for 2 weeks, total dose 3500 cGy). Animals were followed clinically and with laboratory studies and serial magnetic resonance (MR) imaging. They were killed when they developed medical problems or neurological symptoms, lesions appeared on MR imaging, or at study completion. Gross, histological, and molecular analyses were then performed. Nine (82%) of 11 animals that underwent long-term follow up (> 2.5 years) developed neurological symptoms and/or enhancing lesions on MR imaging, which were defined as glioblastoma multiforme (GBM), 2.9 to 8.3 years after radiation therapy. The GBMs were categorized as either unifocal (three) or multifocal (six), and were located in the supratentorial (six), infratentorial (two), or both (one) cranial regions. Histological examination revealed distant, noncontiguous tumor invasion within the white matter of all nine animals harboring GBMs. Novel interspecies comparative genomic hybridization (three animals) uniformly showed deletions in the GBMs that corresponded to chromosome 9 in humans. CONCLUSIONS: The high rate of GBM formation (82%) following a therapeutic dose of WBRT in nonhuman primates indicates that radioinduction of these neoplasms as a late complication of this therapy may occur more frequently than is currently recognized in human patients. The development of these tumors while monitoring the monkeys' conditions with clinical and serial MR imaging studies, and access to the tumor and the entire brain for histological and molecular analyses offers an opportunity to gather unique insights into the nature and development of GBMs.     

Feasibility of in vivo multichannel optical imaging of gene expression: experimental study in mice

PURPOSE: To use semiquantitative autoradiography to investigate fluorodeoxyglucose (FDG) uptake, distribution, and cellular localization in acute, early chronic, and late chronic soft-tissue infections. MATERIALS AND METHODS: Unilateral calf-muscle abscesses were induced in 12 Sprague-Dawley rats by means of intramuscular inoculation of 0.1 mL of bacterial suspension (Staphylococcus aureus, 1.2 x 10(9) CFU/mL). Following injection of 130-180 MBq of fluorine 18 FDG, autoradiography of the abscess and contralateral muscle was performed (10-microm section thickness) on days 2, 5, and 9 after infection. Detailed spatial correlation of autoradiographs and histopathologic samples was performed by means of image fusion. Regions of interest were placed in the abscess wall, and measured gray values were converted to kilobecquerels per cubic centimeter according to kilobecquerels of injected activity per gram of body weight, which yielded standardized uptake values (SUVs). RESULTS: Acute abscess formation was characterized by central necrosis predominantly surrounded by neutrophils and a second necrotic tissue layer that bordered neutrophil infiltrates peripherally. Areas with increased FDG uptake corresponded to cellular inflammatory infiltrates, mainly granulocytes. The corresponding SUV was calculated to be 4.08 +/- 0.65 (mean +/- SD). Early chronic phase showed mixed cellular infiltrate of granulocytes and macrophages that surrounded central necrosis with interspersed fibroblasts and only residual muscle necrosis layer within the abscess wall. FDG uptake was located where granulocytes and macrophages were present, as in acute infection (SUV = 5.32 +/- 2.30). Late chronic infection was characterized by a prominent layer of macrophages around residual central necrosis and fibroblast-enriched granulation tissue delineating the infection from muscle tissue. FDG uptake clearly coincided with the macrophages, and no substantial increase of FDG uptake was detected within fibroblast-enriched granulation tissue. The SUV was calculated as 7.97 +/- 0.21. Results of Kruskal-Wallis ANOVA demonstrated that the change in SUV with time was statistically significant (chi(2) = 7.42, P <.05). CONCLUSION: The highest FDG uptake coincides with areas of inflammatory cell infiltrates, predominantly in neutrophils in the acute phase and in macrophages in the chronic phase of soft-tissue infection.     

Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease

Thymectomy on day 3 after birth (d3tx) depletes CD4+CD25+ regulatory T cells leading to multiple independent organ-specific autoimmune diseases. However, systemic autoimmune disease such as systemic lupus erythematosus has not been reported in d3tx mice. Herein, we investigate the effect of d3tx on spontaneous autoantibody response and immune complex glomerulonephritis (GN) in the lupus-prone (SWR x NZB)F1 (SNF1) mice. The d3tx SNF1 mice developed accelerated antibody responses to double-stranded DNA and DNA-histone complexes, and an increased frequency of activated CD4+ T cells. Unexpectedly, the renal histopathology and mortality from GN were significantly ameliorated in d3tx SNF1 mice, which concomitantly exhibited a Th2-biased antibody response. By 16 weeks, the d3tx mice had higher levels of total and autoantigen-specific IgG1, and at 12 months, the autoantigen-specific IgG2a was significantly below that of the sham thymectomized mice. These differences corresponded with reduction in total and autoantigen-specific IgG2a in the renal eluates of the d3tx mice. In addition, while all the mice had immune complex deposition in the mesangium and peripheral capillary loops of the glomeruli, IgG2a and C3 deposits restricted to the mesangial regions alone were more frequent in d3tx mice. D3tx SNF1 mice, protected from lupus-like GN, developed organ-specific autoimmune responses and diseases including prostatitis, orchitis and oophoritis, and antibodies to prostate, cardiac and skeletal muscle antigens. Therefore, d3tx paradoxically protects SNF1 mice from genetically prone lupus-like GN, yet promotes de novo organ-specific autoimmunity.     

Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.     

Role of testosterone,estradiol, and insulin in diet- and exercise-induced reductions in serum-stimulated prostate cancer cell growth in vitro

Prostate cancer risk is associated with a high-fat diet and a sedentary lifestyle. Placing men on a low-fat diet-and-exercise intervention reduces serum hormones, including estradiol, insulin, and free testosterone, that may play a role in prostate cancer growth. Eight men participated in a low-fat diet-and-exercise program for a mean of 14.2 yr, and LNCaP cell growth in culture was measured in medium supplemented with 10% of each subject's serum as well as with testosterone, estradiol, and insulin added singly or in combination. These results were compared in the fetal bovine serum (FBS)-stimulated growth and cell growth in serum obtained from a control group of 14 overweight men. In separate tissue culture experiments, LNCaP and PC-3 cell growth was also measured in response to the addition of testosterone, estradiol, or insulin to steroid-stripped FBS. LNCaP cell growth in medium with subject serum was 40% less than in FBS-stimulated medium and 49% less than in medium with serum from control, overweight men. Addition of testosterone, estradiol, and insulin to serum from diet-and-exercise subjects significantly stimulated LNCaP cell growth in vitro but accounted for only about half of the difference between the control and diet-and-exercise subjects. Thus other serum changes must also account for the significant reduction in LNCaP cell growth observed using medium with serum from the diet-and-exercise subjects in the cell culture assay.     

Correlation of nuclear color and opalescence with protein S-thiolation in human lenses.

Human lens nuclei were collected during routine cataract surgery and used to study the role of oxidation in cataract formation and brunescence. This study focused on the comparison of the intensities of nuclear opacity and pigmentation (brunescence) with the changes in free glutathione (GSH) and the three species of protein-thiol mixed disulfides: protein-S-S-glutathione (PSSG), protein-S S-cysteine (PSSC) and protein-S-S-gamma-glutamylcysteine (PSSGC). Eighty-one freshly excised human lens nuclei from a population with a mean age of 77 were used. The nuclear color was graded using the CCRG system, ranging from yellow to dark brown. The nuclear cataract opalescence of these lenses was also graded using the LOCS II system, ranging from LOCS II NO-1 to NO-4. Three normal human lenses (average age of 88 yr) were also included in the study as controls. The nuclear samples were each analyzed for free GSH and protein-thiol mixed disulfides, respectively. It was found that nuclear GSH decreased as the nuclear color increased from yellow to dark brown (from 0.73+/-0.13 to 0.13+/-0.03 micromole g wet wt-1) and as the nuclear opalescence increased from NO.1 to NO.4 (from 0. 80+/-0.19 to 0.20+/-0.01 micromole g wet wt-1). All these values were lower than that of GSH in normal controls (1.43+/-0.59 micromole g wet wt-1). Levels of both PSSG and PSSC progressively increased, however, as the nuclear color intensified. PSSG increased from 0.29+/-0.05 to 0.91+/-0.11 micromole g wet wt-1while PSSC increased from 0.13+/-0.04 to 0.41+/- 0.06 micromole g wet wt-1. PSSGC concentration progressively increased with increases in both nuclear pigmentation (from 0.05+/-0.01 to 0.23+/-0.05 micromole g wet wt-1) and nuclear opacity (from 0.02+/-0.00 to 0.20+/-0.02 micromole g wet wt-1). In comparison, normal controls had lower levels of all three mixed disulfide species: PSSG, 0.22+/-0.06; PSSC, 0.08+/-0.02; PSSGC, 0.02+/-0.06 micromole g wet wt-1, respectively. The correlation of lens nuclear color and opalescence intensity with nuclear protein S-thiolation indicates that protein-thiol mixed disulfides may play an important role in cataractogenesis and development of brunescence in human lenses.     

Staging of nasopharyngeal carcinoma: from Ho's to the new UICC system

The independent significance of different tumor factors in 4,514 patients with undifferentiated or non-keratinizing carcinoma of the nasopharynx irradiated at the Queen Elizabeth Hospital during 1976-1985 were analyzed retrospectively. Multivariate analyses showed that the most significant primary factors included cranial nerve palsy, erosion of base of skull and oropharynx. For tumors within the nasopharynx, there was no difference in survival between those with involvement of 1 site vs. more than 1 sites. Patients with cranial nerve palsy had significantly worse prognosis than those with bony erosion alone. Although the nodal characteristics (size, level of extension, fixation, laterality and multiplicity) were inter-related, their independent impact all reached statistical significance. However, the criteria used currently could be simplified: laterality should be revised to unilateral vs. bilateral, level to upper-mid vs. lower neck, and size to < or =6 cm vs. >6 cm. Grouping of N2 together with N3 into Stage IV was inappropriate as the former had significantly better prognosis. Our findings, together with review of the publications, provided clinical data for developing the current UICC staging system for nasopharyngeal carcinoma. Such major revision resulted not only in better distinction of hazards, but also more even distribution of cases between different stages.