Possible Dose-Response Relationship in Palliative Radiotherapy for Non-bone Painful Lesions.

AIMS: Total radiation dose does not predict pain response in conventionally fractionated radiotherapy for bone metastases. By contrast, in radiotherapy for solid painful tumours other than bone metastases, it is unknown whether there is a dose-response relationship. We sought to determine whether a higher total radiation dose predicted a higher pain response rate in palliative radiotherapy for non-bone painful lesions. MATERIALS AND METHODS: We carried out a secondary analysis of a prospective observational study. For patients scheduled for radiotherapy for painful tumours, Brief Pain Inventory data were collected at baseline and at 1, 2 and 3 months after the start of radiotherapy. The predictive value of total radiation dose was evaluated using the Fine-Gray model, in which death without a pain response was treated as a competing risk. RESULTS: Of the 203 patients with solid painful tumours, 78 (38%) had non-bone painful lesions. There were no significant differences in pain response rate, the rate of the predominance of non-index pain or reductions in pain interference scores between the patients with non-bone lesions and those with bone metastases. Multivariable analysis showed that total radiation dose was an independent significant predictor of pain response in patients with non-bone painful lesions. This result was not robust to sensitivity analysis with Cox regression analysis. CONCLUSIONS: Higher total radiation dose seemed to be associated with a higher rate of pain response in patients with non-bone painful lesions. However, this finding was not robust to sensitivity analysis. Dose-response relationship should be investigated in clinical trials enrolling patients with these kinds of painful tumour.

Distribution of CXCR4 and tumour-infiltrating lymphocytes in breast cancer subtypes; their relationship with each other, axillary lymph node involvement, and other prognostic indicators.

We have investigated the distribution of chemokine receptor 4 (CXCR4) and CD8-positive, tumour-infiltrating T lymphocytes (CD8+ TILs) in breast cancer subtypes and explored the relationship between them and the well-established conventional prognostic markers, including axillary lymph node involvement. A total of 250 breast cancer patients were included in the study. The patients were separated into luminal A+B, HER2 enriched/overexpressed (HER2+), and triple- negative, on the basis of their staining characteristics, via conventional staining methods. Immunohistochemical (IHC) staining for CXCR4 and CD8+ TILs were performed on the archival tissues from each patient. With increasing intensity of CXCR4 staining, there was a higher incidence of lymph node metastasis (p < 0.01). Similarly, there was a positive correlation between the primary tumour size, HER2+ subtype, lymphovascular invasion, and axillary lymph node involvement. Dense lymphocytic infiltration was observed in HER2+ and triple-negative patients. No correlation between CD8+ TILs in all sites and breast cancer subtypes was discovered. A reverse correlation was discovered with CD8+ TILs stained only intratumorally and CXCR4 expression. In conclusion, lymph node involvement correlates with higher CXCR4 expression in all breast cancer subtypes. Conversely, no such correlation is found with CD8+ TILs.

The Role of Parafibromin, Galectin-3, HBME-1, and Ki-67 in the Differential Diagnosis of Parathyroid Tumors.

OBJECTIVES: Parathyroid carcinoma (PC) is a rare parathyroid tumor compared to parathyroid adenoma (PA) and atypical parathyroid adenoma (APA). Recent studies have suggested parafibromin has a role in the differential diagnosis of parathyroid tumors. We sought to determine the role of parafibromin as well as galectin-3, Ki-67, and HBME-1 as diagnostic markers in the differential diagnosis of parathyroid tumors. METHODS: A total of 92 cases diagnosed with PA, APA, or PC at Sifa University and Private Ege Pathology Laboratory between 2006-2012 were included in the study. Parafibromin (microarray), galectin-3, Ki-67, and HBME-1 were evaluated using immunohistochemistry in all parathyroid tumors. RESULTS: Eighty-four cases were diagnosed with PA, six with APA, and two with PC. The study group consisted of 82 females and 10 males. Their mean age was 50.9 years, and the mean tumor diameter was 1.97 cm. Parafibromin was negative in the two PC cases but positive in all APA and PA cases. Positivity was observed with galectin-3 in 17 adenoma cases, three atypical adenomas, and two carcinoma cases. Positivity with HBME-1 was found in 26 PA cases and one PC case. Parafibromin and galectin-3 expression was significant between the three tumor groups but not for HBME-1 expression. Parafibromin expression increased in PA whereas galectin-3 expression decreased. A statistical significance was found between the three tumor groups according to the Ki-67 score (p=0.010). Additionally, the Ki-67 proliferation index was under 1% in PAs. CONCLUSION: The number of PCs in our series was small so our data mostly reflects the immunohistochemical characteristics of PAs. Parafibromin expression, galectin-3 negativity, and a Ki-67 proliferation index under 1% were estimated as beneficial in the differential diagnosis of difficult parathyroid tumors.

Montelukast is effective in preventing of ovarian hyperstimulation syndrome; an experimental study.

OBJECTIVES: To determine the efficacy of montelukast in comparison with cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in rats. MATERIAL AND METHODS: An experimental OHSS model was formed in 35 female Wistar rats. Rats (22 days old) were randomized into 5 groups, each containing 7 animals. The control group received no therapy; the mild OHSS group was administered pregnant mare serum gonadotropin (PMSG) 10 IU for 4 days, hCG 10 IU on the 5th day; the severe OHSS group received PMSG 10 IU for 4 days, hCG 30 IU on the 5th day The montelukast group: received montelukast 10 mg/kg/day and the cabergoline group was administered cabergollne 100 microg/kg/day via oral gavage for 6 days (days 22-27), in addition to those of severe OHSS. All groups were sacrificed on 28th day Body weight, ovarian diameter and weight, vascular permeability vascular endothelial growth factor (VEGF), semiquantitative VEGF receptor-1, and VEGF receptor-2 (VEGFR-2) immunohistochemistry were evaluated. RESULTS: Ovarian diameter and VEGF expression were significantly lower in the montelukast and cabergoline groups than in the severe OHSS group. While montelukast was more effective in limiting vascular permeability in the severe OHSS, cabergoline was superior to montelukast with respect to the limiting effect on increased body weight and VEGFR-2 expression. CONCLUSIONS: The VEGF/VEGFR-2 interaction plays an important role in OHSS pathogenesis. Montelukast limits VEGF expression, and cabergoline reduces both VEGF and VEGFR-2 expressions; they are both effective therapies for the prevention of severe OHSS.

Protection of red-legged partridges (Alectoris rufa) against West Nile virus (WNV) infection after immunization with WNV recombinant envelope protein E (rE).

West Nile virus (WNV) is maintained in nature in an enzootic transmission cycle between birds and mosquitoes, although it occasionally infects other vertebrates, including humans, in which it may result fatal. To date, no licensed vaccines against WNV infection are available for birds, but its availability would certainly benefit certain populations, as birds grown for restocking, hunting activities, or alimentary purposes, and those confined to wildlife reservations and recreation installations. We have tested the protective capability of WNV envelope recombinant (rE) protein in red-legged partridges (Alectoris rufa). Birds (n=28) were intramuscularly immunized three times at 2-weeks interval with rE and a control group (n=29) was sham-immunized. Except for 5 sham-immunized birds that were not infected and housed as contact controls, partridges were subcutaneously challenged with WNV. Oropharyngeal and cloacal swabs and feather pulps were collected at several days after infection and blood samples were taken during vaccination and after infection. All rE-vaccinated partridges elicited anti-WNV antibodies before challenge and survived to the infection, while 33.3% of the sham-immunized birds succumbed, as did 25% of the contact animals. Most (84%) unvaccinated birds showed viremia 3 d.p.i., but virus was only detected in 14% of the rE vaccinated birds. WNV-RNA was detected in feathers and swabs from sham-immunized partridges from 3 to 7 d.p.i., mainly in birds that succumbed to the infection, but not in rE vaccinated birds. Thus, rE vaccination fully protected partridges against WND and reduced the risk of virus spread.

Kinetic modeling of enzymatic hydrolysis of pretreated kitchen wastes for enhancing bioethanol production.

It is well known that use of low cost and abundant waste materials in microbial fermentations can reduce product costs. Kitchen wastes disposed of in large amounts from cafeterias, restaurants, dining halls, food processing plants, and household kitchens contain high amounts of carbohydrate components such as glucose, starch, and cellulose. Efficient utilization of these sugars is another opportunity to reduce ethanol costs. In this study, the effect of pretreatment methods (hot water, acid solutions, and a control) on enzymatic hydrolysis of kitchen wastes was evaluated using a kinetic modeling approach. Fermentation experiments conducted with and without traditional fermentation nutrients were assessed at constant conditions of pH 4.5 and temperature of 30°C for 48h using commercial dry baker's yeast, Saccharomyces cerevisiae. The control, which involved no treatment, and hot water treated samples gave close glucose concentrations after 6h. The highest and lowest rates of glucose production were found as 0.644 and 0.128 (h(-1)) for the control (or no-pretreated (NPT)) and 1% acid solutions, respectively. The fermentation results indicated that final ethanol concentrations are not significantly improved by adding nutrients (17.2-23.3g/L). Thus, it was concluded that product cost can be lowered to a large extent if (1) kitchen wastes are used as a substrate, (2) no fermentation nutrient is used, and (3) hydrolysis time is applied for about 6h. Further optimization study is needed to increase the yield to higher levels.

Prognostic value of perfusion MR imaging of high-grade astrocytomas: long-term follow-up study.

BACKGROUND AND PURPOSE: Although the prognostic value of perfusion MR imaging in various gliomas has been investigated, that in high-grade astrocytomas alone has not been fully evaluated. The purpose of this study was to evaluate retrospectively whether the tumor maximum relative cerebral blood volume (rCBV) on pretreatment perfusion MR imaging is of prognostic value in patients with high-grade astrocytoma. MATERIALS AND METHODS: Between January 1999 and December 2002, 49 patients (30 men, 19 women; age range, 23-76 years) with supratentorial high-grade astrocytoma underwent MR imaging before the inception of treatment. The patient age, sex, symptom duration, neurologic function, mental status, Karnofsky Performance Scale, extent of surgery, histopathologic diagnosis, tumor component enhancement, and maximum rCBV were assessed to identify factors affecting survival. Kaplan-Meier survival curves, the logrank test, and the multivariate Cox proportional hazards model were used to evaluate prognostic factors. RESULTS: The maximum rCBV was significantly higher in the 31 patients with glioblastoma multiforme than in the 18 with anaplastic astrocytoma (P < .03). The 2-year overall survival rate was 67% for 27 patients with a low (< or =2.3) and 9% for 22 patients with a high (>2.3) maximum rCBV value (P < .001). Independent important prognostic factors were the histologic diagnosis (hazard ratio = 9.707; 95% confidence interval (CI), 3.163-29.788), maximum rCBV (4.739; 95% CI, 1.950-11.518), extent of surgery (2.692; 95% CI, 1.196-6.061), and sex (2.632; 95% CI, 1.153-6.010). CONCLUSION: The maximum rCBV at pretreatment perfusion MR imaging is a useful clinical prognostic biomarker for survival in patients with high-grade astrocytoma.

Impact of FDG-PET/CT fused imaging on tumor volume assessment of head-and-neck squamous cell carcinoma: intermethod and interobserver variations.

BACKGROUND: Although gross tumor volume (GTV) at the primary site can predict local control of head-and-neck squamous cell carcinoma (SCC) in patients who are treated with organ-preservation therapy, GTV assessment does not eliminate substantial interobserver variation. PURPOSE: To evaluate whether F-18-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) fused imaging provides additional information for GTV assessment. MATERIAL AND METHODS: We obtained FDG-PET/CT fused images on 20 patients with head-and-neck SCC. All had undergone preoperative conventional workup, including contrast-enhanced CT and magnetic resonance imaging (MRI). The GTV of the primary tumors was designed by two independent observers who used routine clinical data. Observer A was a radiologist and observer B a radiation oncologist. GTV1 and GTV2 were designed without and with FDG-PET/CT, respectively. For geometric interobserver comparison, we calculated the concordance rate as the ratio of the intersection (AxB) of the GTVs to their union (AxB). Intermethod (GTV1 vs. GTV2) and interobserver (A vs. B) differences in the GTVs were assessed by Bland-Altman analysis and the Spearman rank-correlation test. The interobserver concordance rates for GTV1 and GTV2 were compared using a two-tailed paired-samples t test. RESULTS: On FDG-PET/CT, all primary tumors were visualized. There was no systemic trend for a volume difference between GTV1 and GTV2. Although the 95% limits of agreement were wider for interobserver than intermethod differences, the 95% limits of interobserver agreement were narrower for GTV2 than GTV1. The mean interobserver concordance rate for GTV2 was higher than for GTV1 (54.5% vs. 39.1%, P=0.0002). CONCLUSION: FDG-PET/CT is a useful modality for consistent GTV assessment, which should not be used as a single modality but rather to obtain supplemental information in patients with head-and-neck SCC.

Time course of reoxygenation in experimental murine tumors after carbon-beam and X-ray irradiation.

We compared the tumor reoxygenation patterns in three different murine tumor cell lines after X-irradiation with those after carbon-beam irradiation using a heavy-ion medical accelerator (HIMAC) system. The tumors of the cell lines SCCVII, SCCVII-variant-1 and EMT6 on the hind legs of mice received local priming irradiation with a carbon-beam (8 Gy, 73 keV/microm in LET, 290 MeV/u, 6 cm SOBP) or X-rays (13 Gy, 250 kVp). After various intervals, the mice were given whole-body test irradiation (16 Gy. 250 kVp X-ray) either in air or after they were killed. The hypoxic fractions were estimated as the proportions of the surviving fractions of the tumors in killed mice to those in air-breathing mice. In the SCCVII tumors, the hypoxic fractions at 0.5 h were 50% and 21% (p < 0.05) after the priming X-irradiation and carbon-beam irradiation, respectively. In the SCCVII-variant-1 tumors, the hypoxic fractions were 85% and 82% at 0.5 h, 84% and 20% at 12 h (p < 0.01), and 21% and 31% at 24 h after X-ray and after carbon-beam irradiation, respectively. In the EMT6 tumors, the reoxygenation patterns after X-irradiation and carbon-beam irradiation were quite similar. We concluded that the reoxygenation pattern differed among the three tumor cell lines, and that reoxygenation tended to occur more rapidly after carbon-beam irradiation than after X-irradiation for SCCVII and SCCVII-variant-1 tumors.

Definitive intraoperative very high-dose radiotherapy for localized osteosarcoma in the extremities.

PURPOSE: To evaluate the outcome and adverse effects in patients with osteosarcoma treated with very high-dose definitive intraoperative radiotherapy (IORT), with the intention of saving the affected limb. METHODS AND MATERIALS: Thirty-nine patients with osteosarcoma in their extremities were treated with definitive IORT. The irradiation field included the tumor plus an adequate wide margin and excluded the major vessels and nerves. Forty-five to 80 Gy of electrons or X-rays were delivered. The median follow-up of the surviving patients was 124 months. RESULTS: The cause-specific and relapse-free 5-year survival rate was 50% and 43%, respectively. Distant metastasis developed in 23 patients; 19 died and 4 were alive for >10 years. Nine local recurrences were found 4-29 months after IORT in the affected limb. No radiation-induced skin reaction or nerve palsy was observed in the patients treated with X-rays. Experiments using phantoms also confirmed that the scatter dose was below the toxic level in the IORT setting with X-rays. CONCLUSIONS: Very high-dose definitive IORT combined with preventive nailing and chemotherapy appeared to be a promising quality-of-life-oriented alternative to treating patients with osteosarcomas in the extremities, although the problem of recurrences from the surrounding unirradiated soft tissue remains to be solved.

Adult T-cell leukemia.

Adult T-cell leukemia (ATL) is endemic in southwestern Japan, in the Caribbean islands, and in central Africa. Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of ATL. The clinical characteristics are (1) onset in adulthood, (2) subacute or chronic leukemia with rapidly progressive terminal course, (3) frequent skin lesions, (4) lymphadenopathy that characteristically spares the mediastinum, (5) hepatosplenomegaly, (6) hypercalcemia, and (7) a tendency toward geographical clustering. Although hypercalcemia and osteoclastic activity due to parathyroid hormone-related peptide are frequently reported histologically, radiographic abnormalities of bone are not common. Two major patterns of osteolytic lesions observed in ATL are "punched-out" lesions resembling multiple myeloma and osteolytic metastasis and subperiosteal bone resorptions similar to those in hyperparathyroidism.

A study of the relationship between metabolism using 1H-MRS and function using several neuropsychological tests in temporal lobe epilepsy.

Several investigators have reported on the relationship between metabolism, using magnetic resonance spectroscopy (MRS), and function, using neuropsychological tests in temporal lobe epilepsy (TLE) patients, but the opinions regarding the results remain in contention. The aim of this study is to examine the relationship between metabolism, using proton MRS ((1)H-MRS), and function using several neuropsychological tests in the temporal lobes of TLE patients. We studied 29 TLE patients at our hospital using(1)H-MRS and neuropsychological tests. We used a clinical 1.5 T MR unit. We conducted five neuropsychological tests to examine the function of the left or right temporal lobe. There were significant correlations between the N-acetylaspartate/creatine + phosphocreatine (NAA/Cr) ratios and the scores of almost all of the neuropsychological tests for the temporal lobe function ipsilateral to the spike focus. However, in two Wechsler Memory Scale-Revised (WMS-R) subtests we found no significant correlation in the ipsilateral side. These findings suggest that the NAA/Cr ratios, which reflect neural metabolism, are closely related to function in the temporal lobes of TLE patients. The disparity between the results in two subtests of WMS-R show that several tests may be necessary in order to assess temporal lobe function.

FDG PET of primary benign and malignant bone tumors: standardized uptake value in 52 lesions.

PURPOSE: To evaluate the standardized uptake value (SUV) of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) at positron emission tomography (PET) in the differentiation of benign from malignant bone lesions. MATERIALS AND METHODS: Fifty-two (19 malignant, 33 benign) primary bone lesions were examined with FDG PET prior to tissue diagnosis. The SUVs were calculated and compared between benign and malignant lesions and among histologic subgroups that included more than four cases. RESULTS: There was a statistically significant difference in SUV between benign (2.18 +/- 1.52 [SD]) and malignant (4.34 +/- 3.19) lesions in total (P =.002). However, giant cell tumors (n = 5; SUV, 4.64 +/- 1.05) showed significantly higher SUV than chondrosarcomas (n = 7; SUV, 2.23 +/- 0.74) (P =.036, adjusted for multiple comparisons) and had no statistically significant difference in SUV compared with osteosarcomas (n = 6; SUV, 3.07 +/- 0.96) (P =.171). There was no statistically significant difference in SUV between fibrous dysplasias (n = 6; SUV, 2.05 +/- 0.98) and osteosarcoma (P =.127) or chondrosarcomas (P =.667). Although the number of cases was small, three chondroblastomas, one sarcoidosis, and one Langerhans cell histiocytosis showed levels of FDG accumulation as high as that of osteosarcomas. CONCLUSION: Radiologists should be aware of the high accumulation of FDG in some benign bone lesions, especially histiocytic or giant cell-containing lesions. Consideration of histologic subtypes should be included in analysis of SUV at FDG PET of primary bone tumors.

Meningeal carcinomatosis in patients with breast cancer: report of 8 patients.

BACKGROUND: Meningeal carcinomatosis (MC) is an uncommon but aggressive complication of advanced breast cancer with a recently increasing incidence. Although the prognosis is extremely poor for MC patients, early diagnosis and appropriate treatment are important. SUBJECTS AND METHODS: We reviewed 8 cases of MC from breast cancer at Kyoto University Hospital from 1990 to 1999. The median age was 51.5 years. All patients had widespread systemic metastases when diagnosed with MC. clinical symptoms were categorized into 3 groups: cranial nerve symptoms, spinal nerve symptoms, and other symptoms. Imaging studies were positive for MC in only 4 patients. Initial CSF cytology studies were positive in 4 patients, and repeated CSF cytology yielded positive results in the remaining 4 patients. Thus the median interval between the onset of any clinical symptom of MC and the initiation of treatment was 22.5 days (range 7 to 120 days ). All patients received whole brain radiotherapy (WBRT). Four patients were given intrathecal chemotherapy and/or intrathecal immunotherapy in addition to WBRT. RESULTS: Improvement of cranial nerve symptoms, spinal nerve symptoms, and other symptoms were observed in 3/5, 1/3, and 5/7 patients, respectively. Patients with cranial nerve symptoms who started WBRT within 29 days of the onset of the symptoms showed at least partial recovery whereas patients who started WBRT later showed no recovery. The median survival was 123 days (53 to 310 days). MC was the direct cause of death in 1 of 8 patients. CONCLUSION: When MC is clinically suspected, neither a negative imaging study nor a single negative CSF cytology can rule out MC. Prompt initiation of WBRT with or without intrathecal chemotherapy may be important for recovery from cranial nerve symptoms.

Intracranial germinoma: radiation therapy with tumor volume-based dose selection.

PURPOSE: To prospectively investigate whether intracranial germinomas, except large ones, can be cured with radiation doses lower than 50 Gy and to determine 10-year follow-up results. MATERIALS AND METHODS: Between 1985 and 1995, 38 patients with intracranial germinoma diagnosed histologically or with established criteria were enrolled. Total radiation doses to the primary tumor site were 36 Gy after total removal, 40 Gy for tumors less than 2.5 cm in diameter, 45 Gy for those 2.5-4.0 cm, and 50 Gy for those greater than 4.0 cm, with 1.6-1.8-Gy daily fractions. Patients underwent irradiation of the primary tumor site or cerebrospinal axis (20-24 Gy), depending on findings at diagnosis. No chemotherapy was allowed. RESULTS: All patients completed radiation therapy. Thirty-five patients were treated according to protocol, and three with relatively slow tumor regression or presence of a cyst received additional radiation (5-7 Gy, 50-52 Gy total). Ten-year overall and relapse-free survival rates were 91% and 95%, respectively. Two patients developed meningeal dissemination, but none had local failure. Treatment complications included chordoma in one patient and internal carotid artery occlusion in another. No treatment-related decline of performance status was observed in the other patients. CONCLUSION: All tumor volume-based radiation doses were effective, without risk of local failure. Intracranial germinoma 4 cm or less in diameter can be cured with doses of 40-45 Gy. Investigation of further dose reduction seems worthwhile. Radiation therapy alone with these doses should be compared with ongoing chemotherapeutic protocols plus low-dose (24-30-Gy) irradiation in future studies.

c-IAP2 is induced by ionizing radiation through NF-kappaB binding sites.

Transcriptional promoters responsive to low doses of X-irradiation may be useful in developing a new strategy in gene therapy combined with conventional radiotherapy. The retrovirus-mediated gene trap screening identified c-IAP2 as one of genes possessing such promoters. The analysis of the cis-elements responsive to X-irradiation in c-IAP2 promoter revealed that the NF-kappaB binding sites were necessary and sufficient for the X-ray-responsiveness. We constructed the plasmid p4NFB-BAX, which had four tandem repeats of the NF-kappaB binding sites of c-IAP2 promoter (4NFB) and a suicide gene BAX under the control of 4NFB. The human tumor cells transfected with p4NFB-BAX significantly reduced the number of cells that survived 2 Gy irradiation.