SU-E-J-183: Dose Distribution Generated from 131 I Radionuclide Using SPECT-CT.

PURPOSE: 131 I radionuclide therapy is widely performed in a thyroid cancer treatment, but there has been almost no evaluation of the dose distribution. The aim of this work is to develop the calculation system using the data of SPECT-CT and to examine the effects of their image resolutions on the dose distribution. METHODS: We designed and constructed an acrylic phantom for measurement. A radioactive iodine capsule and glass dosimeters can be set in the layer structure of the phantom. We put iodine capsules (37MBq, 111MBq, 185MBq) in the middle of the phantom and acquired SPECT-CT (Infinia Hawkeye4 (GE)) images. Both the CT value data (image resolution: 1.1 mm) and the intensity map data of SPECT (image resolution: 4.4 mm) were independently used for the estimation of the cumulative dose distribution generated from the radioactive iodine in the phantom. We adopted Monte Carlo program PHITS2.0 as the simulation of the dose calculation. The absolute dose was measured by glass dosimeters. RESULTS: The measurement result by glass dosimeters was very similar to the Monte Carlo simulation result, in which the difference was about 0.3 %. We obtained the dose distributions reconstructed by the radioactive iodine distribution using CT value data and SPECT data, respectively. The iodine distribution from CT could be finer than that of SPECT data because of its higher image resolution. As a result, the difference was found to be factor two in the middle of the iodine distribution. On the other hand, both of the dose distribution was almost same above 2.2 cm distance from the center. CONCLUSIONS: We can reconstruct the 131I dose distribution using SPECT-CT data. For more accurate calculation of the dose distribution, it would be crucial to increase the resolution of SPECT data.

Esophageal cancer: definitive chemoradiotherapy for elderly patients.

To investigate the efficacy and toxicity of definitive chemoradiotherapy (CRT) for elderly patients with locally advanced esophageal cancer. Twenty-two patients aged over 75 that performed definitive CRT were retrospectively reviewed. The regimen included concurrent CRT consisting of two cycles of chemotherapy (CTx) of platinum and 5-fluorouracil, and radiation therapy (RT) of 50-50.4 Gy (actual range: 45.4-71.4 Gy), and additional CTx where possible. Both CTx and RT were reduced in dose and field where necessary. The disease-free survival rate and the overall survival rate at 3 years were 33.3% ± 11.4% and 25.9% ± 10.8%. Grade 4 leukocytopenia and thrombocytopenia occurred in three (14%) and four (18%) patients. Treatment-related death was suspected in up to four (18%) patients at the most. Univariate analyses for disease-free survival showed that neither total radiation dose nor number of total cycles of CTx was significant. The pattern of relapse was predominantly more frequent in the intra-RT field than outside the RT field. For elderly patients, adverse events are frequent, and decreased organ reserve may cause treatment-related death. Reduction in CTx dose or RT field, appropriate only for two cycles of CTx, and careful monitoring may help to minimize toxicity. Physicians should not be too afraid of adverse events or be negative about CRT for elderly patients, as long as comorbidities and complications are managed carefully.

Edaravone, a known free radical scavenger, enhances X-ray-induced apoptosis at low concentrations.

Edaravone has been reported to have a radioprotective effect at high concentrations. We now report that a lower dose of edaravone enhanced X-ray-induced apoptosis of some cell lines harboring p53 wild-type status, such as MOLT-4, Nalm-6, and HepG2. The knock-down of p53 using siRNA in MOLT-4 cells abolished the radiosensitizing effect of edaravone. Enhanced phosphorylations of p53 at Ser 15 and Ser 20 and up-regulation of PUMA, a p53 target protein, were observed after X-irradiation in the presence of edaravone. We conclude that the low dose of edaravone sensitized cells to X-irradiation by promoting the p53-dependent apoptotic signaling pathway.

Radiation therapy combined with cis-diammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil for Japanese stage II-IV esophageal cancer compared with cisplatin plus 5-fluorouracil regimen: a retrospective study.

To evaluate the treatment outcome of radiotherapy combined with cis-diammine-glycolatoplatinum (nedaplatin) plus 5-fluorouracil (5-FU) for esophageal cancer. From January 2000 to December 2004, a total of 12 esophageal cancer patients with locally advanced and metastatic esophageal cancer (stages II-IVB) were treated with radiation therapy (50.4 Gy) combined with nedaplatin (80 mg/m(2), bolus infusion) and 5-FU (800 mg/m(2)/24 h, continuous infusion for 4 days) (NDP group). We compared the data with those of patients during the same period receiving a different chemotherapy regimen consisting of cisplatin (75 mg/m(2), bolus infusion) and 5-FU (1000 mg/m(2)/24 h, continuous infusion for 4 days) (n = 29, CDDP group) combined with the same radiation therapy. The median survival period was 11.5 months in the NDP group and 13.1 months in the CDDP group. The overall survival rates at 1-, 2-, and 3-years were 40%, 13%, and 13% in the NDP group and 56%, 42%, and 8% in the CDDP group (P = 0.2472), respectively. Grade III and IV leukocytopenia was observed in six (50%) and none of the patients in the NDP group and 14 (48%) and seven (24%) in the CDDP group, respectively. Grade III thrombocytopenia was observed in three (25%) in the NDP group and four (14%) in the CDDP group. Radiation combined with nedaplatin and 5-FU is a safe and effective method for treating esophageal cancer. We recommend that NDP should be used rather than dose-reduction of CDDP combined with 5-FU in patients with impaired renal function as indicated by low creatinine clearance value (40-60 mL/min).

Isocapnic hyperpnoea accelerates recovery from isoflurane anaesthesia.

BACKGROUND: Hyperventilation should speed up elimination of volatile anaesthetic agents from the body, but hyperventilation usually results in hypocapnia. We compared recovery from isoflurane anaesthesia in patients allowed to recover with assisted spontaneous ventilation (control) and those treated with isocapnic hyperpnoea. METHODS: Fourteen patients were studied after approximately 1 h of anaesthesia with isoflurane. Control patients were allowed to recover in the routine way. Isocapnic hyperpnoea patients received 2-3 times their intraoperative ventilation using a system to maintain end tidal PCO(2) at 45-50 mm Hg. We measured time to removal of the airway and rate of change of bispectral index (BIS) during recovery. RESULTS: With isocapnic hyperpnoea, the time to removal of the airway was markedly less (median and interquartile range values of 3.6 (2.7-3.7) vs 12.1 (6.8-17.2) min, P<0.001); mean (SD) BIS slopes during recovery were 11.8 (4.4) vs 4.3 (2.7) min(-1) (P<0.01) for isocapnic hyperpnoea and control groups, respectively. Isocapnic hyperpnoea was easily applied in the operating room. CONCLUSIONS: Isocapnic hyperpnoea at the end of surgery results in shorter and less variable time to removal of the airway after anaesthesia with isoflurane and nitrous oxide.

[Tracheal tube/laryngeal mask exchange to prevent coughing in lung volume reduction surgery].

We report the use of laryngeal mask airway (LMA) to facilitate smooth emergence from anesthesia in 3 patients who underwent lung volume reduction surgery (LVRS) for severely symptomatic emphysema. To prevent coughing during emergence we replaced the endotracheal tube with LMA while patient was still in deep anesthesia. Emergence was smooth without coughing in all three patients, and ventilation with facemask was not needed after removal of LMA. We believe this technique is safe and beneficial for anesthetic management of LVRS.

Expression of prohormone convertase, PC2, in adrenocorticotropin-producing thymic carcinoid with elevated plasma corticotropin-releasing hormone.

An autopsy case of ACTH-producing thymic carcinoid with Cushing's syndrome is reported. The patient was a 63-yr-old man with multiple bone metastases from an undetermined primary site. Hyperpigmentation was observed at the terminal stage. The plasma levels of ACTH, cortisol, chromogranin A, and urinary 17-hydroxy-corticosteroids were extremely high, and ectopic ACTH-producing neuroendocrine tumor was diagnosed. In addition, plasma CRH was high. Autopsy revealed that the patient had primary thymic carcinoid with extensive metastases. Remarkable hyperplasia of the adrenal cortexes and Crooke's hyaline degeneration of the pituitary gland were consistent with Cushing's syndrome by ectopic ACTH production. There were multiple CRH-producing cells without degenerative changes in the hypothalamus. The tumor cells were immunoreactive to ACTH, CRH, and the cleavage enzyme PC2. POMC messenger ribonucleic acid and PC2 messenger ribonucleic acid were detected in the tumor cells by an in situ hybridization method. Expression of PC2 was considered to induce hyperpigmentation by producing alpha MSH. Despite hypercortisolism and ectopic production of CRH by the tumor cells, hypothalamic CRH cells were not atrophic. This case is a good example to demonstrate the correlation between CRH and the hypothalamo-pituitary-adrenal axis as well as hyperpigmentation in Cushing's syndrome.

Potential of the histoculture drug-response assay to contribute to cancer patient survival.

The histoculture drug-response assay (HDRA) was recently evaluated in a retrospective clinical trial and was found to correlate to drug sensitivity, resistance, and patient survival. To further investigate the potential of HDRA to contribute to patient survival, 215 patients with gastric cancer from 45 medical centers were tested with the HDRA in a blinded study after resection of the primary lesion. One hundred sixty-eight patients received at least 20 mg/m2 of mitomycin C and a minimum of 30 g UFT, a mixture of tegafur and uracil at a molar ratio of 1:4, thereby making them eligible for the study. Of these cases 128 were evaluable by the HDRA. The evaluable patient tumors were tested by the HDRA with the [3H]thymidine incorporation end point measured by microautoradiography to be drug "sensitive" or "resistant." The in vitro conditions for distinguishing sensitivity and resistance that matched the response rates for historical controls for gastric carcinoma were 90% inhibition rate and 0.12 microgram/ml for mitomycin C and 70% inhibition rate and 1 microgram/ml for 5-fluorouracil, respectively. Most importantly in the blinded study, the overall and disease-free survival rates of the HDRA-sensitive group were found to be significantly higher than those of the HDRA-resistant group tested under the above conditions. The data further indicate the importance of three-dimensional tumor culture for obtaining accurate clinical information. The results demonstrate that the HDRA response correlates to patient survival, which suggests the potential of the HDRA to contribute to patient survival in gastric cancer when used prospectively.

[Periodical blood pressure variation during cardiopulmonary bypass--effects of cervicothoracic epidural anesthesia and phentolamine].

We studied the effects of cervicothoracic epidural anesthesia or intravenous phentolamine on periodical blood pressure variation during cardiopulmonary bypass in 12 adult patients undergoing open heart surgery under fentanyl anesthesia. Spontaneous periodical fluctuation of the blood pressure was analyzed by means of autoregressive power spectrum method. Amplitudes of the low frequency (0.02-0.15 Hz) component of the blood pressure variation amplitudes were calculated. The amplitudes decreased significantly 10 minutes after cervicothoracic epidural block with 15 ml of 2% lidocaine solution (P < 0.05), and after infusion of 0.4 mg.kg-1 of phentolamine (P < 0.05). Since amplitudes of the blood pressure variation were reduced by adequate epidural block or phentolamine, they are likely to reflect sympathetic vasomotor activity.

Two cases of Graves' disease with presentation of unilateral diffuse uptake of radioisotopes.

We present two cases of Graves' disease whose initial thyroidal scintiscan with 99mTcO4- (Case 1) and 123I (Case 2) showed unilateral diffuse uptake of radioisotopes. Initial diagnosis was possibility of malignancy in Case 1 and Graves' disease or Plummer's disease in Case 2. Both cases underwent right hemithyroidectomy. Histopathology of the resected thyroid gland in both showed hyperplastic columnar epithelium and infiltrative lymphocytes which was compatible with Graves' disease. Twenty seven (Case 1) and eight months (Case 2) after operation, both presented with thyrotoxic symptoms associated with enlarged left lobe, increased serum free thyroid hormone concentrations, suppressed TSH concentration, increased thyroidal 123I uptake in the remaining left lobe, and positive thyrotropin receptor antibodies. Both cases were successfully treated with methimazole. It was concluded that initial radioisotope uptake as well as scintigram in rare subgroup of patients with Graves' disease could be similar with that of non-autoimmune autonomous goiter (Plummer's disease).

Immunohistochemical comparison between anaplastic seminoma and typical seminoma.

In order to study the possible biological differences between anaplastic and typical seminoma, the following factors were studied in 11 cases of anaplastic seminoma and 15 cases of typical seminoma: mitotic activity, proliferating cell nuclear antigen (PCNA) expression, immunohistochemical analyses for cytokeratin, vimentin, placental alkaline phosphatase (PLAP), beta-human chorionic gonadotropin (beta-hCG), alpha-fetoprotein (AFP) and c-myc oncoprotein. Anaplastic seminoma was classified according to Mostofi's criteria, which is primarily based on the mitotic activity of the tumor. Mitotic activity was evaluated by both mitotic count and rate. Statistically significant correlations were observed between mitotic count and mitotic rate (R = 0.891), and between the mitotic count and PCNA labeling index (R = 0.792), in both typical and anaplastic seminomas. Immunostaining patterns for cytokeratin, vimentin, PLAP, beta-hCG, AFP and c-myc oncoprotein were not significantly different between typical and anaplastic seminoma. The present data indicated that no apparent clinicopathologic and immunohistochemical parameters discerning anaplastic seminoma from typical seminoma were present, when identifying anaplastic seminoma on the basis of high mitotic count. Anaplastic seminoma may therefore simply represent seminoma with high proliferative activity.

Immunohistochemical localization of gonadotropin-associated peptide (GAP) in the human hypothalamus.

GAP was immunohistochemically localized for the first time in the human hypothalamus. GAP-immunoreactivity was present in the cytoplasm of neuronal cells in the arcuate nucleus. GAP-immunoreactive nerve fibers were also present in the primary plexus around capillaries in the infundibular region. No GAP-immunoreactive neurons were detected in the paraventricular nuclei or supraoptic nuclei.

[A case of adrenal mixed tumor of pheochromocytoma and adrenocortical adenoma presenting diabetes mellitus and hypertension].

A 61-year-old woman with hyper-catecholaminemia and hyper-glucocorticoidemia due to a mixed tumor of the right adrenal gland is described. The patient, who had been medicated for hypertension since 1977, complained of thirst and general malaise in 1986. Body weight loss was remarkable. There was neither absolute truncal obesity nor moon face. In September 1986, her blood pressure was 180/110 mmHg and blood glucose level was 400mg/dl. Noradrenaline levels in plasma and in urine were remarkably elevated (1659 pg/ml and 120 micrograms/day, respectively), and adrenaline levels were also high (397 pg/ml in plasma, 34 micrograms/day in urine). Plasma cortisol and urinary 17-OHCS were elevated (39.2 micrograms/dl and 11.9 mg/day, respectively). Plasma ACTH was in the normal range (42.6 pg/ml). Oral administration of neither 1mg nor 8 mg of dexamethasone suppressed plasma cortisol or ACTH levels. Both 131I-metaiodobenzylguanidine and 131I-adosterol accumulated in the right adrenal gland. In 1987 the adrenal tumor (3.0 x 3.5 cm, 30 g) was resected. After the operation, her blood pressure and blood glucose level returned to normal, so that the medication became unnecessary. Histologically it was revealed that the tumor was a mixed adenoma consisting of adreno-medullary and cortical cells (corticomedullary adenoma). The literature on 21 cases of pheochromocytoma associated with Cushing's syndrome was briefly reviewed. Mathison (1969) reported the first case of a mixed tumor of adreno-medullary and cortical cells. So far as we know the present case is the second.

Early stage of development in testicular choriocarcinomas.

Choriocarcinoma is the most malignant among germ cell tumors in the testis. However little is known about the early stage of its development. To understand the development of testicular choriocarcinomas, twenty cases of testicular choriocarcinoma were studied histologically and immunohistochemically. It was found that in the early stage of development, choriocarcinomas imitate the morphologic or functional differentiation of normal trophoblasts. It was also found that some choriocarcinomas regress spontaneously in the early stage. The majority of choriocarcinomas seemed to develop by first going through the embryonal carcinoma phase. However, there were some choriocarcinomas that showed no relationship with embryonal carcinoma.

Melanin-concentrating hormone in the human brain.

The presence of human melanin-concentrating hormone (MCH) was studied in the human brain by radioimmunoassay and immunocytochemistry. Immunoreactive MCH concentrations in the human brain ranged from 0.07 to 19.7 pmol/g wet weight. High performance liquid chromatography of the hypothalamus showed a large immunoreactive peak in the position of human/rat MCH, which was eluted 9 min later than that of salmon MCH. Free-floating sections (40 microns) of the hypothalamus were immunostained. Positive MCH immunostaining was found in perifornical, tuberomammillary, and posterior nuclei. Numerous MCH-immunoreactive nerve fibers were observed throughout the hypothalamus. The presence of high concentrations of MCH in the human brain, in particular in the hypothalamus, suggests that MCH is a neurotransmitter, a neuromodulator, or a neurohormone in man.

Colocalization of corticotropin-releasing factor and vasopressin in the paraventricular nucleus of the human hypothalamus.

The anatomical relationship between corticotropin-releasing factor (CRF)-containing cells and arginine vasopressin (AVP)-containing cells in the human hypothalamus was investigated by immunocytochemistry. In the paraventricular nucleus of the hypothalamus (PVH), CRF-like immunoreactivity (CRF-LI) was present exclusively in parvocellular cells, while AVP-like immunoreactivity (AVP-LI) was present in both parvocellular and magnocellular cells. No CRF-immunoreactive neurons were observed in the supraoptic nucleus. All CRF-immunoreactive parvocellular cells in the PVH were also AVP immunoreactive. We confirmed the presence of AVP in the CRF-immunoreactive cells by using two kinds of anti-AVP antisera, one of which recognized the side chain of AVP while the other recognized the ring structure of AVP. Colocalization of CRF-LI and AVP-LI was observed not only in the same perikarya but also in the same nerve fibers of parvocellular cells. The present results raise the possibility that AVP and CRF may be secreted together into the human portal circulation.

De novo expression of aromatase in gastric carcinoma. Light and electron microscopic immunohistochemical and immunoblot study.

We have performed immunohistochemical and immunochemical studies of steroidogenic enzymes involved in estrogen biosynthesis in 30 cases of gastric carcinoma in order to investigate possible in situ production of estradiol (E 2) in carcinoma cells. Positive incidence of immunoreactivity for E 2, testosterone (T), cholesterol side-chain cleavage enzyme (P-450 scc) and aromatase (P-450 arom) were 17/30 (56.7%), 11/30 (36.7%), 3/30 (10.0%) and 23/30 (76.7%), respectively on light microscopy. Estrogen receptor (ER) immunoreactivity was not observed in any of the 30 cases examined. Normal gastric mucosa was negative for P-450 arom and P-450 scc. Examination of serial sections revealed that immunoreactivity of E 2 and P-450 arom were located in the same cells of carcinomatous glands. Immunoelectron microscopy demonstrated that E 2 and P-450 arom were located along the membrane and cisternae of smooth endoplasmic reticulum (sER). Western blot analysis showed one major band of 55 kDa of P-450 arom in the gastric carcinoma tissues examined. Retrospective analysis of immunohistochemistry of E 2 in 108 cases of gastric carcinoma revealed that E 2 positive carcinoma cases were likely to demonstrate better survival rate than negative cases. These results above strongly suggest that E 2 is produced by de novo expressed aromatase in gastric carcinoma cells and is possibly involved in the biology of gastric carcinoma cells.

Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare but an interesting adrenocortical disorder associated with ACTH-independent hypercortisolism. We have studied eight cases of the adrenals with PPNAD by immunohistochemistry of all steroidogenic enzymes involved in cortisol biosynthesis (P-45scc, 3 beta-HSD, P-450c21, P-45017 alpha, and P-45011 beta) and also by performing in situ hybridization of P-45017 alpha in seven cases in order to localize the sites of specific steroidogenesis in this unique disorder. Immunoreactivity of all the enzymes examined was intense in almost all of the cells in adrenocortical nodules, especially the cells with abundant eosinophilic cytoplasm in all the cases examined. The internodular cortex, which demonstrated atrophy in five cases, normal appearance in two cases and hyperplasia in one case, was negative for the enzymes with an exception of 3 beta-HSD. Hybridization signals of P-45017 alpha were condensed over the nodules in in situ hybridization study, suggestive of an increased production of the enzyme itself in cortical cells of the nodules. These results may be consistent with autonomous cortisol production by the nodular cells and indicate that almost all of the cells in the nodules produce cortisol, which can also explain the presence of hypercortisolism despite small sizes of adrenals in PPNAD. Immunoreactivity of steroidogenic enzymes is observed in a small cluster of cortical cells with abundant eosinophilic cytoplasm located at the zona reticularis but not in adjacent non-nodular cortex, which may support an abnormal development of the zona reticularis as a possible pathogenesis of this disorder.