Phosphatidylinositol-4-phosphate 5-kinase localized on the plasma membrane is essential for yeast cell morphogenesis.

Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2), an important element in eukaryotic signal transduction, is synthesized either by phosphatidylinositol-4-phosphate 5-kinase (PtdIns(4)P 5K) from phosphatidylinositol 4-phosphate (PtdIns(4)P) or by phosphatidylinositol-5-phosphate 4-kinase (PtdIns(5)P 4K) from phosphatidylinositol 5-phosphate (PtdIns(5)P). Two Saccharomyces cerevisiae genes, MSS4 and FAB1, are homologous to mammalian PtdIns(4)P 5Ks and PtdIns(5)P 4Ks. We show here that MSS4 is a functional homolog of mammalian PtdIns(4)P 5K but not of PtdIns(5)P 4K in vivo. We constructed a hemagglutinin epitope-tagged form of Mss4p and found that Mss4p has PtdIns(4)P 5K activity. Immunofluorescent and fractionation studies of the epitope-tagged Mss4p suggest that Mss4p is localized on the plasma membrane, whereas Fab1p is reportedly localized on the vacuolar membrane. A temperature-sensitive mss4-1 mutant was isolated, and its phenotypes at restrictive temperatures were found to include increased cell size, round shape, random distribution of actin patches, and delocalized staining of cell wall chitin. Thus, biochemical and genetic analyses on Mss4p indicated that yeast PtdIns(4)P 5K localized on the plasma membrane is required for actin organization.

Comparison of Tc-99m pertechnetate with Tl-201 and Ga-67 scintigraphy of malignant soft-tissue tumors.

Tc-99m pertechnetate scintigraphy was compared with Tl-201 chloride and Ga-67 citrate to evaluate the avidity of Tc-99m pertechtate for malignant soft-tissue tumors. Twenty-three patients with malignant soft-tissue tumors underwent scintigraphic studies. All 23 received Tc-99m and Tl-201, whereas 14 also were injected with Ga-67. In 21 (91%) of the 23 patients, Tc-99m accumulated extensively in the tumors. Tl-201 accumulated in 12 (52%) of the 23 tumors. Ga-67 accumulated in only 5 (36%) of the 14 tumors. The avidity of Tc-99m for myxoid tumors was markedly different from the other two agents. Tc-99m accumulated in all eight myxoid tumors, while neither Tl-201 or Ga-67 showed marked accumulation except for one patient with increased accumulation of Tl-201. This study shows that Tc-99m pertechnetate has the potential to localize malignant soft-tissue tumors and may be useful in the evaluation of these tumors.

Thallium-201 scintigraphy to assess effect of chemotherapy in osteosarcoma.

UNLABELLED: Imaging results in patients with high-grade osteosarcoma of the extremities were reviewed to determine whether scintigraphic appearance correlated with histologic response to preoperative chemotherapy. METHODS: Histologically, the percent tumor necrosis in specimens from 30 patients were classified into three grades: grade 1 = necrosis less than 60%, grade 2 = 60%-89% necrosis and grade 3 = diffuse necrosis greater than 90% based upon whole transverse sections. Scintigraphically, we analyzed 201TI uptake before and after preoperative chemotherapy. The changes in the tumor-to-background ratio were defined by an alteration ratio. RESULTS: Of the 11 patients with a grade 1 response, the ratio showed -67.1% +/- 45.4% (mean +/- s.d.). Of the 9 patients with a grade 2 response, the ratio showed 37.9% +/- 29.9% of the 10 patients with a grade 3 response the ratio showed 105.5% +/- 12.4%. The ratios correlated well with the histologic grades (p < 0.0001; analysis of variance). CONCLUSION: Thallium-201 scintigraphy accurately assesses the effect of chemotherapy on osteosarcoma.

[99mTc pertechnetate scintigraphy for malignant soft-tissue tumors].

The purpose of this study was to investigate the accumulation of technetium-99m pertechnetate (99mTc) in malignant soft-tissue tumors. Twenty-one patients with malignant soft-tissue tumors were subjected to 99mTc scintigraphic studies. In 19 of 21 patients (90%), 99mTc accumulated extensively in the tumors. 99mTc accumulation was especially thorough in all cases of MFH and liposarcoma. Therefore, 99mTc is useful for the local evaluation of malignant soft-tissue tumors.

Role of technetium-99m pertechnetate scintigraphy in the management of extra-abdominal fibromatosis.

The purpose of this study was to investigate technetium-99m pertechnetate (Tc-99m) as a tumor-scanning agent in patients with extra-abdominal fibromatosis, and to establish the sensitivity of this type of scintigraphy. Eleven patients with extra-abdominal fibromatosis were studied: all but one having postsurgical recurrences. Of the 11 patients, diagnosed histologically, 5 underwent repeated Tc-99m scintigraphic follow-up examinations. The injected 370 MBq Tc-99m gave us an early scintigram within 10 min and a delayed one 2 h later. For adequate comparison, the region of interest (ROI) of the scintigram was placed over the tumor. The tumor-to-background (T/BG) count ratio was computed. Extra-abdominal fibromatoses, even recurrences, were demonstrated scintigraphically in both the early and the delayed phase, in all 11 patients. The average T/BG ratio was 2.11 in the early scintigram and 2.15 in the delayed one. The sensitivity and the specificity were both 100%. Tc-99m scintigraphy has proved useful in detecting extra-abdominal fibromatoses and in the follow-up of patients.

On clinical usefulness of Tl-201 scintigraphy for the management of malignant soft tissue tumors.

The purpose of this study was to investigate Tl-201 as a tumor scanning agent in patients with malignant soft tissue sarcomas and to establish the sensitivity of this type of scintigraphy concerning local recurrences or metastases that may remain clinically suspected. Seventy-eight patients with malignant soft tissue sarcomas and 22 with benign soft tissue tumors were studied. Of these 78 malignant soft tissue sarcomas patients, the sensitivity of Tl-201 (81.2%) was higher than that of Ga-67 (68.8%). Thirty-three out of 78 patients received a total of 95 consecutive scintigraphic follow-up examinations. Therapeutic effects was assessed by comparing the results of Tl-201 examinations with the clinical findings. Of these 33 patients, the therapeutic effects observed were as follows: complete remission 1, partial remission 8, progress of disease 1, and no remarkable change 23. Tl-201 scintigraphy has proved itself very useful not only in clinically detecting the malignant soft tissue sarcomas and in assessing therapeutic effects on these diseases, but also in assessing the follow-up patients with malignant soft tissue sarcomas.

[Clinical usefulness of thallium-201 chloride in the diagnosis of tumor (II)--An evaluation in bone, soft tissue and mediastinal tumors].

The clinical usefulness of scintigraphy with thallium-201 (201Tl) chloride injection was evaluated in 79 patients with suspected bone, soft tissue or mediastinal tumors. No abnormal changes of subjective or objective signs and clinical test values were observed post injection. It is considered that 201Tl chloride is a safe radiopharmaceutical. In comparison with benign tumors, malignant tumors showed longer retention or more increased uptake of the 201Tl in the lesions on delayed images. The results suggested that the evaluation of changes of 201Tl uptake might be useful to some extent to differentiate malignant tumor from benign tumor. It is considered that 201Tl scintigraphy is useful for evaluating the location and extent of tumor and differentiating malignant from benign tumor.

Lymphoscintigraphy of head-and-neck cancer.

To achieve the visualization of regional lymph nodes by lymphoscintigraphy, 21 patients with head-and-neck cancer were studied with the aid of 99mTc-labeled rhenium sulfur colloid (99mTc Re). Four injection sites were selected; the injections were given into the subcutaneous tissue of the parietal area of 11 patients, into the submucosa of the retromolar area of 6 patients, into the subcutaneous tissue of the postauricular area of 2 patients, and into the thyroid glands of 2 patients. Lymphoscintigraphy was done three hours after the injection. The cervical regions were visible in 85.7% of the patients on the affected side and in 90.5% on the healthy side. The visualization comprised the following regions: submental, submandibular, deep cervical, accessory, and supraclavicular regions. In total, 102 nodes were visualized on the affected side (average 4.8 per patient) and 110 nodes in the healthy side (average 5.5). Histologically, 15 of 21 patients had lymph nodes metastases and 6 did not. Of these 21 patients, 66.7% (14/21) had confirmed lymph node metastases in the visualized regions. This technique appears to be a relatively easy and efficient method of imaging the regional lymph nodes in head-and-neck cancer both before treatment and after neck surgery.

Distribution and therapeutic effect of intraarterially transferred tumor-infiltrating lymphocytes in hepatic malignancies. A preliminary report.

Indium-111-labeled tumor-infiltrating lymphocytes (111In-TIL) were transferred as an intrahepatic arterial bolus to determine their in vivo distribution in patients with hepatic malignancies. In the in vitro culture system, TIL were expanded upon simultaneous stimulation by recombinant interleukin-2 (rIL-2) and immobilized anti-CD3 monoclonal antibody. This double activation led not only to a larger cell yield, but also to a significantly more dominant subpopulation with CD4+ phenotype than occurred with activation by rIL-2 alone. Accumulations of 111In-TIL in the liver were identified by scintigraphy in all of three patients, corresponding to the tumor localization by computed tomography. Such accumulation had persisted for at least 48 hours after infusion. After intraarterial chemoimmunotherapy that included TIL, two of three patients achieved a partial therapeutic response. The authors conclude that their method of culture and transfer can facilitate the accumulation of TIL at tumor sites, which may augment the antitumor effects of adoptive immunotherapy.

Lymph node metastasis in thoracic esophageal carcinoma.

Seventy-nine patients with thoracic esophageal carcinoma underwent transthoracic esophagectomy with neck, mediastinal, and abdominal lymphadenectomy. The operative mortality rate was 3.8%. Fifty-seven patients (72.2%) had metastasis in the lymph nodes. Though three patients with carcinoma classified as pTis had no positive nodes, nine (50.0%) of the patients with a pT1 carcinoma had positive nodes. The 5-year survival rate for 57 patients with positive nodes was 33.6%. Twenty-nine patients (36.7%) had positive nodes in the neck; 47 (59.5% ), in the mediastinum; and 33 (41.8%), in the abdomen. Their 5-year survival rates were 30.0%, 24.4%, and 38.4%, respectively. The differences between these rates were not statistically significant. These results indicate that the neck lymph nodes should be regarded as part of the regional lymph nodes and that esophagectomy with wide lymph node dissection improves the long-term survival of patients with thoracic esophageal carcinoma.

[Hepatoblastoma: clinico-radiological study of fifteen cases].

From January 1976 to October 1989, 15 patients with hepatoblastoma who underwent surgery at the National Cancer Center Hospital were evaluated by clinico-radiological techniques. Eight patients were boys and seven were girls; their average age was 3 years and 5 months. Abdominal mass or distention was initially noted in 12 patients. Alpha-fetoprotein level was extremely high (average, 327 micrograms/ml) in all cases but one. Hepatitis B surface antigen was negative in all cases. Tumors occupied mainly the right lobe of the liver in 67% of patients, and the mean tumor diameter was 11.1 cm. Of 15 hepatoblastomas, 10 were grossly classified as massive type and five as multinodular. Histopathological diagnosis was well differentiated (fetal type) hepatoblastoma in 10 patients and poorly differentiated (embryonal type) hepatoblastoma in five. Fibrous capsule was also recognized in eight. The noncancerous liver was normal in all cases. Ultrasonography (US) (n = 7 patients) demonstrated an inhomogeneous internal echo with well demarcated margin in five cases and without such margin in two. Nonenhanced CT (n = 6) showed an isodense or low density mass in all cases. Drip infusion CT (n = 5) revealed isodensity in the early phase. Dynamic CT performed in one patient showed a well enhanced mass that appeared hypervascular on angiography. Preoperative chemotherapy and radiation therapy provoked histological changes such as necrosis, fibrosis and calcifications. These changes were reflected on CT images. Both US and CT demonstrated the characteristic internal structure and gross appearance of hepatoblastoma.

Serious chemical sclerosing cholangitis associated with hepatic arterial 5FU and MMC chemotherapy.

A case of iatrogenic sclerosing cholangitis secondary to hepatic intra-arterial 5-fluorouracil (5FU) and Mitomycin C (MMC) chemotherapy is described. When any unexplained elevation of liver function results in alkaline phosphatase and bilirubin level, chemotherapy should be discontinued, and further examination carried out using ultrasonography, transhepatic cholangiography and endoscopic retrograde cholangio-pancreatography (ERCP). Although percutaneous transhepatic biliary drainage has been effective in some cases, in our case, the clinical course was irreversible and the patient died of hepatic failure and gastrointestinal bleeding. When clinical signs of hepatic dysfunction occur in the absence of tumor progression, iatrogenic sclerosing cholangitis must be suspected.

New simplified lymphoscintigraphic technique in patients with breast cancer.

To achieve the visualization of regional lymph nodes using lymphoscintigraphy, 100 preoperative patients with breast cancer were studied, with [99mTc]rhenium colloid having been injected into the periosteum of their ribs. In order to identify the exact location of the visualized nodes, the obtained lymphoscintigram was superimposed onto the patient's chest roentgenogram. The visibility of the internal mammary region was 91% on the affected side, and 93% on the healthy side, whereas the visibility of the axillary region was 85% and 86%, respectively. The injection resulted in simultaneous visualization of both the internal mammary and the axillary nodes: in our series, it meant the visualization of 82 patients (82%) on the affected side and 83 patients (83%) on the healthy side. Our technique appears to be a rather efficient method for imaging the regional lymph nodes in breast cancer patients.

Primary esophageal reconstruction after resection of the cancer in the hypopharynx or cervical esophagus: comparison of free forearm skin tube flap, free jejunal transplantation and pull-through esophagectomy.

Sixty-six patients with carcinoma of the hypopharynx or cervical esophagus received esophageal extraction and primary reconstruction. The methods of reconstruction were free forearm skin tube grafting, free jejunal transplantation and immediate pharyngo-gastrostomy after pull-through esophagectomy. Considering the postoperative complications of each method, free forearm skin tube transplantation is the safest, but it can only be used for a short defect of the esophagus. With pull-through esophagectomy, we are able to extract the whole esophagus and have no fear of leaving any remaining cancer in the thoracic esophagus, but the operative burden and the rate at which complications occur are higher. Free jejunal transplantation can be used for a short or long defect of the cervical esophagus with small operative burden. Among three methods of reconstruction, free jejunal transplantation is recommended for primary reconstruction of the cervical esophagus.

[Diagnosis and treatment of metastatic bone cancer of the extremities].

Eight hundred and thirty-six patients with metastatic cancer in the bone excluding autopsy findings, occurring between January, 1976 and December, 1985 were reviewed. The most frequent site of primary focus was the breast (33.2%), followed by lung (24.6%). Three hundred and forty-two patients (40.9%) were male and 494 (59.1%) female. Diagnosis of bone metastasis was based on abnormal accumulation in the bone scintigram and abnormal findings in the bone X-ray at the same site. Out of 836 patients, 285 had metastatic skeletal lesion including extremities and 43 had a solitary lesion of the extremity. The most frequent site of bone metastases in the extremity was proximal femur and involvement of the femur was 65.2% and that of humerus was 25.6%. The majority of the patients were treated by irradiation (24.9%), irradiation with chemotherapy and/or hormone therapy (21.1%), chemotherapy (18.6%) and chemotherapy with hormone therapy (17.2%), on the other hand, only 25(8.8%) of 285 patients were treated by surgical procedures. Cumulative survival rate after diagnosis of bone metastasis varied with site of primary focus and 5 year survival rate of all cases was 6.1%. Clinical courses after skeletal metastasis were separated into two types, and one type was breast type which was slow and other type was lung type which was rapid. The most important factor for the prognosis of the patients with bone metastasis is thought to be the primary site of origin.

Thyroxine-binding globulin as a marker of liver tumors.

This investigation was undertaken to evaluate the level of thyroxine-binding globulin (TBG) as a marker of liver tumors. TBG examination was performed on 42 patients with primary hepatocellular carcinoma (PHC) and 50 postoperative patients with metastases to the liver. alpha-Fetoprotein (AFP) and carcinoembryonic antigen (CEA) concentrations were determined at the same time. AFP was positive in 90.5% of the patients with PHC, and TBG was higher than normal in 69% of patients with PHC. In the 50 patients with liver metastasis, the TBG was higher than normal in 72%, and CEA was also increased in 64%. CEA was negative in 18 of 50 patients with liver metastasis. On the other hand, of the 18 CEA-negative patients, 14 (77.8%) had a higher than normal TBG concentration. This was a significant, but not specific, increase. Therefore, elevated TBG levels are a sensitive, although nonspecific, tumor marker to determine the presence of liver tumors, especially in cases of metastasis to the liver.