Functional role of ALK-related signal cascades on modulation of epithelial-mesenchymal transition and apoptosis in uterine carcinosarcoma.

BACKGROUND: Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs). Here we examined the functional role of the ALK gene in UCSs. METHODS: Regulation and function of the ALK gene were assessed using two endometrial carcinoma cell lines. Expression of ALK and its related molecules were also investigated using clinical samples of UCSs. RESULTS: In cell lines, ALK promoter activity was significantly increased by transfection of Sox11 and N-myc, which are known to contribute to neuronal properties. Cells stably overexpressing full-length ALK showed an enhancement of EMT properties mediated by TGF-ß1 and HGF, along with an increase in phosphorylated (p) Akt and nuclear p65. Overexpression of p65 also led to transactivation of Twist1 gene, known as an EMT inducer. Finally, treatment of the stable ALK-overexpressing cells with doxorubicin resulted in inhibition of apoptosis with progressive increase in the expression ratio of both pAkt and bcl2 relative to total Akt and bax, respectively. In clinical samples, strong cytoplasmic ALK immunoreactivity and mRNA signals without rearrangement or amplification of the ALK locus were frequently observed in UCSs, particularly in the sarcomatous components. Further, ALK IHC score was found to be positively correlated with Sox11, N-myc, Twist1, and bcl2 scores. CONCLUSION: ALK-related signal cascades containing Akt, NF-κB, Twist1, and bcl2 may participate in initial signaling for divergent sarcomatous differentiation driven from carcinomatous components in UCSs through induction of the EMT process and inhibition of apoptotic features.

Musculoskeletal Simulation for Determining Influences of the Magnitude of Sensory Noise and Stiffness on the Selection of Hip or Ankle Movement Strategies.

While standing, the elderly exhibit different move- ment behaviors compared to young people. However, the causes of these differences remain clear. The purpose of this study was to verify a hypothesis that only the magnitude of sensory noise and stiffness can reproducibly determine trends in the hip or ankle movement strategies. Simulations of postural control of a musculoskeletal model for three noise conditions and three stiffness conditions were performed. Variations in the angles of the hip and ankle suggested that the sensory noise amplitude had no influence on the selection. However, the ankle strategy tended to be selected with the increase of stiffness. Strategy shifts of elderly may be derived from other components; muscle weakness, increase of neurological time delay, or learning based on other evaluation index.

Genes encoding nitrilase-like proteins from tobacco.

Nitrilase (nitrile aminohydrolase, EC 3.5.5.1) catalyzes the hydrolysis of indole-3-acetonitrile (IAN) to indole-3-acetic acid (IAA). Arabidopsis thaliana genome has four nitrilase genes (NIT1, NIT2, NIT3 and NIT4). Three (NIT1, NIT2 and NIT3) of the four genes have high similarity. We have cloned two NIT4 homologs (TNIT4A and TNIT4B) from tobacco (Nicotiana tabacum). Genomic Southern hybridization, among other experiments, strongly suggests that tobacco has NIT4 homologs but not NIT1 to NIT3 homologs. Introduction of Arabidopsis NIT2 into tobacco conferred IAN-mediated growth inhibition, probably due to hydrolysis of IAN to IAA, while ectopic expression of TNIT4A had little effect on the sensitivity of transgenic plants to IAN. Nitrilase activity of TNIT4 proteins is discussed.

Papillary adenoma of type II pneumocytes might have malignant potential.

Papillary adenoma of type II pneumocytes is a rare tumour. It is considered to be a benign neoplasm and is derived from immature cells in the bronchioloalveolar epithelium, however, its biological nature has not been elucidated. We report a case of an adenomatous tumour; a papillary adenoma of type II pneumocytes, which we regard as possessing malignant potential. Light microscopically, as well circumscribed, papillary tumour of predominantly cuboidal cells resembling type II pneumocytes was found, but Clara type and ciliated cells were also present. Immunohistochemically, the tumour cells reacted positively with antibodies to surfactant apoproteins (A, B), carcinoembryonic antigen, cytochrome P-450 1A1-2 and 2B1-2. Ultrastructurally, many osmiophilic lamellar bodies and electron-dense granules were demonstrated. Semi-serial sections revealed signs of transbronchial dissemination and vascular invasion. Morphometry using 12-dimensional cluster analysis disclosed features of the tumour cells which resembled those of pneumocyte type II adenocarcinoma. These findings suggest that the present case has some malignant characteristics and originates from immature bronchiolar or alveolar cells, with a potential to develop into both type II pneumocyte and Clara cell type adenocarcinomas.

A case-control study evaluating occult blood screening for colorectal cancer with hemoccult test and an immunochemical hemagglutination test.

A case control study to evaluate the occult blood screening for colorectal cancer was conducted in a town where colorectal cancer screening had been performed by Hemoccult test during the early years and subsequently by an immunochemical hemagglutination test. All residents aged >/=40 years had been offered the annual screening. Case series consisted of 51 subjects with fatal colorectal cancer. Three controls per case were selected from the list of residents who were alive at the time of diagnosis of the corresponding case and had been living in the town, matched by gender and by age. The odds ratio (OR) of dying of colorectal cancer for those having their most recent screening histories with Hemoccult test or the immunochemical test during the preceding 1 year and 1-2 year segment before case diagnosis were 0.20 [95% confidence interval (CI): 0.08-0.49] and 0. 17 (95% CI: 0.04-0.75), respectively. The OR increased towards 1.0 as the number of years since the most recent screening increased. The OR of dying of colorectal cancer was calculated to be 0.19 (95% CI: 0.05-0.70) for those screened with the immunochemical test alone during the preceding 1 year after adjustment for previous screening histories with the Hemoccult test. Corresponding OR was 0.36 (95% CI: 0.11-1.17) for those screened with Hemoccult test during the preceding 1 year. These results suggest that screening for colorectal cancer by fecal occult blood testings or immunochemical test alone would reduce mortality and that efficacy of the screening would be higher for the immunochemical test than for Hemoccult test.

Varying grades of epithelial atypia in the pancreatic ducts of humans. Classification based on morphometry and multivariate analysis and correlated with positive reactions of carcinoembryonic antigen.

To establish an adequate statistical classification of epithelial atypia in the pancreatic duct, a total of 78 areas of duct epithelia with varying grades of atypia were subjected to nine-parameter morphometry and nine-dimensional multivariate cluster analysis. The material was derived from 53 pancreases resected for various epithelial tumors or acute or chronic pancreatitis. The result was correlated with immunohistochemical findings in which the pattern of intraepithelial distribution of carcinoembryonic antigen changed with the degree of ductal atypia. Finally, atypical cells classified by cluster analysis and immunohistochemistry were subjected to computer-aided three-dimensional mapping to visualize their distribution in the ductal tree. Cluster analysis demonstrated that the various epithelial forms were classifiable into Clusters 1, 2, and 3, representing ordinary epithelia and mild and severe dysplasias, respectively. The last category was created so as to include not only in situ and invasive carcinoma but the so-called borderline atypical lesions. The reproducibility of this classification was proved by two sorts of discriminant analyses. Also, the grades of atypia shown by the clustering proved to correlate with the reaction patterns for carcinoembryonic antigen. In the computer-aided three-dimensional mapping, severely dysplastic areas were shown surrounded by zones of mild dysplasia, justifying the assumption of a stepwise carcinogenesis in the pancreatic ducts.

Corneal arcus in Japanese family with type IIa hyperlipoproteinemia.

We examined ophthalmologically five affected members of a family with type IIa hyperlipoproteinemia. All of them had increased levels of cholesterol and low-density lipoprotein. Corneal arcus was found in three of the five members; a 50-year-old man, a 43-year-old woman and a 13-year-old boy. We believe that the corneal arcus begins at around 10 years of age in untreated type IIa hyperlipoproteinemia. Detection of corneal arcus at an early age is important to reduce cardiovascular complication in this disorder.

[Determination of yohimbine in serum by high performance liquid chromatography].

An automated method for determination of yohimbine (Yoh) in the serum was developed by means of column switching high performance liquid chromatography (HPLC). TSK-precolumn BSA-ODS and TSK-gel ODS-120T were used as a precolumn and analytical column, respectively. The wavelengths of detection were used at 280 nm (excitation) and 360 nm (emission). A 100 microliter serum sample is directly injected onto the precolumn. Yoh is then eluted within 30 min with an methanol-potassium phosphate buffer mixture. The analytical recoveries (99.3-110.4%), reproducibilities (within-run, C.V. less than 2.27%), and detection limit (0.80 ng/ml, S/N = 3) indicate that this system is suited for determination of Yoh. The five healthy volunteers received a single oral dose 10 mg of HYoh powder. The average of the maximal serum concentration and the area under the curve (AUC) from 0 to 4 h were 10.3 +/- 0.88 ng/ml and 19.70 +/- 0.87 ng.h.ml-1, respectively. The elimination rate constant (Kc1) was 0.52 +/- 0.03 h, and biological half-life (t1/2el) was 1.32 +/- 0.12 h.

[Pathological changes associated with topical chemotherapy of adriamycin for bladder cancer].

Since the study of intravesical instillation of thio-TEPA by Jones and Swinney, the method of topical chemotherapy with several anti-cancer drugs for superficial bladder tumors have been reported and it is now an established method of anti-bladder cancer treatment. Adriamycin is one of the most common topical agents against bladder tumor today. We studied the histopathological changes associated with the topical treatment in 26 cases of bladder cancer, all in which either TUR-Bt or cystectomy (partial or radical) had been performed after intravesical instillation of adriamycin. Transurethral biopsies of bladder tumor were done before the chemotherapy, and these findings were histopathologically compared with those of the surgical specimens. In 3 of the 26 cases, the tumors disappeared completely. In the other 23 cases, the main changes were: 1) cellular atrophy of tumor, 2) exfoliation, 3) interstitial hyalinous degeneration, 4) hemorrhage, and 5) dystrophic calcification. These changes are nonspecific of adriamycin, which seems to act as a toxic substance despite its potential activity to inhibit RNA replication.

[Surgical experience of ureteral varices].

Ureteral varices have been considered to be a relatively rare disease. Recently, reports on varices have been increasing with the development of X-ray examination, especially with the popularization of renal phlebography. We diagnosed left ureteral varices in 8 cases by renal venography. In 7 of these cases, gross hematuria was the main symptom, and varicocele accompanied it in the other case. In 7 cases of hematuria, surgery, ligation and removal of the varices was performed as palliative therapy for symptom; and, in all 7 cases, the gross hematuria disappeared in 7 to 18 months postoperatively. Ureteral varices should be classified into idiopathic and secondary types. In the case of idiopathic varices, a regional operation is sufficient to prevent venous reflux of the ureteral vein, and extensive surgery is needed in cases of collateral circulation on the venograms and secondary varices because of the unchangeable postoperative venous hypertension. We concluded that surgical treatment of ureteral varices is effective and is a useful palliative procedure in spite of the short postoperative follow up.

[Two cases of giant condyloma with malignant degeneration].

We report two rare cases of giant condyloma with malignant degeneration. Case 1: A 70-year-old male noticed a small nodule on his glans penis 5 years ago that had recently grown larger and larger. After admission, the biopsy of the mass revealed giant condyloma with malignant degeneration. Partial amputation of the penis was performed. Meatoplasty was performed by Whisnant 's procedure. Case 2: A 49-year-old male had received exstirpation of the condyloma of the penis eleven years earlier. Local recurrence and exstirpation were repeated. In June 1981, the mass was diagnosed as giant condyloma. In December malignant degeneration was suspected. In 1982, radiation therapy failed to reduce the mass and it made an ulcer on the penis. Total amputation of the penis was performed. The pathological diagnosis was invasive keratinizing squamous cell carcinoma. Meatoplasty was performed, applying Toyoda 's ureterocutaneostomy and Abercrombie 's procedure. Though giant condyloma is pathologically benign, in many cases it is clinically indistinguishable from squamous cell carcinoma and may have a malignant potential like our cases. It may be concluded that giant condyloma should be treated as malignant and that partial or total penectomy may be the best treatment because conservative treatment including local excision is not effective.

[Effectiveness of tiaprofenic acid on clinical symptoms of acute simple cystitis in women].

Acute simple cystitis is very easily cured by the proper use of an antibiotic. However, at times, such irritation symptoms in the bladder as micturition pain, pollakisuria and pyuria disappear. Consequently, medication to remove these irritation symptoms in the bladder at the earliest possible date, is required. However, there are no established standards for treatment in terms of the administration method and the administration period, etc. We gave a new non-steroid anti-inflammatory drug, tiaprofenic acid (SURGAM) to women suffering from acute simple cystitis who strongly complained of bladder irritation symptoms especially of micturition pain. The administration was carried out concurrently with an antibiotic, and its effectiveness was studied. As a result, micturition pain showed 86% improvement on the 1st day after starting administration, and it is thought that the concurrent use of this product with an antibiotic can probably remove the patients' complaints quickly and prevent the meaningless administration of antibiotics due to the persistence of symptoms and, subsequently, there is the possibility of shortening the period of administration.

[A study of transrectal aspiration biopsy of the prostate].

We studied 35 needle aspiration biopsies of the prostatic cancer to evaluate the reliability for screening, as compared with the transrectal or transperineal needle biopsy of the same patients. Eight specimens were unsatisfactory for cytological study, only 77.4% of the 35 aspirations being cytologically evaluable. False negative aspiration biopsies occupied 22.7%. Histopathological evaluation was possible for all of the needle biopsies and the false negative rate was 5.7%. To examine how accurately aspiration biopsy or needle biopsy reflects the true histologic grade of prostatic cancer, both the cytologic grade of the aspirations and histologic grade of the biopsies were compared with the grade of the prostatectomy specimens. The aspiration biopsy was undergraded in 2 (11.8%) overgraded in 2 (11.8%) and correctly graded in 14 (82.4%) out of 17 cases. The needle biopsy was undergraded in 1 (3.2%), overgraded in 2 (6.5%) and correctly graded in 28 (90.3%) out of 31 cases. There was no significant difference in grading accuracy rate between cytology of the aspiration and histology of the needle biopsy. We conclude that the cytological grade is as reliable as needle biopsy, but aspiration biopsy is not a more efficient screening test for prostatic neoplasms than needle biopsy, considering the higher percentage of speciments unsatisfactory for aspiration and false negative in this small series.

[Prostatic tissue levels of ceftizoxime].

The concentration of Ceftizoxime (CZX) was determined in the prostatic tissue and serum of 130 patients with benign prostatic hypertrophy. Two grams of CZX was given by intravenous injection prior to TUR. The mean value of CZX levels in prostatic tissue and prostatic level/serum levels ratio (p/s ratio) after administration were 47.2 +/- 2.8 micrograms/g, 49.1% at 30 minutes, 33.3 +/- 2.2 micrograms/g, 51.4% at one hour, 22.2 +/- 2.7 micrograms/g, 60.8% at 2 hours, 13.6 +/- 3.9 micrograms/g, 64.2% at 4 hours, 3.04 +/- 0.54 micrograms/g, 74.5% at 8 hours, respectively. In conclusion, the concentration of CZX in the prostatic tissues attained the minimal inhibitory concentration of 80% for the gram-negative bacteria, the excluding P. aeruginosa. Thus clinical effectiveness of CZX could be expected on bacterial prostatitis and bacterial infection after prostatic operations.

[Two cases of primary sclerosing lipogranuloma in scrotum--review of 63 cases reported in Japan].

We reported two cases of primary sclerosing lipogranuloma in the scrotum. We performed tumor resection in both cases, but in one of the two cases tumor recurrence was observed 7 days after the removal. Sixty-three cases have been reported in our country, and we discuss the diagnosis and treatment with reference to previous reports.

[Flow cytometric analysis of prostatic adenocarcinomas after hormone therapy].

A DNA ploidy pattern of prostatic adenocarcinoma was studied by flow cytometry using the formalin-fixed, paraffin-embedded tissues obtained from 65 patients. These patients received hormone therapy preoperatively. Forty cases (61.5%) showed a diploid pattern, and 25 (38.5%) an aneuploid pattern. Comparing this ploidy pattern with histological classification, the aneuploid pattern was found in 13 cases (52%) of poorly differentiated group, 12 cases (48.0%) of moderately differentiated group and 0 case (0%) of well differentiated group. Thus, rate of aneuploid pattern increased with an increase in the grade of malignancy. Five years survival rate was 62.6% in the diploid group while it decreased to 30.9% in the aneuploid group. There was a significant difference between the two groups. In 23 cases with stage D, the ploidy pattern of primary region could be compared with that of metastatic region (lymph nodes). The prognosis of patients who exhibited the aneuploid pattern in metastatic region was significantly worse than that of other patients. These data suggested that flow cytometric DNA analysis of prostatic cancer materials after hormone therapy also produces meaningful information in predicting the prognosis of prostatic cancer.

[Histological effects of short term endocrine therapy on prostatic cancer].

BACKGROUND: The objective of this study is to investigate the pathological changes which occurred in prostatic cancer shortly after the commencement of endocrine therapy. METHODS: Fourty-three patients underwent radical prostatectomy immediately after the short term endocrine therapy (treatment period was within one month) and the histological pictures of operative specimens were compared to those obtained from the pretreatment biopsy specimens. RESULTS: Degenerative changes of cancer cells, such as nuclear and cytoplasmic vacuole, collapse of the cytoplasm and the appearance of naked hyperchromatic nucleus were noticed after the short term endocrine therapy. Especially in the cases which were histologically evaluated to be poorly differentiated in the biopsy specimens, not only degenerative changes but also destruction of cancer nests caused by cell death were observed. The histological effects affected by short term endocrine treatment had no relation to the prognosis, but in the cases of stage D2, the pathological grade judged by post-therapeutic specimens were found to be useful for the prediction of prognosis. CONCLUSION: Endocrine therapy induces remarkable pathological changes in prostatic cancer within a very short time after beginning treatment.

[Morphometrical and statistical detection of cancer cells].

Morphometrical and multivariate statistical methods were applied to detection of carcinoma cells in cytologic studies. A total of 70 clumps of epithelial cells were selected from endometrial samples (10 adenocarcinomas, 4 hyperplasias and 56 normal controls), and their cytologic characters were reduced to a combination of five quantitative parameters (nuclear size, degree of anisokaryosis, nuclear from index, homogeneity of nuclear chromatin texture and regularity of cellular arrangement). The 5-variate cluster analysis demonstrated that the 70 clumps could be classified into three definite groups; A(17), B(41), and C(12). Group C, characterized by cells of large nuclear size, marked anisokaryosis, heterogeneous chromatin texture and irregular cellular arrangement, was derived from 10 samples of adenocarcinoma and 2 hyperplasia, while Groups A and B were not derived from any malignant samples. In conclusion, morphometrical-statistical classification can be of great aid in improving the cytodiagnostic validity and reproducibility.

[Arterial infusion of microencapsulated mitomycin C for the treatment of locally recurrent carcinoma of the pelvic cavity].

Ethylcellulose microcapsules of mitomycin C (MMC) were prepared. The potential therapeutic effects of intra-arterial infusion of the microencapsulated anti-cancer drugs were considered to be a function of microembolization and prolonged the drug action, that is, chemoembolization. A total of 19 patients with locally recurrent carcinoma of the pelvic cavity was subjected to transcatheter arterial chemoembolization with microencapsulated MMC. These included 7 bladder carcinomas, 7 prostatic carcinomas, 2 ureter carcinomas, 1 rectal carcinomas, 1 ovarian carcinoma and 1 cervical carcinoma. Thirteen patients had several distant or lymph node metastases. The single dose of MMC ranged from 10 to 40 mg and the total dose in each patient varied from 10 to 90 mg (mean 35 mg). The therapeutic response was evaluated by Karnofsky's criteria in terms of subjective and objective changes. Of 18 patients, 11 patients were assessed to category of I-A, B or C and 9 patients were survived over one years. Hematological toxicity occurred in 4 (22%) of 18 patients, but no treatment was needed for 3 of 4 patients. Local pain and high fever lasted more than one week were experienced in one patient. Skin necrosis lasting for a few months occurred in 10 (56%) of 18 patients. Surgical ligation of the gluteal arteries considerably prevented this painful condition. In conclusion, our clinical experiences indicate that chemoembolization is effective as a preoperative and palliative measure in the treatment of locally recurrent carcinoma of the pelvis and also helpful to control intractable symptoms such as hemorrhage or pain in patients with several metastases.

[The grading of cellular and structural atypia in cancer and related lesions using multivariate analysis].

In morphologically diagnosing cancer, pathologists' attention is focussed on the presence or absence of atypia, i.e., the form of cells and tissues deviated from the norm, and if it is present, on its grade. However, due to retarded development of techniques for the objective evaluation of its grade, separation of cancer from premalignant lesions still meets great ambiguity. Particularly, the boundaries of "dysplasia" with cancer and noncancerous lesions are not defined in clear morphological terms and are susceptible to a strong between-observers fluctuation. In this paper we outlined our recent efforts to establish in various organs a statistically most adequate, and therefore reproducible, classification of atypical lesions, resorting to morphometry and multivariate analysis. Two examples were given: atypia of the pancreatic duct epithelia as an object for the study of purely cellular abnormalities, and hepatocellular carcinoma, which required also to quantify the atypia of tissue structures, The classifications thus established proved to be the most adequate, in that, they closely reflected the grade of malignancy in a clinical as well as biological sense, as shown by the clear between-categorier differences in oncogene mutation, DNA ploidy pattern, the patients' prognoses, and so on.