Occult lymph node metastases detected by cytokeratin immunohistochemistry predict recurrence in node-negative endometrial cancer.

OBJECTIVE: Even after curative resection of early endometrial cancer, some patients die as a result of recurrence. We believe that these patients likely had occult lymph node metastases at the time of diagnosis. In an attempt to identify the responsible occult metastases, the clinicopathological significance of cytokeratin expression in lymph nodes with unconfirmed metastasis was evaluated retrospectively in patients with endometrial carcinoma. METHODS: We examined 304 pelvic lymph nodes and 46 primary tumors excised from 46 patients with endometrial cancer, including 36 with Stage I disease and 10 with Stage IIIc disease. Formalin-fixed paraffin-embedded tissue sections were stained immunohistochemically using antibodies against cytokeratin, CA125, and macrophage-related antigen. Sections were also stained with hematoxylin and eosin. RESULTS: In 10 patients with Stage IIIc disease, cytokeratin expression was detected in cells other than the tumor cells in all 13 lymph nodes with metastasis and also in 20 (30.3%) of 66 lymph nodes without metastasis. Cytokeratin expression was observed in 37 (16.4%) of 225 lymph nodes with unconfirmed metastasis, which were obtained from 14 of 36 patients with Stage I disease. Five of fourteen patients with lymph nodes expressing cytokeratin had recurrent disease in the pelvic cavity, while all 22 patients with unconfirmed cytokeratin expression in their lymph nodes showed no recurrence. Cytokeratin and CA125 were detected simultaneously on macrophages in lymph nodes. Cytokeratin expression in lymph nodes was closely related to lymph-vascular space involvement of the primary tumor, but was not related to either histological grade or depth of myometrial invasion. Multivariate analysis identified cytokeratin expression as an independent risk factor for recurrence in Stage I endometrial cancer. CONCLUSIONS: The immunohistochemical expression of cytokeratin in lymph nodes with undetected metastases predicts occult metastasis to these nodes and is a risk factor for recurrence in early-stage endometrial cancer.

The association of transforming growth factor-beta 1 with myometrial invasion of endometrial carcinomas through effects on matrix metalloproteinase.

OBJECTIVE: The association of transforming growth factor-beta 1 (TGF-beta 1) with a matrix metalloproteinase (MMP) and a tissue inhibitor of metalloproteinase (TIMP), as well as myometrial invasion of endometrial cancer was studied. METHODS: The effects of TGF-beta 1 on cellular invasiveness, gelatinase activity, and expression of TIMP-1 were examined in 2 endometrial adenocarcinoma cell lines, KLE and Ishikawa. Plasma was obtained from 8 endometrial cancer patients with Stage-Ia disease, from 6 with Stage-Ib disease, and from 4 with Stage-Ic disease, and the levels of TGF-beta 1 were measured by enzyme immunoassays. The immunohistochemical expression of MMP-9, TIMP-1, TGF-beta 1, and TGF-beta receptor Type I in tumor tissue from the same patients also was detected. RESULTS: Invasiveness, gelatinase activity, and the expression of TIMP-1 were higher in KLE cells than in Ishikawa cells, and they were increased by treatment with rTGF-beta 1. The expression of TGF-beta receptor Type I was higher in KLE cells than in Ishikawa cells, which were unresponsive to exogenous TGF-beta 1. The plasma levels of TGF-beta 1 were greater in Stage-Ib and Stage-Ic patients than in Stage-Ia patients. MMP-9 and TGF-beta receptor Type I were expressed mainly in tumor cells, while TIMP-1 and TGF-beta 1 were localized in both tumor epithelial cells and stromal cells. MMP-9 and TIMP-1 were expressed only in Stage-Ib and Stage-Ic patients, although TGF-beta 1 and TGF-beta receptor Type I were ubiquitous. CONCLUSIONS: Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF-beta 1 in an autocrine or paracrine fashion.

[Clinical studies of oral antiemetic drugs on delayed emesis induced by cancer chemotherapy].

The effects of oral antiemetic drugs on delayed emesis induced by emetogenic chemotherapy were studied in seventeen patients (43 courses) with gynecological malignancies. On day 1, all patients received intravenous granisetron (40 micrograms/kg) and methylprednisolone (250 mg/body) for the control of acute emesis 0-24 hrs after receiving CDDP or CBDCA. Then they received each oral maintenance drug (dexamethasone 4 mg/day, ondansetron 4 mg/day and metoclopramide 40 mg/day) for the control of delayed emesis from day 2 to day 5. Efficacy rates for delayed emesis were 82.4% in dexamethasone, 75.0% in metoclopramide and 50.0% in ondansetron. The complete response for delayed nausea was 88.5% in metoclopram ide, and the complete response for delayed anorexia of 64.7% in dexamethasone was higher than for other oral drugs. The results suggest the usefulness of oral antiemetic therapy of dexamethasone plus metoclopramide or ondansetron for delayed emesis induced by cancer therapy.

Component wave analysis of flash visual evoked potentials in preterm infants.

Waveform analyses of flash visual evoked potentials (VEPs) in neurologically normal preterm infants (postconceptional age 31-42 weeks) were performed using an autoregressive moving average (ARMA) model to interpret the evoked potentials as dynamic high-order responses to natural and experimental stimulation. Averaged VEP waveforms obtained were decomposed into 7-11 component impulse response waveforms by an ARMA component wave analysis. Based on the histogram of damping frequencies of different component impulse response waveforms, the waveforms were divided into 6 groups. All characteristic values in Group IV (6.5-12.0 Hz), such as the energy, the percent energy and the damping time of component impulse responses, changed significantly with increasing postconceptional age. Among the component impulse responses, neuronal networks generating impulse responses classified into Group IV appeared to be important to the developmental change of VEPs in preterm infants. The identification of an impulse response component with a dominant frequency which undergoes a well-identified change with age might prove to be a useful tool for discriminating between normal and abnormal changes in the VEP with age in preterm infants and could aid in the early diagnosis of abnormalities.

Does p53 overexpression cause metastases in early invasive colorectal adenocarcinoma?

OBJECTIVE: To find out whether p53 overexpression correlates with metastatic potential and other adverse prognostic factors in early invasive colorectal carcinoma and whether measurement of the expression of p53 protein could be helpful in the choice of treatment (endoscopic/local or radical resection). DESIGN: Retrospective study. SETTING: University hospital, Japan. SUBJECTS: Overexpression of p53 protein in the primary tumour was examined immunohistochemically in 50 patients with early invasive colorectal cancer. MAIN OUTCOME MEASURES: Differences in p53 overexpression between subgroups. RESULTS: Abnormal accumulation of nuclear p53 was detected in the primary tumour of 20 patients (40%) with early invasive colorectal cancer. We found p53-positive cells in 7 (78%) of 9 that had metastasised to regional lymph nodes or distant organs, or both, and in 13 (32%) of 41 that had not metastasised (p = 0.02). p53 Immunoreactivity was also present in 10 (71%) of 14 superficial (type II) lesions compared with 10 (28%) of 36 protruding (type I) ones (p = 0.009) and in 12 (57%) of 21 moderately differentiated adenocarcinomas compared with 8 (28%) of 29 well-differentiated adenocarcinomas (p = 0.045). There was no significant correlation between p53 overexpression and the depth of tumour invasion or angiolymphatic involvement. The p53-positive metastasising tumours had features that corresponded to those of early carcinoma arising de novo. CONCLUSION: Our results seem to support the postulate that p53 overexpression in early invasive colorectal carcinomas is associated with an increase in their metastatic potential.

Keio multicenter trial in high-dose interferon-alpha 2b treatment for chronic hepatitis C. Keio Interferon-alpha 2b Study Group.

The efficacy of two different high-dose treatment of IFN-alpha 2b was evaluated in this study. Serum hepatitis C virus (HCV) RNA levels were semi-quantified by simplified reverse transcription-polymerase chain reaction. Seventy-one patients with chronic hepatitis C received 10 million units of IFN-alpha 2b daily for 2 weeks or twice a week for 24 weeks. Alanine aminotransferase (ALT) levels overall normalized in 78.1% and 51.6% of the cases at the end of the therapy and 6 months after that, respectively. HCV RNA disappeared in 71.9% and 35.7% of the patients at the end of the therapy and 6 months after that, respectively. There was no significant difference between the 2 different regimes. The efficacy of the treatment was fair in cases in which the pretreatment level of the viral amount was low. The results of this study indicate that daily administration of IFN in the first 2 weeks during 6-month course does not increase the efficacy of the therapy in such a high-dose treatment regime.

Antibody-dependent cell-mediated cytotoxicity against cell lines generated by liver-specific idiotype-bearing antibody.

We produced a murine monoclonal antibody (mAb), designated H2-mAb, against a fractionated soluble phase of human liver homogenate which antibody reacted with human liver cells. A human antibody possessing the same idiotype as the H2-mAb, designated LSIA (liver-specific idiotype-bearing antibody), can be measured by a sandwich enzyme-linked immunosorbent assay, using the anti-H2 idiotype antibody. The serum level of LSIA in patients with histologically proven chronic hepatitis (CH) was significantly higher than that in healthy subjects and it was also higher than that in subjects with other diseases, including systemic lupus erythematosus. In a comparison between patients with CH type B and those with CH type C, there was no significant difference in serum levels of LSIA. It was possible to purify LSIA from the sera of patients with CH. The purified LSIA bound to the human cell lines Chang and HCC-M, derived from liver cells and a hepatoma respectively, but not to HeLa cells, a uterine carcinoma derivative. The reactivity of this mAb to HCC-M was weaker than that to Change. Moreover, the presence of LSIA caused an antibody-dependent cell-mediated cytotoxic challenge against Change cells in vitro.

Measurement of antibody titer to fowl pox virus by enzyme-linked immunosorbent assay.

The usefulness of the measurement of antibody titer to fowl pox virus (FPV) by enzyme-linked immunosorbent assay (ELISA) was evaluated in SPF chickens with or without inoculation with FPV. The optimum concentration of purified antigen was 10 micrograms/ml of protein. The absorbance at 492 nm was less than 0.10 in the chickens negative to FPV from 1 to 63 days old. By contrast, a higher titer was detected in SPF chickens with various FPVs inoculated into the wing web than in non-inoculated chickens. Moreover, there was no cross response to chicken sera immunized with Haemophilus paragallinarum, Marek's disease virus, Newcastle disease virus or infectious bronchitis virus. The titers increased after vaccination were not increased after subsequent challenge with virulent FPV. These findings suggested the usefulness of the measurement of the antibody response to FPV vaccine by ELISA.

Superficial-type adenomas and adenocarcinomas of the colon and rectum: a comparative morphological study.

BACKGROUND/AIMS: It has been uncertain whether colorectal carcinomas preferentially arise on preexisting adenomas or de novo. However, from a morphological viewpoint, it seems unlikely that pedunculated or exophytic malignant polyps progress to the deeply ulcerated advanced carcinomas usually found clinically. METHODS: The morphological features of 26 nonpolypoid, superficial-type colorectal tumors (17 adenomas and 9 adenocarcinomas) were compared to clarify the developmental route of colorectal carcinomas. RESULTS: The adenomas and adenocarcinomas were very similar in size and gross appearance; however, examination of the surface appearances of unsectioned tumors by dissecting microscopy was helpful for distinguishing the two. Histologically, no adenomatous tissue was found in any case of superficial-type adenocarcinoma. Five of the nine adenocarcinomas, even including those of small size, invaded the submucosal layer, and two showed lymph node metastasis. CONCLUSIONS: These findings suggest that superficial-type adenocarcinomas show rapid growth and aggressive behavior. We suggest that this type of carcinoma may not progress by the adenoma-to-carcinoma pathway but that it may arise from a very small superficial-type adenoma.

Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas.

Clinicopathological evidence is accumulating that a superficial-type (flat) colorectal tumor is a distinct neoplastic entity. To clarify the genetic characteristics of this tumor, we investigated the K-ras gene mutations and morphological features of 43 tumors of this type. A mutation of the K-ras codon 12 was detected in only 5 (16%) of 31 adenomas and 2 (17%) of 12 adenocarcinomas. The presence or absence of this mutation was not correlated with the tumor size or stage or with histopathological findings. None of these tumors had a mutation in codon 13 or exon 2, including codon 61. This low incidence of K-ras mutations (16%) suggests that superficial-type colorectal tumors are etiologically distinct from ordinary colorectal polypoid tumors and that there may be an alternative pathway of colorectal tumorigenesis.

Early invasive colorectal carcinomas metastatic to the lymph node with attention to their nonpolypoid development.

Clinicopathologic study of six cases of early invasive colorectal carcinoma metastatic to lymph node was performed in order to elucidate possible characteristics relating to the risk of metastasis, with particular attention to the growth pattern of the primary tumor. All of the cases had at least one of the well-known risk factors for lymph node metastasis, including moderately or poorly differentiated histologic characteristics, considerable degree of submucosal invasion, and lymphatic invasion. An interesting finding of the present study was the identification of a nonpolypoid growth pattern with no concomitant adenomatous tissue, which seemed to be different from that of "malignant polyps" of previously reported cases showing adenoma-carcinoma sequence. This unique growth feature was found in all of the cases. Therefore, in addition to the accepted risk factors, nonpolypoid growth pattern and absence of adenomatous component may be risk factors predictive of nodal metastasis in patients with early invasive colorectal carcinoma.

Growth potential of endometrial cancers assessed by a Ki-67 Ag/DNA dual-color flow-cytometric assay.

Ki-67 is a monoclonal antibody directed against a nuclear antigen present only in proliferating cells. To assess the growth potential of uterine endometrial cancer, the population of cells in proliferating cycle (%PC) was examined with Ki-67, using flow cytometry. The %PC of 27.18 +/- 12.00% in 22 endometrial cancers was significantly higher than the 14.5 +/- 5.94% found in 28 normal endometrial tissues. In premenopausal endometrial tissue, the %PC in the proliferatory phase was significantly higher than the %PC found in the secretory phase. In endometrial cancers, an increase of %PC was found in cases with deep myometrial invasion, and the %PC was elevated in groups containing histologically poorly differentiated types when compared to groups of well-differentiated and moderately differentiated types. Sorted cells reactive with Ki-67 antibody were large and had a high nuclear/cytoplasmic ratio. On the bases of these results, it was concluded that a Ki-67 Ag/DNA dual-color assay would be useful to examine the growth fraction in endometrial carcinoma and that an increased growth fraction was related to deep myometrial invasion or poorly differentiated types.

Immunohistochemical assessment of the growth fraction in cervical cancers using the monoclonal antibody Ki-67; relationship to the clinical stage, histologic type and DNA content.

To assess the growth potential of cervical cancer, cell populations in proliferating cycle (%PC) were examined by an immunohistochemical technique using the monoclonal antibody Ki-67. The %PC was 31.63 +/- 16.61% in 36 cervical cancers and was significantly higher when compared to the 7.8 +/- 3.81% found in 24 samples of normal ectocervical tissues. In cervical cancer tissues, the %PC increased in accordance with progression of the clinical stage of the disease, however, the %PC was not different among the various histologic types of invasive cervical cancers. The DNA index also increased in accordance with progression of the clinical stage of cervical cancer, however, there was no correlation between the %PC and the DNA index. These results suggest that the value of %PC obtained using the monoclonal antibody Ki-67 can be used as a parameter for evaluating the growth activity of cervical cancer and for predicting biological heterogeneity in a tumor.

[The clinical significance of thrombin-antithrombin III complex (TAT) and fibrinogen and fibrin degradation products (FDP) levels in ovarian cancer].

We measured the levels of thrombin-antithrombin III complex (TAT) and fibrinogen and fibrin degradation products (FDP) in 115 patients with gynecological malignancies (ovarian cancer 34, cervical cancer 34, endometrial cancer 47). These concentrations were compared to those in control groups of 15 patients with benign ovarian tumor. The levels of TAT and FDP were significantly higher in patients with ovarian cancer compared to the control group (both: p less than 0.01), and these levels were higher than in other gynecological malignancies. In stages I and II the positive rate of TAT and FDP (TAT greater than 3.0 ng/ml, FDP greater than 1.40 microgram/ml) in patients with ovarian cancer was higher than that in other gynecological malignancies. TAT and FDP were increased following cancer dissemination, and the recovery of coagulative and fibrinolytic factors (TAT, FDP) with effective treatment was correlated to the prognosis for patients with ovarian cancer. These levels had no correlation with the levels of CA125 and histological classification in patients with ovarian cancer. Accordingly, these results suggest that these changes in TAT and FDP may be useful, together with other clinical signs, in detecting early stage ovarian cancer.

Cytoarchitecture and intrafrontal connections of the frontal cortex of the brain of the hamadryas baboon (Papio hamadryas).

A study was made of the cytoarchitecture of the lateral and medial frontal cortex in the hamadryas baboon (Papio hamadryas). The frontal cortico-cortical connections of areas 46, 8, 6, and 4 were investigated by injection of wheat-germ agglutinine conjugated to horseradish peroxiase (WGA-HRP) into different regions of areas 46, 8, and 6. The lateral region of the frontal lobe of the baboon consists of broad areas of motor (area 4), premotor (area 6), and the dorsolateral prefrontal cortex, each of which is further divided into subdivisions with distinct cytoarchitectural features: areas 4a, 4b, 4c; 6 a alpha, 6a beta, 6a gamma, and 6b beta; 8A and 8B; 45; 46 and 46ps; 9; 10; and 12. Although the frontal cortex of the baboon brain exhibits the same basic cytoarchitectural features as the frontal corticies of the cercopithecus (campbelli?) (Vogt and Vogt, '19) or the macaque (Walker, '40; Barbas and Pandya, '87, '89), the baboon frontal cortex is very different from that of the macaque and cercopithecus in terms of cytoarchitecture: (1) the baboon frontal cortex has an additional area, termed here "6a gamma", within area 6, which has cytoarchitectural characteristics that are intermediate between those of areas 6 and 8; (2) the aggregation of giant pyramidal cells (greater than 50 microns in diameter) is found only in area 4a in the baboon, whereas such aggregates are found in areas 4a and 4b and, occasionally, in area 4c in the macaque; and (3) area 46 of the prefrontal cortex of the baboon can be subdivided into the cortex that surrounds the principal sulcus (area 46) and the upper and lower banks of the principal sulcus (area 46ps). Retrogradely WGA-HRP labeled cells and anterogradely WGA-HRP labeled terminals coexisted in the frontal cortex in a columnar fashion, indicative of a reciprocity among the connections. The frontal cortico-cortical connections of areas 46, 8, 6, and 4 in the hamadryas baboon were organized as follows: (1) areas 46, 8, and 6 were connected to one another, (2) area 4 was connected only to area 6, and (3) these connections showed a gross ventrodorsal topography: the ventral regions of each of areas 46, 8, and 6 were connected more strongly to the ventral than the dorsal regions of the other areas; the dorsal regions of each of areas 46, 8, and 6 were connected more strongly to the dorsal than the ventral regions of the other areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Anisakiasis of the colon: report of two cases with emphasis on the diagnostic and therapeutic value of colonoscopy.

Anisakiasis of the colon is a rare entity as compared with gastric anisakiasis, and its diagnosis is very difficult. We present here two cases--a 42-year-old woman and a 30-year-old woman--of anisakiasis of the colon treated by colonoscopic removal of the worm without surgery. The importance of colonoscopy for the diagnosis and treatment of this disease is briefly discussed.

Recombinant fowlpox viruses inducing protective immunity against Newcastle disease and fowlpox viruses.

The haemagglutinin-neuraminidase gene of Newcastle disease virus was inserted into a non-essential region of the fowlpox virus genome and expressed under control of the vaccinia virus 7.5 kDa polypeptide gene promoter. Immunization with the recombinant fowlpox virus elicited protective immunity in chickens against both virulent Newcastle disease and fowlpox virus infection.

[Long-term arterial infusion chemotherapy to the cancer patients].

Arterial infusion chemotherapy is an effective method for unresectable and recurrent cancer patients. But this method had some problems, in terms of efficacy, side effect and safety. Thus, we studied these problems in 33 patients. We inserted the tube into the proper hepatic artery in 25 cases and into the aorta in 8 cases, and used anticancer drugs, such as MMC, ADM and CDDP. In this study, no serial or severe side effects were noted. On the other hand, the obstruction of catheter and artery was found in a few cases. We encountered 2 cases of CR and 11 cases of PR. The effectiveness of this method is approximately 46.4%. These results suggested that long term arterial infusion chemotherapy for outpatients was a safe and effective method from the view point of quality of life in cancer patients.

[Study of intraarteric infusion chemotherapy with drug delivery system].

We have studied the effect of intraarteric infusion chemotherapy with missile chemotherapy, induced hypertensive chemotherapy and/or two-route infusion chemotherapy in 14 liver tumors (7 cases with liver metastasis from gastric cancer, 3 cases with liver metastasis from colonic cancer, 4 cases with hepatoma). Results indicated that PR in 6 (46.1%) out the 13 evaluated cases. The toxicity was not evident except for slight bone marrow depression with 5 cases and a low grade fever with 2 cases. These results indicate that intraarterial infusion chemotherapy with drug delivery system can be considered one of the treatment therapies available for a nonresectable tumor.