Pathology and pathogenesis of idiopathic portal hypertension with an emphasis on the liver.

Idiopathic portal hypertension (IPH) is characterized by a long-standing presinusoidal portal hypertension of unknown etiology in adults. Some unidentified agent(s) affect(s) the intrahepatic small portal veins or portal tracts. Immunological disturbance, thromboembolism, infectious etiology and/or increased fibrogenesis in portal tracts are suspected as being candidates for the primary agent(s). During the long clinical course of IPH, several pathological changes may occur, including subcapsular parenchymal atrophy, atrophy of the liver, portal and parenchymal fibrosis, and portal venous phlebosclerosis and thrombosis. The last-named of these lesions is mostly found in patients with a history of splenectomy. Subcapsular parenchymal and hepatic atrophy may result from a hepatocellular dropout via apoptosis or necrosis because of intrahepatic hemodynamic disturbances, particularly chronic portal venous blood insufficiency. Pericellular fibrosis and thin fibrous septa are also frequently found and associated with activated perisinusoidal cells positive for smooth muscle actin. At the same time, vague nodular hyperplasia of hepatocytes not surrounded by fibrous septa is not infrequently seen. It may resemble nodular regenerative hyperplasia, partial nodular transformation, or focal nodular hyperplasia. However, liver cirrhosis does not occur even at the terminal stage. Taking these findings into consideration, a new staging of IPH with a combination of hepatic parenchymal atrophy and portal venous thrombosis was proposed: non-atrophic liver without subcapsular parenchymal atrophy (stage I), non-atrophic liver with subcapsular parenchymal atrophy (stage II), atrophic liver with subcapsular parenchymal atrophy (stage III), and portal venous occlusive thrombosis (stage IV). IPH livers are likely to progress from stage I to stage III. Stage IV, which occurs relatively late, has a poor prognosis. This staging is applicable to clinical and autopsy cases without any histological data.

Alpha-Fetoprotein-producing esophageal adenocarcinoma: report of a case.

Alpha-fetoprotein (AFP)-producing esophageal tumors are extremely rare. We report herein the case of a 51-year-old man found to have an AFP-producing adenocarcinoma arising from esophageal proper mucosa. The patient presented for investigation of dysphagia, and esophagogram and endoscopy revealed a lesion about 2 cm in size with a depressed center surrounded by low nodular protrusions in the lower esophagus. The preoperative serum AFP concentration was elevated to 52.4 ng/ml. A subtotal esophagectomy was performed, and macroscopic examination of the resected specimen revealed a superficial protruding lesion. Histopathological studies showed a poorly differentiated adenocarcinoma with a single lymph node metastasis. The tumor had infiltrated the submucosal layer, but there was no evidence of lymphatic or venous invasion. Immunohistochemical study revealed tumor cells positive for AFP. There were no findings of Barrett's epithelium or any mucosal changes due to reflux esophagitis. An elevated AFP level 2 years after the operation led us to suspect tumor recurrence; however, diagnostic imaging studies showed no evidence of a recurrence or metastases. The serum AFP levels responded well to chemotherapy with transient decreased levels, but continued to rise until finally, 5 years after the operation, adenocarcinoma cells were detected in the pleural effusion. Thus, careful monitoring of the serum AFP levels at regular intervals could be a useful marker to indicate recurrence of esophageal carcinoma.

Expression of cell cycle regulatory proteins in the multistep process of oesophageal carcinogenesis: stepwise over-expression of cyclin E and p53, reduction of p21(WAF1/CIP1) and dysregulation of cyclin D1 and p27(KIP1).

AIMS: Cell cycle regulatory proteins were analysed by immunohistochemistry in order to clarify how their expression changes with the degree of atypia as oesophageal surface squamous epithelium progresses from normal mucosa, through reactive change, low-grade dysplasia, and high-grade dysplasia to mucosal invasive carcinoma. METHODS AND RESULTS: Immunostaining for cyclin D1, cyclin E, p21, p27, p53 and Ki67 proteins was performed using 22 normal mucosa, 17 reactive change, 22 low-grade dysplasia, 15 high-grade dysplasia and 22 mucosal invasive carcinoma specimens. Normal mucosa, low-grade dysplasia and high-grade dysplasia samples were taken from patients without any oesophageal invasive carcinoma by endoscopic biopsy or endoscopic mucosal resection, and reactive change and mucosal invasive carcinoma were obtained from oesophagectomy material. Stepwise over-expression of cyclin E (P < 0.0001) and p53 (P < 0.0001), reduction of p21 (P=0.0189) and dysregulation of cyclin D1 and p27 were observed in the multistep process of oesophageal carcinogenesis. Significant differences in expression of p27 (P < 0.0001), p53 (P=0.0299) and Ki67 (P=0.0101) were observed between reactive change and low-grade dysplasia. Furthermore, expression of cyclin D1, cyclin E, p27 and p53 in mucosal invasive carcinoma were significantly different from those in high-grade dysplasia (P=0.0079, P=0.0237, P=0.0042 and P= 0.0299, respectively). CONCLUSIONS: Cell cycle regulatory proteins, cyclin E, p53 and p21 show stepwise over-expression or reduction with progression of oesophageal carcinogenesis, correlating with the increased cell proliferation observed with Ki67 labelling. We conclude that immunohistochemical analysis for p27, p53 and Ki67 is practically useful for the discrimination between low-grade dysplasia and reactive change. Cyclin D1, cyclin E, p27 and p53 help to distinguish high-grade dysplasia from mucosal invasive carcinoma.

Benign esophageal schwannoma: report of a case.

We report herein the case of an otherwise asymptomatic 62-year-old woman who was found to have an incidental esophageal lesion during endoscopic follow-up of an unrelated disorder. An esophageal submucosal tumor was diagnosed, and the patient was subsequently monitored on a regular yearly basis. As the diameter of the tumor doubled over a 4-year period, the possibility of a malignant lesion could not be excluded, and she was admitted to our hospital for further investigations. Esophagography, endoscopy, endoscopic ultrasonography, and computed tomography confirmed a submucosal tumor, 35 mm in length, in the thoracic midesophagus. A leiomyoma or leiomyosarcoma was suspected based on the known incidence of such tumors, and tumor enucleation was performed. Gross inspection revealed a solid tumor arising from the wall of the esophagus. Histopathologic examination showed intertwined bundles of spindle cells with spiral-like proliferation, and immunohistochemical studies were positive for S-100 protein, whereby a diagnosis of esophageal schwannoma was established. The patient experienced no postoperative complications, and her clinical course to date has been satisfactory. To date, 2 years 8 months after surgery, she has shown no sign of tumor recurrence and remains in good health.

Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepharanthin.

Suppressive effects of Cepharanthin (CE) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) production followed by liver injury were investigated. Pretreatment with CE reduced limulus activity of LPS. Intraperitoneal treatment with CE 10 min before an i.v. challenge of LPS resulted in protection from LPS lethality in D-galactosamine (GalN)-sensitized BALB/c but not in C57BL/6 and C57BL/10ScSn mice. Treatment with CE before the LPS challenge significantly reduced serum TNF levels in a dose-dependent manner. The suppression was most effective when CE was administered 10 min before the LPS challenge. Increased levels of enzymes released from hepatocytes into the circulation, as a result of LPS-induced liver injury, were reduced by CE administration. Histological evaluation demonstrated that massive cell infiltration after severe injury developed in liver of mice injected with LPS plus D-GalN unless they were pretreated with CE. Apoptotic cells decreased by treatment with CE. Treatment with CE retarded lethal shock induced by an infection with 10(8) CFU Salmonella typhimurium deltaaroA mutant. These results suggest that action of CE is initiated through suppression of LPS-induced TNF production.

Primary squamous cell carcinoma of the endometrium.

A rare case of primary squamous cell carcinoma of the endometrium, probably originating from adenomyosis, is presented. A 58-year-old Japanese woman was referred to Kitasato Institution Medical Center Hospital to explore the cause of her postmenopausal bleeding. The endometrial cytology specimen obtained with the Endocyte (an device for endometrial check up) showed cells suggesting well differentiated squamous cell carcinoma. The patient underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy, followed by postoperative radiation therapy. The dissected uterus revealed keratinizing-type squamous cell carcinoma localized in the fundal portion of the uterine body and invading deeply into the myometrium, coexistent with a large area of adenomyosis with a transitional area to carcinoma. The residual endometrium was atrophic. There was no atypical finding in the cervix. Human papilloma virus DNA was not detected. The carcinoma recurred 26 months after the surgery, and the patient died of the disease.

Absence of human papillomavirus genomic sequences detected by the polymerase chain reaction in oesophageal and gastric carcinomas in Japan.

AIMS: To estimate the occurrence of human papillomavirus (HPV) infection in oesophageal or gastric carcinomas in patients in Japan. METHODS: 103 oesophageal and 99 gastric carcinomas were investigated by polymerase chain reaction (PCR) assays using two consensus (targeting either the L1 or the E6-E7 regions) and two type specific (type 16 and 18) primer sets. A beta globin gene specific primer set was also applied to examine the quality of the extracted DNA. RESULTS: Amplification of beta globin gene was clearly visible in 92 (89.3%) of the 103 oesophageal, and 89 (89.8%) of the 99 gastric carcinoma specimens. However, the entire series of tumour DNA was negative for HPV sequences by PCR assay using all four primer sets. CONCLUSION: HPV is not likely to be involved in oesophageal or gastric tumorigenesis in Japanese patients.

Expression of bcl-2 protein in esophageal squamous cell carcinomas and its association with lymph node metastasis.

BACKGROUND: Recent studies on the role of bcl-2 in malignant tumors have suggested its prognostic significance. The goals of the current study were to determine any correlation between bcl-2 expression in esophageal squamous cell carcinoma and histopathology, lymph node metastasis, and clinical variables, and to assess its applicability as a parameter for prognosis. METHODS: Immunohistochemical staining for bcl-2 (clone 124) was performed on archival material from 105 esophageal squamous cell carcinomas. The results were compared among patient subgroups. RESULTS: bcl-2 was expressed in 58% of esophageal carcinomas, demonstrating positive correlations with a lack of keratinization and an early stage of disease. Lymph node metastasis was significantly less frequently observed in the subset of early stage carcinomas with bcl-2 staining. Univariate analysis revealed significantly longer disease free survival in patients with bcl-2 positive carcinomas than in those bcl-2 negative. bcl-2 expression did not have independent prognostic value in a multivariate survival analysis. CONCLUSIONS: bcl-2 is frequently expressed in esophageal carcinomas, and this expression is positively associated with nonkeratinization and an early stage, whereas it is negatively linked with lymph node metastasis and may indicate a favorable prognosis.

[A case of solitary metastasis from renal cell carcinoma to the thyroid gland].

A case of solitary metastasis with renal cell carcinoma to the thyroid gland is presented. The patient was a 54-year-old man found to have an abnormal mass in the neck. He had a past history of radical nephrectomy orignating from the right renal cell carcinoma 5 years earlier (pT2N0M0, G2 > 3, alveolar type, clear cell subtype). Ultrasonography revealed a tumor mass in the right hemithyroid gland. Right hemithyroidectomy was performed on April 19, 1995. Histopathologically, the removed thyroid tumor showed clear cell carcinoma. The possibility of a primary thyroid tumor was ruled out by immunohistochemical thyroglobulin staining, and the present case was thus diagnosed as of metastatic thyroid tumor of renal cell carcinoma. The present case is the 12th case of thyroid solitary metastasis of renal cell carcinoma reported in Japan to date.

Correlation of apoptosis with tumour cell differentiation, progression, and HPV infection in cervical carcinoma.

AIMS: To clarify the significance of apoptosis in the progression of uterine cervical neoplasias, including cervical intraepithelial neoplasia (CIN), microinvasive carcinoma (MIC), and invasive squamous cell carcinoma (ISCC) categories, in relation to cell proliferation and human papilloma virus (HPV) infection. METHODS: Forty six cases of CIN I/II, 75 of CIN III, 16 of MIC, and 44 of ISCC were examined using formalin fixed and paraffin wax embedded samples. The TdT mediated dUTP-biotin nick end labelling (TUNEL) method for detection of apoptotic cells was performed along with Ki-67 immunohistochemistry. Presence of HPV-DNA was confirmed by PCR-RFLP assay. RESULTS: Apoptotic labelling indices, calculated after counting positive nuclei among at least 2000 nuclei, showed significant positive correlation with histological malignant grading in CIN and tumour cell invasion into stroma. In contrast, similar Ki-67 labelling index values were found in CIN, MIC, and ISCC. Although HPV-DNA was detected in 35/46 CIN I/II (76.1%), 53/74CIN III (71.6%), 9/16 MIC (56.3%), and 36/44 ISCC (81.8%), there was no apparent relation with the apoptotic labelling indices. CONCLUSIONS: Apoptosis in cervical neoplasias may be closely related to tumour cell differentiation and progression. It also seems unlikely that HPV itself is directly related to pathways regulating apoptosis.

Apoptosis and cellular proliferation in oesophageal squamous cell carcinomas: differences between keratinizing and nonkeratinizing types.

To assess cell death and cellular proliferation activity, the apoptosis index, the Ki67 proliferative index and overexpression of p53 protein were evaluated in 69 oesophageal squamous cell carcinomas (ESCC), all surgically resected from Japanese patients. Apoptosis was examined by Gavrieli's method in histological sections, and proved to be significantly related to keratinization and ESCC progression. Overall labelling indices were 15.68 +/- 4.04 (positive/1,000 nuclei) and 6.79 +/- 0.64 respectively, in keratinizing and nonkeratinizing types. The apoptosis labelling index increased, especially in keratinizing lesions, from 4.50 +/- 0.59 with cancer invasion to mucosa through 11.46 +/- 2.70 with involvement of the submucosa up to 21.18 +/- 3.72 in cases of penetration to the muscularis propria or adventitia. The relationship between apoptosis, Ki67 scores and p53 expression was determined in identical cancer nests on serial sections. An inverse correlation was shown between the apoptosis score and the Ki67 score in both keratinizing and nonkeratinizing types. There was no significant correlation between apoptosis score and p53 expression, either overall or separately in keratinizing or nonkeratinizing types of ESCC. Our results suggest that a mechanism of induction of apoptosis similar to that operating in normal epidermis acts in keratinizing ESCC, and that as tumour volume increases, single cell death becomes more frequent.

Epidemiological and clinical features of Budd-Chiari syndrome in Japan.

The Japanese Ministry of Health and Welfare Research Committee on Aberrant Portal Blood Flow carried out an epidemiological survey and clinical study on Budd-Chiari syndrome in 1990. In the primary survey for determining the prevalence of the disease, a questionnaire was sent to all major hospitals throughout Japan and 160 cases seen in 1989 were compiled. More epidemiological details were obtained in 87 of these 160 cases. The number of patients with Budd-Chiari syndrome in this country was estimated to be about 300 (prevalence of 2.4/million) with about 20 new cases occurring every year. In the clinical study, 157 authentic cases of Budd-Chiari syndrome studied in 15 years (1975-89) were analyzed. There were 87 males (average age, 36.4 years) and 70 females (46.5 years), and the average period from the likely onset to the first medical consultation was 6.6 years, suggesting that these patients were mostly chronic cases. The main clinical features were hepatomegaly, leg edema, ascites and venous dilatation over the trunk. Abdominal pain was recorded in only four (2.5%). There were 16 (10.2%) with known identifiable etiologies. Of the patients 93% showed an obstructing lesion of various thickness in the hepatic portion of the inferior vena cava. Only nine (5.7%) had hepatic vein obstruction without caval lesions. Thus, the majority of Budd-Chiari syndrome patients in Japan are idiopathic, having an obstructing lesion in the inferior vena cava. The main causes of 33 deaths (21%) were liver failure, variceal bleeding and hepatocellular carcinoma. Hepatocellular carcinoma occurred in 10 (6.4%) in the 15-year period. However, the incidence of Budd-Chiari syndrome among all cases of hepatocellular carcinoma was less than 1% in the survey made by the Liver Cancer Study Group of Japan.

Histopathological study of intrahepatic aberrant vessels in cases of noncirrhotic portal hypertension.

Aberrant vessels, which are defined as dilated blood vessels immediately adjacent to the peripheral portal tract, appear under conditions of extrahepatic portal obstruction and nodular regenerative hyperplasia as well as idiopathic portal hypertension. Our study was undertaken to compare their morphological aspects in these three disease cases. Aberrant vessels were found in 84% of cases of idiopathic portal hypertension, 67% of cases of extrahepatic portal obstruction infantile type, 78% of cases of extrahepatic portal obstruction adult type and 83% of cases of nodular regenerative hyperplasia. They were divided into three types: type I--no communication with the portal vein, the lumen of which is normally open; type II--communication with the portal vein; and type III--no communication with the portal vein, which is occluded. The most common types of aberrant vessel were type III in idiopathic portal hypertension (51%), type I in extrahepatic portal obstruction infantile type (46%), type II in extrahepatic portal obstruction adult type (43%) and type III in nodular regenerative hyperplasia (45%). Serial sections revealed transition between types I, II and III, at frequencies between types II and III, types I and II, and types I and III of 35.7%, 33.7% and 30.6%, respectively. Aberrant vessels demonstrated the same immunoreactivity as portal veins for collagen type IV, laminin, factor VIII and ulex europaeus agglutinin-I. They were concluded to arise from the vasa septalis or inlet venules, which would be used as intrahepatic shunts draining portal blood flow blocked by stenosed portal veins. Increased portal pressure would be expected to enhance development of aberrant vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

[Bronchial carcinoid tumor with multiple brain metastasis].

Carcinoid tumor is regarded as a tumor with low grade malignancy, mostly originating from the gastrointestinal tract with little danger of metastasis. The authors encountered a very rare case of bronchial carcinoid tumor that had multiple metastasis to the intracranial space. The characteristics of radiological and hormonal examinations of this tumor are reported and discussed. The patient was a 73-year-old woman who gradually developed unsteadiness in walking and somnolence in daytime one month prior to admission. Those symptoms were aggravated and she began to vomit. On admission, neurological examination showed slight ataxia of left upper and lower extremities and dominant truncal ataxia. Chemical and hormonal examinations of blood and urine showed, gastrin was 230 pg/ml (37-172), ACTH was 67 pg/ml (< 60), serotonin was 565 ng/ml (53-200), and urinary 5-HIAA was 9.9 mg/day (0.8-4.8). Tumor markers (CEA, AFP, HGG, NSE) were all negative. Radiological examinations (chest X-P, CT scan) of her lung demonstrated a 3 x 3 cm tumor mass adjacent to the hilum of the left lower lobe. CT-scan of the head demonstrated cystic tumor in the vermis of the cerebellum (3 x 3 cm), the right posterior parietal lobe and the right temporal lobe. The wall of each tumor was enhanced by contrast medium. T1 weighted MRI demonstrated the walls of cystic tumors as iso intensity and the contents as low and high intensity with niveau formation. Little edema was recognized around the tumors. The wall of each cystic tumor was enhanced by Gd-DTPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical study of thymic B cells in myasthenia gravis and ulcerative colitis.

The phenotypes of B cells and dendritic cells in human thymus were examined immunohistochemically using various monoclonal antibodies. Normal thymus contained a few B lymphocytes recognized by CD19, CD20, CD22, L26 and LN-2, which were localized in the medulla. These B cells were negative for LN-1, L30 and CD11c (Leu M5). Activated B cells recognized by CD23 (B6) and L29 antibodies were not present in normal thymus. Dendritic cells stained by CD11c were weakly positive for L26 and CD20. There was no difference in the distribution of dendritic cells between normal thymus and thymus from the patients. In the thymus from patients with myasthenia gravis, numerous B cells were demonstrated in the medullary area and lymphoid follicles. Activated B cells were seen mainly in the germinal center of lymphoid follicles and were scarce in the medulla. Many B cells were also found in the medulla and lymphoid follicles of the thymus from patients with ulcerative colitis. However most of those B cells were not activated, even in the lymphoid follicles. These results suggest that thymic B cells may contribute to the induction of immune abnormalities in patients with myasthenia gravis and those with ulcerative colitis, however, the mechanisms by which thymic B cells participate in the pathogenesis of these two diseases would be different.

[Brain metastasis of testicular yolk sac tumor with massive hemorrhage: case report].

A rare case of yolk sac tumor of the testis which metastasized to the brain parenchyma with repeated intra-tumoral hemorrhage is reported. The patient was a 38 year-old-man admitted to the Department of Urology with the chief complaint of painless swelling of the left testis for a period of one year. He underwent orchiectomy with highly suspected malignancy, because chest X-ray examination demonstrated metastatic coin lesions. Pathological examination of the operated specimen showed typical yolk sac tumor of the testis. Postoperative clinical course was uneventful. However, on the 4th postoperative day, the patient suddenly fell into a coma with left hemiplegia and dilated right pupil. CT scan demonstrated an intra-parenchymal hematoma in the right parietal lobe. Emergency craniotomy with evacuation of the hematoma clot was performed. Histological examination of the hematoma clot showed the same histology (yolk sac tumor) as found in the operative specimens of the left testis. After regaining full consciousness, chemotherapy (PEB and PVB) was started. It was effective to reduce the high serum AFP level and the size of the metastatic coin lesions in the lung. However, it was not effective in preventing brain metastasis. He again relapsed into coma due to a newly-developed intra-tumoral hematoma with multiple brain metastasis and died 6 months after the orchiectomy. Yolk sac tumor of the testis is rare in adult Japanese and there is no previous report of its metastasis to the brain parenchyma with intratumoral hemorrhage. We have reviewed the previously reported cases and discussed the brain metastasis of this malignant urogenic tumor.

[Primary intracranial melanoma: a case report].

A rare case of primary intracranial melanoma is presented in a 34-year-old man with initial symptoms of persistent headache. In magnetic resonance imaging(MRI), this case had all the characteristic findings of intracranial melanoma which had been reported previously. In 123I-iodoamphetamine-single photon emission CT (123I-IMP-SPECT), abnormal accumulation of 123I-IMP was recognized in early and late phase imaging, which was very specific to the lesion. This is the first report of 123I-IMP-SPECT performed on a primary intracranial melanoma. Tumor mass originated from pia mater was surgically resected, but the dissemination of tumor cells was recognized macroscopically. Pathological examination of the specimen showed very little malignant changes of melanoma cells, which was in contrast to the previous reports. Although, no standard chemotherapy of the primary intracranial melanoma has been established, DAV therapy to the dissemination of tumor cells into the subarachnoid space, and intravenous administration of interferon-beta were performed in this case. Methods of differential diagnosis and treatments of primary intracranial melanoma are reviewed and discussed.

[Pure yolk sac tumor of the testis with brain metastasis: report of an adult case].

Herein we report an adult case of pure yolk sac tumor with brain metastasis. The patient was a 37-year-old male who presented with indulation of his left scrotum for 10 months. The plain computerized tomographic (CT) scan on entry demonstrated tumor metastasis to his lung and liver and serum alpha-fetoprotein (AFP) level was 786 ng/ml. Five days after admission, he developed hemiplegia secondary to the cerebral metastasis and hemorrhage. After chemotherapy and operation of right-posterior lobectomy, PVB (cisplatinum, vinblastine, bleomycin) chemotherapy produced a complete remission and the elevated serum AFP was normalized. However, the second course of chemotherapy had to be discontinued because of drug-induced hepatitis. He died of massive tumor metastasis to his brain 6 months after craniotomy.

Mouse and rat strain variations in sensitivity to N-nitroso-diethylamine, hereditary transmission of the trait and the effect of 3-tert-butyl-4-hydroxyanisole on sensitivity.

1. Strain variations among male mice were studied in terms of the number of days of survival with chronic administration of N-nitroso-diethylamine (NDEA). Four inbred strains, two F1 progenies and one F2 progeny were tested. 2. BALB/c mice survived for the longest period, whereas C3H mice survived for the shortest time. Results of examinations of BALB/c-C3H-F1, -F2 and C57BL-CBA-F1 mice revealed that the hereditary trait could be adequately explained by postulating two loci of genes or gene clusters that regulate the sensitivity to NDEA. 3. Simultaneous chronic administration of 3-tert-butyl-4-hydroxyanisole (BHA) could prolong the survival period. 4. Preliminary histopathological examinations of the liver tissues revealed that the lesion at the time of death of the mice varied considerably depending on the strain and the length of survival. Evidence for hereditary transmission of the characteristics of histopathological changes, including development of liver hemangiosarcoma, is presented. 5. The strain variations among male and female rats were also studied in terms of the number of days of survival with chronic administration of NDEA. Five strains and one F1 progeny were tested. 6. From these and previous observations, the possible biochemical factors determining sensitivity to NDEA were discussed.