Fatal carotid blowout syndrome after BNCT for head and neck cancers.

Boron neutron capture therapy (BNCT) is high linear energy transfer (LET) radiation and tumor-selective radiation that does not cause serious damage to the surrounding normal tissues. BNCT might be effective and safe in patients with inoperable, locally advanced head and neck cancers, even those that recur at previously irradiated sites. However, carotid blowout syndrome (CBS) is a lethal complication resulting from malignant invasion of the carotid artery (CA); thus, the risk of CBS should be carefully assessed in patients with risk factors for CBS after BNCT. Thirty-three patients in our institution who underwent BNCT were analyzed. Two patients developed CBS and experienced widespread skin invasion and recurrence close to the carotid artery after irradiation. Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion from recurrent lesions after irradiation is an ominous sign of CBS onset and lethal consequences.

Acute fatty liver of pregnancy complicated with anterior pituitary insufficiency.

Acute fatty liver of pregnancy complicated with anterior pituitary insufficiency in a 24-year-old nullipara woman who presented fever and progressing liver damage after the delivery by Cesarean section is described. The liver biopsy revealed severe fatty changes with microvesicular fat drops in the hepatocytes. Serum growth hormone and adrenocorticotropic hormone levels were low, and did not respond to the stimulation. The daily urinary excretion of 17-hydroxycorticosteroid was also low. Acute fatty liver of pregnancy and antehypophyseal insufficiency were diagnosed. Secondary adrenal failure was also suspected. The co-existing hypercoagulable state could cause an ischemic attack on the pituitary gland.

Well-differentiated papillary mesothelioma involving the peritoneal and pleural cavities: successful treatment by local and systemic administration of carboplatin.

Well-differentiated papillary mesothelioma (WDPM) of the peritoneum is a rare form of epithelial mesothelioma. It usually shows an indolent course and no standard treatment is available. Only a few cases of WDPM in the pleural cavity have been reported. We report on a 56-year-old post-menopausal woman who presented with ascites and right pleural effusion. Laparotomy followed by biopsy established the presence of WDPM in the peritoneum and pleural cavity. The patient was successfully treated with local and systemic administration of carboplatin.

Markers of apoptosis and angiogenesis indicate that carcinomatous components play an important role in the malignant behavior of uterine carcinosarcoma.

Carcinosarcoma of the uterine body is a relatively uncommon neoplasm that contains carcinoma components (CCs) and sarcoma components (SCs). Which component is responsible for the aggressive biologic behavior of this tumor has been a matter of discussion. Recently, many studies have indicated that angiogenesis and apoptosis play an important role in the biologic behavior of tumors. The aim of this study was to clarify, through the exploration of angiogenesis and apoptosis, which compartment is more important for the biologic behavior of carcinosarcoma. Paraffin sections from 10 uterine carcinosarcomas were stained by using anti-CD34 monoclonal antibodies for quantifying tumor vascularization. DNA nick was labeled immunostained by using an Apop Tag in situ apoptosis detection kit for exploring apoptosis. In addition, immunohistochemical staining for Ki-67 labeling index (LI) was conducted for evaluating cell proliferation. Although there was no significant difference in Ki-67 LI between SCs and CCs (P =.06), the microvessel density (MVD) in CCs was significantly higher than in SCs (P =.003), and the apoptotic index (AI) was significantly higher in SCs than in CCs (P =.002). Accordingly, CCs may play an important role in aggressive biologic behavior in carcinosarcoma. HUM PATHOL 31:1448-1454.

Hypersensitivity reaction to carboplatin during treatment for ovarian cancer: successful resolution by replacement with cisplatin.

Development of hypersensitivity reactions to carboplatin (CP) during cancer treatment makes optimal chemotherapy difficult to achieve. Many approaches have previously been used following the development of reactions to CP. We report on a patient with ovarian cancer who developed a hypersensitivity reaction to CP. The patient was successfully treated following replacement of carboplatin with cisplatin.

Establishment of a cell line from a neuroendocrine carcinoma of the endometrium and an invasion model.

A new cell line (YKK) was established from a primary tumor of neuroendocrine carcinoma of the endometrium. Cultured YKK cells are polygonal in shape. The modal chromosome number is 46 XX. The doubling time of the cells, after the 19th passage, is 38 hours and this cell line has been propagated continuously by serial passage over 50 passages for the past 2 years. YKK displays characteristics resembling the original tumor cell from the donor patient: it contains the neuron-specific enolase and chromogranin antibody, produces neuron-specific enolase, and is sensitive to cisplatin, carboplatin, and etoposide. When YKK cells are transplanted subcutaneously together with Matrigel into nude mice they form a very large tumor invading the subcutaneous muscular tissue. This experimental model is useful for studying the mechanism(s) regulating the invasion of this tumor into muscular tissue, and for the establishment of new anti-cancer treatments for neuroendocrine carcinoma.

Establishment of a liver metastatic model of human ovarian cancer.

We have established an in vivo experimental model in which human ovarian cancer grows in the ovary of nude mice and metastasizes to parenchymatous organs. An ovarian cancer cell line was orthotopically injected into the nude mouse ovary together with Matrigel by microsurgical techniques. The cells grew locally in the ovary and metastasized to the peritoneum, colon, omentum, liver, and spleen. When the cells were injected into the intraperitoneal cavity with Matrigel, they formed carcinomatous peritonitis but neither ovarian tumor formation nor the metastasis to parenchymatous organs was detected. Taken together, these findings indicate that the microenvironment of the ovary seems to be essential for metastasis of implanted human ovarian cancer cells. This in vivo experimental model allows us to investigate the mechanism of the metastasis of ovarian cancer, it will be also useful for the establishing a new therapeutic approach to preventing metastasis of human ovarian cancer to parenchymatous organs.

In vitro development of bovine embryos in conditioned media from bovine granulosa cells and vero cells cultured in exogenous protein- and amino acid-free chemically defined human tubal fluid medium.

We have investigated the effect of protein- and amino acid-free simple human tubal fluid (HTF) medium conditioned with bovine granulosa cells (BGC) or Vero cells on the development of early bovine embryos to the blastocyst stage. Serum-containing medium (SCM) and serum-free medium (CM) conditioned by BGC (BGC-SCM, BGC-CM) and by Vero cells (VC-SCM, VC-CM) were prepared. Early embryos (1-cell stage and 5- to 8-cell stage) were obtained by in vitro maturation and fertilization of oocytes from slaughtered cows. Embryos were randomly divided into 7 culture groups as follows: culture with BGC-SCM, BGC-CM, VC-SCM, or VC-CM; coculture with BGC or Vero cells; or culture with fresh HTF medium without serum. The proportion of 5- to 8-cell embryos developing to the blastocyst stage in BGC-CM (16%) and VC-CM (12%) was significantly lower (p < 0.05) than in BGC-SCM (41%) and in VC-SCM (29%) and after coculture with BGC (48%) and Vero cells (30%). Similarly, the percentages of 1-cell embryos developing to blastocyst in BGC-CM and VC-CM were significantly lower than in BGC-SCM and VC-SCM and after coculture. Cell numbers per blastocyst developed from 5- to 8-cell embryos in BGC-CM (96.8 cells) and in VC-CM (94.0 cells) were somewhat lower than those in BGC-SCM (128.5 cells) and VC-SCM (117.1 cells) and after coculture with BGC (124.2 cells) and Vero cells (115.3 cells). These results suggest that BGC and Vero cells cultured in a protein- and amino acid-free simple HTF medium synthesize and secrete factor(s) promoting blastocyst formation in vitro. Physiochemical analysis indicated that the embryotrophic substances in BGC-CM were distributed in two molecular size ranges, one between 10 kDa and 30 kDa and another greater than 30 kDa.

Serum human hepatocyte growth factor in human menstrual cycle and pregnancy: a novel serum marker of regeneration and reconstruction of human endometrium.

Serum concentrations of human hepatocyte growth factor (hHGF) were measured in normal menstrual cycles and during uncomplicated pregnancies. In the normal menstrual cycle, the concentrations of hHGF increased through the mid and the late luteal phases to reach the highest peak during the menstrual phases, followed by a gradual decline during the follicular phase toward the trough levels seen in the ovulatory and the very early luteal phases. During pregnancy, serum hHGF concentrations increased continuously from the late luteal levels and constituted 4 distinct peaks. By immunostaining, c-Met protein, a receptor for hHGF, was localized not in the stromal but in the epithelial layer of the endometrium. In cultured isolated endometrial cells, hHGF stimulated the proliferation of both the epithelial and the stromal cells. It is likely that hHGF is involved in the repair or reconstruction process of the endometrium after menstrual shedding and implantation.

Management of an infected urachal cyst during pregnancy.

An infected urachal cyst complicating a pregnancy is extremely rare, but is considered to present a high risk to both the mother and the fetus. We treated a patient with an infected urachal cyst diagnosed at 29 weeks of gestation. A healthy infant was delivered by cesarean section at 37 weeks of gestation. The patient underwent excision of the unruptured cyst 37 days later. This is the first reported case of an infected urachal cyst complicating a pregnancy, that was diagnosed before rupture and was managed without serious sequelae for either the mother or the fetus. The diagnosis and management of the infected urachal cyst complicating the pregnancy is discussed.

Bovine theca and granulosa cell interactions modulate their growth, morphology, and function.

We have developed a culture system in which bovine granulosa and theca cells are allowed to attach to opposite sides of a collagen membrane. We studied the interaction between theca and granulosa cells by investigating the morphology, proliferation, and steroidogenesis of the cells. Granulosa cells cultured alone were flattened and polygonal and formed monolayer sheets. Granulosa cells cocultured with theca cells formed multilayer sheets. The apical surface of each cell appeared convex. Numerous filopodia spread over the cellular surface connecting cells. Theca cells cultured alone were thin, flat, and spindle-shaped. Theca cells cocultured with granulosa cells were also spindle-shaped; however, the apical surface appeared convex. Cocultured cells were more densely packed than theca cells cultured alone. The number of both granulosa and theca cells in the cocultured group increased approximately twofold compared to control cells cultured alone. Progesterone content per 1 x 10(5) granulosa cells in 24-h culture medium of the cocultured group was reduced to 40% of that of the control group. In contrast, androstenedione content per 1 x 10(5) theca cells of the cocultured group increased approximately threefold compared to androstenedione content of control group. These results indicate that communication between these two types of follicular cells results in reciprocal modulation of their proliferation, morphology, and function.

The synthesis and release of gonadotropins in response to gonadotropin-releasing hormone of the rat anterior pituitary gland during weight reduction.

It is well recognized that weight reduction produces the suppression of serum LH but not FSH level in rodents. In order to clarify the mechanism by which the discrepancy between LH and FSH levels is brought about, the influence of weight loss on the pituitary function was explored using female rats. The changes of the pituitary response to GnRH and the basal secretion of gonadotropins with progressive weight loss were investigated by in vitro short-term incubation of the pituitary gland after prolonged weight loss in female Wistar rats. On the first day of diestrous and until day 14 of the diet, GnRH induced LH and FSH release from the pituitary and a decrease in pituitary content of them, but the total amount of gonadotropin in culture medium and pituitary tissue was not affected. On day 30 of the diet, the decrease in pituitary content disappeared. On day 60 LH release disappeared, whereas pituitary FSH and the total amount of gonadotropins were increased by GnRH. Non-stimulated FSH but not LH secretion per mg of pituitary was augmented during dieting. The data indicate that pituitary responsiveness to GnRH and non-stimulated FSH release were modified by weight loss: the LH-releasing action of GnRH was diminished, the gonadotropin-synthesizing action of GnRH was augmented, and non-stimulated FSH release was increased.

Experimental local administration of CDDP to in vitro models of gynecological malignant tumors transplanted into nude mice (compared with medroxyprogesterone acetate orally administered).

In order to develop a new method of administration for CDDP, in vitro models of malignant tumors in the field of gynecology were prepared using two cell lines maintained by the authors, and fundamental experiments on the topical injection of CDDP were carried out. In experimental topical injection of CDDP in tumor-bearing nude mice, the test drug demonstrated an excellent tumor regression effect and an inhibitory effect on tumor growth. In the histopathologic examinations, specific necrosis of tumor cells was observed. It was confirmed that this is a highly safe method, as tissue separation, ulceration, or hemorrhagic lesions attributable to the local administration of CDDP were not observed. In the present study, treatment with oral medroxyprogesterone acetate was also used. At the doses used in this study, however, no inhibitory effect on tumor growth or synergism between medroxyprogesterone acetate and CDDP was observed. Topical injection is an excellent pharmacodynamic method that permits the injection of free platin into the tumor itself or in the boundary area between the tumor and normal tissues, with no loss of the drug, and it is considered a safe and effective mode of local administration. Intra-arterial injection of this drug alone or in conjunction with OK-432 can also be used, even though further studies will be required to determine the optimum dosage and reduce side effects. At present, data are being collected on terminal cancer patients for whom no other therapy is available. In the near future this method of administration is expected to be utilized in the clinical treatment of malignant tumors, be it early tumor or progressive cancer.

[Ultrastructural studies of tumors transplanted into nude mice using the TTK-1 cell lines derived from normal human early decidual tissue].

Tumors transplanted into nude mice using the TTK-1 cell lines [TTK-1(E) and TTK-1(F)] derived from normal human early decidual tissue were studied morphologically. The epithelial-like cell line TTK-1(E) and the fibroblast-like cell line TTK-1(F) were maintained in culture through one hundred and ten subcultures since July 1979. Rapidly growing tumor nodules formed at the implantation sites. The incidence of tumor growth was 100% for both cell lines. Histologically the tumors were composed of poorly-differentiated cells arranged in a cord-like structure and showed typical malignant characteristics. Immunohistochemical studies, electron microscopy and immunocytochemical studies revealed that the tumors from the two cell lines differed in many respects. The tumors formed by TTK-1(E) showed epithelial characteristics and the tumors formed by TTK-1(F) showed both epithelial and mesenchymal characteristics. Therefore, TTK-1(E) might be useful as an in vitro model of endometrial cancer and TTK-1(F) as an in vitro model of both endometrial cancer and endometrial stromal tumor (containing mixed mesodermal tumor). These tumors will be valuable for future studies of the tumorigenicity and therapy of uterine malignant tumors. They may reflect the various functions of decidual tissue.

Morphological studies on the established cell lines obtained from normal human decidual tissue of an early stage of gestation.

The two cell lines, TTK-1 (E) and TTK-1 (F), were established from normal human decidual tissue of early gestation. The primary culture was initiated by a fragment culture technique in July, 1979 and the cultures were passaged about once every two months. Meanwhile two kinds of the cultures, the epithelial-like cell dominant one and the fibroblast-like cell dominant one, had appeared. The former has been subcultivated and maintained at a constant growth rate and designated as the TTK-1 (E) cell line. The latter showed a gradual decline in growth rate and finally growth ceased at 3 years after the initiation of the culture. The sudden onset of growth and colony formation occurred after 4 months of senescence and the fibroblast-like cell culture has been maintained at a constant growth rate and designated as TTK-1 (F) cell line. Morphological studies revealed that the TTK-1 (E) cell line had epithelial-like characteristics and TTK-1 (F) cell line had fibroblast-like features. Both cell lines showed heteroploid karyotypes and tumorigenicity in nude mice transplantation. The two cell lines appeared to be established by spontaneous neoplastic transformations and should be useful cellular models for the study of malignant endometrial tumors.

[Selective intra-arterial administration of CDDP in a malignant ovarian tumor with peculiar ultrastructural findings].

Selective intraarterial administration of CDDP in combination with sodium thiosulfate (STS) was performed in a 39-year-old patient with a malignant ovarian tumor suspected of being a malignant granulosa cell tumor. The primary tumor was in the left ovary, and there were widespread metastases in the abdominal cavity. A total hysterectomy with bilateral adnectomy and partial omentectomy was performed. The tumor showed several different histologic patterns, including serous papillary cyst-adenocarcinoma and granulosa cell tumor of the microfollicular type with Call-Exner bodies in which bizarre nucleoli, deep indentations of the nuclear membrane, nuclear bodies, small mitochondria, lipid droplets, rER, and ribosomes were noted. Serum markers E1, E2, CA-125 and ferritin were elevated. CDDP (total 200 mg) was administered through the abdominal aorta, inferior mesenteric artery, and common hepatic artery in addition to STS, resulting in higher levels of plasma-free platin to the residual tumor. There were hardly any side effects due to this therapy, except for a slight upper digestive tract disturbance and anemia. The result of treatment in this patient was excellent, there is no sign of recurrence, and the serum level of CA-125 3 years after surgery is normal.

The efficacy of every-other-day administration of gonadotropin-releasing hormone in women with hypothalamic amenorrhea: gonadotropin-releasing hormone treatment can induce clomiphene responsiveness.

The efficacy of every-other-day gonadotropin-releasing hormone administration was investigated in clomiphene-human chorionic gonadotropin (hCG) resistant, anovulatory women with hypogonadotropism or normogonadotropism. One hundred micrograms of gonadotropin-releasing hormone was injected intramuscularly three times a week for four weeks (one course). Ten of 11 hypogonadotropic patients responded to clomiphene or clomiphene-hCG after one to three courses of gonadotropin-releasing hormone treatment. Once the patients were converted to clomiphene responsiveness, ovulatory response continued without additional treatment, and all four patients who desired pregnancy conceived. Among eight normogonadotropic women, four with amenorrhea of one year or less became clomiphene-hCG responders after one or two courses of gonadotropin-releasing hormone treatment. They were subsequently treated with gonadotropin-releasing hormone after every one or two ovulatory cycles. One of the four women who desired to be pregnant conceived. We conclude that intramuscular gonadotropin-releasing hormone treatment is effective in inducing responsiveness to clomiphene, especially in hypogonadotropic anovulatory women. In normogonadotropic women, gonadotropin-releasing hormone treatment may be useful in those who have been amenorrheic for less than a year.