Goro Kosaki

Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer

The effect of cyclophosphamide (CY) on ovarian function was studied in patients with breast cancer receiving prolonged daily administration of this agent (100 mg/day) after radical surgery. Out of 18 premenopausal patients that received 8.4–39.9 g CY, 15 developed permanent amenorrhea. The average dose given before the onset of amenorrhea was 5.2 g in patients in their 40s and 9.3 g in their 30s. Urinary estrogens and serum progesterone were measured weekly for approximately 6 months postoperatively in six patients receiving CY. After the onset of amenorrhea, the levels of both hormones ceased to show their normal cyclic changes and remained low persistently, meanwhile serum FSH and LH were markedly elevated. No ovarian follicle was histologically found in three amenorrheic patients who underwent therapeutic oopho‐rectomy after CY therapy. These findings indicate that CY induced primary ovarian failure.

INTERNAL FISTULA AS A ROUTE OF INFECTION IN ACUTE SUPPURATIVE THYROIDITIS

Seven cases of acute suppurative thyroiditis are described. Six patients had a recurrent painful swelling of the left anterior neck and one was seen at her first episode of the disease. A barium meal revealed a fistula originating from the apex of the left pyriform sinus in all cases. The fistula, a remnant of the fourth pharyngeal pouch, thus seems to be a common route of infection in acute suppurative thyroiditis, allowing bacterial infection to begin in the perithyroidal space and spread to the thyroid gland. Complete extirpation of the fistula is required for a permanent cure.

Homotypic and heterotypic Ca++-independent cell adhesion activities of biliary glycoprotein, a member of carcinoembryonic antigen family, expressed on CHO cell surface

Homotypic and heterotypic cell adhesion activities of a carcinoembryonic antigen (CEA) family member, biliary glycoprotein a (BGPa), have been examined. CHO cells transfected with the cDNA for BGPa, CEA, non-specific cross-reacting antigen (NCA) and CGM6 have been used. The BGPa producers showed both homotypic and heterotypic adhesion to CEA and NCA producers. However, they hardly adhered to CGM6 producers. Calcium ion was not required for BGPa-mediated homotypic and heterotypic cell adhesion as well as for the adhesions of other members of CEA family. The results strongly suggested that BGPa may play some important roles through Ca(++)-independent cell adhesion activities.

Radioimmunoassay for human pancreatic secretory trypsin inhibitor: measurement of serum pancreatic secretory trypsin inhibitor in normal subjects and subjects with pancreatic diseases

A reliable radioimmunoassay (RIA) for human pancreatic secretory trypsin inhibitor (PSTI) has been developed. The method is highly sensitive (0.4 ng/ml), reproducible and specific. A good parallel relationship was observed between the standard curve and dilution curves for serum and urine. The PSTI bound to trypsin-alpha 2-macroglobulin complexes was found not to be immunoreactive, whereas a part of the psti-trypsin complex was immuno-reactive. In healthy individuals, serum PSTI level ranged from 5.4 ng/ml to 16.0 ng/ml, the average being 11.3 ng/ml (S.D. +/- 2.7). Elevated values were observed in patients with acute pancreatitis (highest value 3200 ng/ml), and in some patients with chronic relapsing pancreatitis.

Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on yoshida sarcoma-bearing rats

Methionine‐depleting total parenteral nutrition (methionine‐depleting TPN), which infuses an amino acid solution devoid of L‐methionine and L‐cysteine as the sole protein source, showed enhancement of the effect of several anti‐cancer agents. In this study, the combined effect of the methionine‐depleting TPN with the administration of doxorubicin was examined in Yoshida sarcoma (YS)‐bearing rats with regard to effects on the primary tumor growth, the extension of metastasis, and the host animals life span.

FOY: [Ethylp-(6-guanidinohexanoyloxy) benzoate] methanesulfonate as a serine proteinase inhibitor. I. Inhibition of thrombin and factor Xa in vitro

Abstract The inhibitory effect of [Ethyl p -(6-guanidinohexanoyloxy) benzoate]methanesulfonate (FOY) on thrombin and factor Xa was examined in comparison with the inhibitory effect of FOY on plasmin and plasma kallikrein. FOY was found to exert an anticoagulant effect on the clotting activity of thrombin, and to inhibit competitively the hydrolytic reactions with synthetic substrates by thrombin and factor Xa as well as by plasmin and plasma kallikrein. The most potent inhibition was observed to plasma kallikrein (Ki: 0.2 μM), secondly to thrombin (Ki: 0.97 μM), thirdly to plasmin (Ki: 1.6 μM), and then to factor Xa (Ki: 8.5 μM), judging from their Ki values. The inhibitory action of FOY against thrombin or factor Xa was not affected by the presence of antithrombin III or antithrombin III and heparin, since the Km values of synthetic substrates and the Ki values of FOY for thrombin and factor Xa were not altered in the presence of antithrombin III and heparin. FOY inhibited the residual activity of thrombin or factor Xa, which was not neutralized by antithrombin III or antithrombin III and heparin.

Intra‐arterial infusion chemotherapy as a preoperative treatment of locally advanced breast cancer

Intra‐arterial infusion chemotherapy was made through the internal mammary artery and subclavian artery in 12 cases of locally advanced breast cancer. Continuous infusion of 5‐fluorouracil and intermittent injections of Mitomycin C were jointly made for 1 to 4 weeks in each artery. Marked response in not only the primary tumor but also lymph node metastasis was clinically observed, permitting extended radical mastectomy successfully in all cases. Remarkable regressive changes were histologically observed in cancer foci, especially in small ones, of resected specimens including axillary, parasternal, and supraclavicular lymph nodes. All cases except 1 have been healthy without any recurrence for 22 to 78 months after treatment. Intra‐arterial infusion chemotherapy with this method is a useful preliminary procedure for surgical treatment of locally advanced breast cancer.

In Vivo Platelet Production from Mature Megakaryocytes: Does Platelet Release Occur via Proplatelets?

Although platelets are universally accepted to be born from megakaryocytes (MKs), the mechanism by which platelets are formed and released from MKs in vivo remains controversial. One theory, known as the proplatelet theory, postulates that platelets are released from proplatelet processes protruding from MKs into sinusoids located in the bone marrow hematopoietic compartment. Proplatelet formation (PPF) has been observed in in vitro experiments involving detailed analyses of related molecular events. PPF has also been used as a marker of MK maturation. However, PPF is suggested to be a non-physiological phenomenon. On the other hand, transmission electron microscopy (TEM) analyses have revealed platelet formation via explosive fragmentation of MK cytoplasm in bone marrow and lung capillaries prepared by immersion fixation. Moreover, TEM and scanning electron microscopy studies of liquid-cultured MKs kept in suspension show that platelet formation occurs without PPF. Rather, an explosive and global fragmentation of the MK cytoplasm composed of platelet territories has been reported as the mechanism of platelet formation. In addition, in vivo and ex vivo observations of platelet release from MKs with phase-contrast microscopy strongly support the explosive-fragmentation theory. With all observations taken into account, PPF may not be a prerequisite for platelet release from MKs under real-life conditions. In this review, a new “protoplatelet” concept is proposed to support the explosive-fragmentation theory. Additionally, the role of the lungs in platelet production is reviewed and discussed.

A pregnancy-specific β1-glycoprotein, a CEA gene family member, expressed in a human promyelocytic leukemia cell line, HL-60: structures of protein, mRNA and gene

Both genomic and cDNA clones encoding a precursor for a pregnancy-specific beta 1-glycoprotein (PS beta G) belonging to the CEA family, expressed in a human promyelocytic leukemia cell line, HL-60, have been isolated and the entire primary structure of the precursor is deduced. The 335-AA precursor has a 34-AA signal peptide followed by domains of N, IIA, IIB and C, which are encoded by separate exons. The genomic sequence contains extra exons IA and IB between exons N and IIA. Apparently, exon IA is excluded from the mRNA by alternative splicing while IB is a pseudo-exon having a stop codon formed by a deletion of dinucleotide in the middle of the sequence. This provides another mechanism to render exon IB abortive and is different from that we reported for another PS beta G (Biochem. Biophys. Res. Comm. (1988) 156, 68-77).

Surgical adjuvant chemotherapy with mitomycin C and cyclophosphamide in Japanese patients with breast cancer

A controlled trial of surgical adjuvant chemotherapy for breast cancer was carried out using 551 Japanese patients. Single or combined treatment with mitomycin C (0.2 mg/kg i.v. three times within five days postoperatively) and cyclophosphamide (100 mg postoperatively daily for four months or longer) was used after radical surgery. In patients of the chemotherapy group with one to three lymph nodes involved in the axilla, the five‐year cancer‐free survival rate was 84.8% compared with 57.3% in the control group (P < 0.05), and the five‐year cumulative recurrence in distant sites was 5.1% compared with 31.1% in the control (P < 0.05). The effectiveness of chemotherapy was much less marked in patients without nodal metastasis and with four or more nodes involved. Histologically, scirrhous cancer was the type that responded most favorably to chemotherapy, even in patients without axillary involvement. Premenopausal patients benefited more than postmenopausal patients from chemotherapy. A combination of mitomycin C and cyclophosphamide was more effective than their use singly. The present chemotherapy regimen was effective primarily in moderately advanced stages of breast cancer with decreased incidence of distant metastasis.