Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.

The cellular changes in primary and recurrent infection with herpes simplex virus type 2 in an in vitro model.

The cellular changes of primary and recurrent herpes simplex virus (HSV) infection were investigated in in vitro models. In the primary infection model, nuclear changes were characterized by clumping and margination of the nuclear chromatin, a homogeneous ground-glass nuclear appearance, multinucleation and the appearance of two different types of intranuclear inclusions. One of the two types of inclusions appeared as early as six hours postinfection, reached a maximum at nine hours postinfection and gradually decreased thereafter. This early inclusion, relatively small in size as compared to the other type of inclusion, gave a basophilic staining when the Papanicolaou staining method was used. The other type of inclusion was the typical Cowdry type A inclusion, which appeared as early as 12 hours postinfection. Both types of inclusions contained clear perinuclear halo. In the recurrent infection model, the appearance of all the nuclear changes was delayed, the appearance of early inclusions was infrequent, and the Cowdry type A inclusions were observed more frequently than in the primary infection model. These results may indicate that the early inclusion is a sign of rapid virus replication while the Cowdry type A inclusion is one form of the remains of an HSV infection.

Hormonal status and mycoplasma colonization in the female genital tract.

Three hundred seventy-four cervical or vaginal specimens from patients with various hormonal states were cultured for Ureaplasma urealyticum and Mycoplasma hominis. Significantly, low recovery rates of U urealyticum were obtained in the prepuberty (5%), puerperium (24%), and postmenopause (25%) groups, whereas pregnant women showed the highest incidence of U urealyticum (82%). The recovery rate of U urealyticum from neonates was 42%. The incidence of U urealyticum in sexually inactive females was significantly lower (40%) than that in sexually active nonpregnant women (67%). Significantly, a higher incidence (36%) was observed in postmenopausal women with a uterine cervix than in those whose cervix had been removed by surgery (10%). It is suggested that there is a close relationship between hormonal status and the occurrence of genital mycoplasmas. Possible modes of transmission of genital mycoplasmas other than sexual contact are also discussed.

Genital mycoplasma colonization in neonatal girls.

Specimens obtained from the genital tract of 90 pairs of mothers and their female infants were cultured for Ureaplasma urealyticum (Ureaplasma) and Mycoplasma hominis (M.hominis). Ureaplasma and M.hominis were isolated from 80% and 17% of pregnant women, and 41% and 4.4% of female infants, respectively. Fifty nine per cent of infants were positive for Ureaplasma when they were borne per vaginam by Ureaplasma-positive mothers. However, Ureaplasma was not isolated from any of 11 infants delivered by cesarean section before rupture of the fetal membranes, in spite of positive colonization by Ureaplasma in the mothers. Quantitation of Ureaplasma revealed that neonatal colonization was closely associated with the colonization number of this microorganism in the cervical canal of mothers. Prolonged interval between rupture of fetal membranes and delivery caused a slightly increased frequency of isolation of this organism, but it was less significant. A study of mean birth weight revealed that there was no correlation between maternal or neonatal colonization by Ureaplasma and low birth weight.

Endometriosis associated with ascites.

Pelvic endometriosis associated with massive ascites is an unusual occurrence. Only 12 cases have been reported since 1954 when Brews first described this entity. The authors present two cases recently encountered at Saga Medical School Hospital. Clinical courses and operative findings are described and other cases from the literature are reviewed. The possible etiologic mechanisms of the ascites are explored and the possibility of conservative surgery and hormonal therapy with danazol is discussed.

[Establishment and characterization of a cell line derived from mucinous cystadenocarcinoma of human ovary].

A human tumor cell line MCAS, which was derived from mucinous cystadenocarcinoma of the ovary, was established. The tissue specimen was obtained on December 1, 1983 and the culture was maintained in Ham's F-12 medium supplemented with 20% fetal calf serum. Continuous growth made possible cell transfer every 3-5 days and the seventy-third passage was achieved on August 15, 1984. This cell line has the following characteristics. The doubling time of the MCAS cell line was 27 hours and the saturation density was 5.1 X 10(4)/cm2. The cultured cells appeared monolayer and the cellular arrangement was a pavement-like pattern. Rather large cells with vacuoles in the cytoplasm appeared in the confluent state and PAS staining proved to be positive specifically in these large cells. A chromosomal analysis revealed a peritetraploid tendency. By heterotransplantation of MCAS cells to the nude athymic mouse, the tumor developed and had both cystic and solid components. The cystic content was mucinous. Histopathological diagnosis of the tumor was papillary adenocarcinoma and alcian blue staining was positive. The characteristics of the original mucinous cystadenocarcinoma have been precisely maintained in this cell line.

[FT-207 maintenance therapy of malignant gynecologic cancer].

Maintenance treatment with FT-207 was applied to 92 patients with uterine cancers after initial treatments were performed. Daily dosage of FT-207 was either 600 or 800 mg and the drug was administered orally. The duration of 6 months and the total dosage of 100 g were proposed as administration schedule and 34 patients (37%) received this regimen. Side effects during the treatment were observed in 35 cases (38%). Gastrointestinal disturbance was most frequently observed and other side effects included myelosuppression, general fatigue, hepatic dysfunction and skin toxicities. There were no serious side effects, the treatment was continued in most patients and was interrupted only in 7 cases (8%). In the cases of recurrence or advanced cancer, however, the side effect was the predominant cause for interruption of administration. As for the antitumor effect of the treatment, a survival rate of the patients with cervical cancer of early stages was evaluated. Three-year survival rate in the treatment group was higher comparing to the one reported hitherto.

[Over diagnosis of the biopsy: from the analysis of the extirpated uterus after radical hysterectomy (author's transl)].

From January, 1973 to December, 1980, 396 cases of cervical cancer were treated with radical hysterectomy under the diagnoses of stage Ib, IIa and IIb. Precise postoperative pathological examinations about the extirpated uterus revealed that 63 of them had only early invasive cancer or less advanced lesions though they had been considered as frank invasive cancer by preoperatively performed biopsies. The major causes of the misinterpretations were, 1) misjudging the glandular involvements as frank invasive lesions, or 2) misjudging the tangentially sectioned lesions of the bulky outgrowth as frank invasions. Furthermore, it is sometimes difficult to identify the invasive lesions in the biopsy specimens whether they are early invasive or frank invasive. Colposcopic and cytological examinations were simultaneously performed to each cases. Either cytology or colposcopy did not suggest frank invasions in 44.2% of cases. Both of them did not suggest frank invasions in 37.2% of cases. At least, cone biopsy should have been performed to identify the degree of invasions of these 37.2% cases. The authors emphasize that the directed biopsies are not always accurate to diagnose the early invasions, and one should use colposcopy, cytology and directed biopsy to make an accurate diagnosis.

[Combined chemotherapy of ovarian cancer with special reference to carboquone].

Carboquone (CQ) was administered to 20 patients with ovarian cancer as a main drug in the multiple chemotherapy. Picibanil and Futraful (FT-207) were medicated simultaneously. CQ was given 3 mg each, 2 times a week, up to total 30 mg intravenously or intraperitoneally. 1) The effect of CQ was evaluated in 6 cases. The response was good in 2 cases, fair in 3, and poor in 1. In the other 3 cases after surgery long-lasting remission suggested the effectiveness of this drug. 2) When compared with 43 cases of control group(historical control), apparent higher survival rate was observed until 3 years in this group. 3) Side effects were noted in 89% of the patients. In 5 patients CQ treatment was discontinued because of severe complications. These complications were more pronounced when it was administered intraperitoneally or combined with radiation.