A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Embryo-dependent induction of embryo receptivity in the mouse endometrium.

The effect of intraoviductal embryos on endometrial receptivity was studied by intraendometrial and intrauterine embryo transfer. Five-week-old female ICR mice were mated after superovulation; a vaginal plug confirmed day 1 of pregnancy. On day 4 (90 h after hCG injection), blastocysts were collected and transferred to pseudopregnant female mice and to recipient mice in which the uterotubal junction had been ligated bilaterally on day 1 of pregnancy. Three embryos per uterine horn, a total of six embryos per recipient mouse at days 1-6, were transferred to the endometrium or uterine cavity and implantation and pregnancy rates were calculated. The implantation rate for intraendometrial embryo transfer to recipients of days 3, 5 and 6 was significantly higher for uterotubal junction-ligated mice (72.2, 20.8 and 9.7%, respectively) than for pseudopregnant mice (55.0, 8.3 and 0.0%, respectively). The implantation rate for intrauterine embryo transfer to recipients at days 2, 5 and 6 was significantly higher for uterotubal junction-ligated mice (11.1, 25.0 and 8.3%, respectively) than for pseudopregnant mice (0.0, 3.3 and 0.0%, respectively). Uterotubal junction-ligated mice achieved implantation and bore neonates by intrauterine embryo transfer on days 2 and 6, whereas no implantation was achieved in pseudopregnant mice. The difference in implantation rate could not be explained by a difference in progesterone concentration between the groups. The distribution of proliferating cells in the endometrium was also studied immunohistochemically by use of anti-proliferating cell nuclear antigen (PCNA) antibody in the recipient mice. PCNA-positive cells were more abundant in uterotubal junction-ligated mice and demonstrated a marked extension from the epithelium to the stroma over time, in contrast to those in pseudopregnant mice. These findings indicate that an intraoviductal embryo exerts a biological effect by sending a signal to the endometrial epithelium and stroma, thus facilitating endometrial receptivity to the embryo and improving the rate of implantation.

DNA flow cytometric quantification and DNA polymorphism analysis in the case of a complete mole with a coexisting fetus.

PURPOSE: Our purpose was to investigate whether DNA flow cytometric quantification and DNA polymorphism analysis are useful for cytogenetic diagnosis in the case of a complete hydatidiform mole that coexists with a living fetus. METHODS: Flow cytometric analysis of the nuclear DNA content and polymerase chain reaction (PCR) amplification of the minisatellite locus with the MCT118 probe were performed on the tissues (fetus, placenta and mole) obtained at the initial evacuation. RESULTS: DNA histograms of placental, fetal, and molar tissues showed diploid peaks. PCR products demonstrated that the allele of the mole was homozygous and inherited solely from the husband and that the mole differed genetically from the fetus and the placenta. CONCLUSIONS: These results suggested that DNA flow cytometry and DNA polymorphism analysis may be useful for the cytogenetic diagnosis of a complete hydatidiform mole and a coexisting fetus.

Combined intrauterine and ovarian pregnancy: a case report.

A case of combined intrauterine and ovarian pregnancy diagnosed by postoperative microscopic observations is reported in this paper. The patient was a 23-year-old, Japanese nulligravid female. On the 32 day after a previous D & C when normal chorionic tissues of very early gestation were obtained, she complained of severe lower abdominal pain. Immediate laparotomy revealed hemorrhaging from a hematoma-like region on the surface of the left ovary, and partial resection of the left ovary was performed. The resected ovary was composed of an intact corpus luteum and another thin corpus luteum around a hematoma-like region containing chorionic villi, confirming this case to be an ovarian pregnancy. Histological findings of chorionic villi of the ovary indicated that ovarian pregnancy took place during the same menstrual period as intrauterine pregnancy, and not after the prior D & C. From these observations, this case was diagnosed as a combined intrauterine and ovarian pregnancy.

DNA ploidy and proliferative characteristics of human trophoblasts.

By using DNA cytofluorometry, DNA ploidy and the distribution pattern of human trophoblasts at different sites were studied throughout pregnancy, and the proliferative activity during cell differentiation of trophoblasts was discussed. In the first and second trimesters, cytofluorometric nuclear DNA analysis demonstrated that cytotrophoblasts in the tip of the anchoring villi (proximal portion of the cell column) consisted of proliferating diploid and tetraploid populations. Cytotrophoblasts in the distal portion of the cell columns consisted of non-proliferating diploid and tetraploid trophoblasts, as also did intermediate trophoblasts invading the maternal tissue. Villous trophoblasts consisted of proliferating diploid populations. In term placenta, villous trophoblasts were proliferating, diploid, whereas X-cells in the decidual tissue consisted of non-proliferating diploid and tetraploid populations. It was concluded that (1) trophoblasts in the generative zone consist of proliferating diploid and tetraploid populations, (2) intermediate trophoblasts having 4c DNA content were not proliferative, and (3) cytrotrophoblasts in the chorionic villi still had proliferative activity even in the term placenta.

[Detection of human papillomavirus types 16, 18 and 33 in exfoliated cervical cells by polymerase chain reaction].

Human papillomavirus (HPV) types 16, 18 and 33 were identified by means of the polymerase chain reaction using exfoliated cells from the uterine cervix in 361 patients. Of 261 patients without cervical lesions, 10(3.8%) patients had HPV DNA whereas 7(70.0%) of 10 patients with invasive cervical carcinomas had HPV DNA. The younger patients' group (29 year-old or less) without cervical lesions had a 6.5% HPV positive rate which was distinctly higher than the older patients' groups. No menopausal patient without cervical lesions had HPV DNA. In the cervical dysplasia group, the HPV DNA positive rate tended to be higher in the older patients. Type 16 was detected more often than types 18 or 33. However, the detectable incidence of type 16 in the follow up group was lower than in the cervical carcinoma groups. The younger patients without cervical lesions had a higher incidence of type 16 than the older patients. The younger patients with cervical neoplastic lesions had a lower incidence of type 16 than the older patients. These results suggest that type 16 has a higher frequency of cervical HPV infections than types 18 and 33. In addition, human papillomavirus is not the only causative factor in cervical carcinomas.

Analysis of cell cycle kinetics using flow cytometry from paraffin-embedded tissues in endometrial adenocarcinoma.

Flow cytometric analysis of cell cycle kinetics from paraffin-embedded tissues was performed to evaluate the DNA heterogeneity and risk factor of endometrial adenocarcinoma. We studied 54 tumor samples and 6 controls with normal endometrium, and all samples were measured for S-phase fraction (SPF) and proliferative index (PI). Intratumor variations of SPF and PI values were evaluated at 3 different sites of the tumor; (1) primary endometrial lesion, (2) the site of myometrial invasion, and (3) metastatic lesions. SPF and PI values of endometrial adenocarcinoma were significantly higher than those of normal endometrium. There was a significant correlation between the PI value and the histological grade. SPF and PI values at the primary endometrial lesion had a significant correlation with the prognosis of this cancer at stage III or IV. SPF and PI values which were measured at the site of myometrial invasion tended to be lower than those from other sites. Our results indicate that the SPF and PI values of endometrial lesions are one of the important prognostic factors of endometrial adenocarcinoma at stage III or IV. In addition, DNA syntheses of endometrial adenocarcinoma cells display intratumor heterogeneity.

[Cytofluorometric nuclear DNA analysis and immunohistochemical study on the proliferative activity of the trophoblasts in human early gestation].

Changes in proliferative activity in trophoblastic cells were evaluated in various different sites of implantation. DNA content analysis by cytofluorometry and immunohistochemical study using a monoclonal antibody Ki-67 was performed in 5 cases with a gestation period of 8-9 weeks. The measurement of proliferative activity of trophoblastic cells was analysed in four different sites of implantation: (1) the top of the anchoring villi, (2) the cell column, (3) the intermediate trophoblasts in the decidua basalis and myometrium, and (4) the free villi. A large number of Langhans cells on the top of the anchoring villi (L-cells) were mononuclear and tetraploid. It was demonstrated that the L-cell group had 2C, 4C and 8C peaks and also had a 4C mode. S-phase fraction was also found in the L-cell group. The so-called intermediate trophoblasts (IMT) in the cell column, decidua basalis and myometrium had 2C and 4C peaks and no S-phase fraction. Ki-67 positive cells existed only in the L-cell group. The findings are as follows: 1. The L-cell group had a higher proliferative activity than the other trophoblasts. It was found to have a mononuclear tetraploidy pattern. 2. It is suspected that the cells having 4C DNA content in the IMT originated in the L-cell group. 3. In conclusion, L-cells may differentiate to syncytial trophoblasts and IMT.

[Compound therapy including PSK for malignant head and neck cancer].

The effect of protein-bound polysaccharide preparation, PSK was studied in 44 cases with head and neck cancer. 1) Eight cases with laryngeal cancer received radiation therapy and PSK as immunotherapy, and eight cases as control received radiation alone. During radiation, the mean values of peripheral lymphocyte counts showed statistically significant difference (P less than 0.05) between the cases with immunotherapy and those without immunotherapy. 2) Twenty-eight cases received adjuvant immunochemotherapy with Carboquone and PSK. 22 out of 28 evaluable cases in the group received adjuvant immunochemotherapy were judged as effective. These studies suggest that PSK is one of the valid immunopotentiators.