Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report.

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.

Safety of immune checkpoint inhibitors after proton beam therapy in head and neck mucosal melanoma: a case series.

Proton beam therapy (PBT) has shown promising efficacy in treating locally advanced head and neck mucosal melanoma despite its poor prognosis. Although PBT may improve the efficacy of subsequent immune checkpoint inhibitors (ICIs), the safety of ICIs in patients who have previously received PBT has not been established. Hence, this study evaluated the safety of ICIs in patients who had recurrent mucosal melanoma after PBT. Between April 2013 and June 2022, we retrospectively reviewed the medical records of patients diagnosed with cutaneous or mucosal melanoma at the National Cancer Center Hospital East. Seven patients were treated with ICIs after their head and neck mucosal melanoma (HNMM) recurred after PBT. Four of the seven patients experienced grade immune-related adverse events (irAEs). Due to irAE in the irradiation field, two patients had grade 3 hypopituitarism. Other grade 3 or higher irAEs included an increase in serum alanine aminotransferase in two patients and gastritis in one, and two patients discontinued ICI due to the irAEs. All irAEs were resolved with appropriate management. Although administering ICIs after PBT may increase the risk of irAEs, especially in the irradiation field, they appear manageable. These findings could help in the development of a treatment strategy for locally advanced HNMM that includes PBT and subsequent ICIs.

The impact of the COVID-19 pandemic on perioperative chemotherapy for breast cancer.

BACKGROUND: Since it was first reported in December 2019, coronavirus disease 2019 (COVID-19) spread rapidly across the globe resulting in a pandemic. As of August 2022, seven outbreak peaks have been confirmed in Tokyo, and the numbers of new cases in the fifth and later outbreak periods have been far greater than in the preceding periods. This retrospective study examined the impact of the COVID-19 pandemic on perioperative chemotherapy for breast cancer. METHODS: Patients with breast cancer who received perioperative chemotherapy at the National Cancer Center Hospital East were divided into 2 groups: 120 and 384 patients who started chemotherapy before and during the pandemic, respectively. The incidence of critical events that had potential detrimental effects on the prognosis, such as start of adjuvant chemotherapy ≥91 days after surgery and relative dose intensity of chemotherapy <85% were compared between groups. RESULTS: No significant difference in the incidence of critical events was found. When stratified by outbreak period, the incidence of critical events was positively correlated with the increasing number of new cases of COVID-19 (r = 0.83, p = 0.04). Moreover, 25/173 patients (14%) who started perioperative chemotherapy during the fifth and sixth outbreak periods developed COVID-19 infection, 80% of whom (20/25) had a delay or interruption to their surgery or other perioperative treatments. CONCLUSIONS: Although the impact of the COVID-19 pandemic on perioperative chemotherapy on whole groups of patients was not evident when comparing periods before and after the pandemic, the impact is becoming prominent in parallel with increasing numbers of new COVID-19 cases.

[NTRK Gene Fusions and Treatment in NTRK Fusion-Positive Solid Cancers].

Neurotrophic tyrosine receptor kinase(NTRK)gene variants have been reported in a variety of cancer types. The prevalence of NTRK gene variants is less than 1% in many types of solid cancer. The highest NTRK gene fusions frequencies were found in secretary breast carcinoma and infantile fibrosarcoma. There are several methods to detect NTRK gene variants, including RT-PCR, and comprehensive genome profiling. Two NTRK inhibitors, entrectinib and larotrectinib, are approved for NTRK gene fusion positive solid cancers in Japan. NTRK inhibitors provide a durable response, but duration of response may be limited by acquired resistance. A next-generation TRK inhibitors are expected to overcome acquired resistance.

Ovulation patterns affect the offspring sex ratios and change with the women's age.

BACKGROUND: The aim of this study was to evaluate whether women's ages at conception and the ratio of male to female infants are associated with various ovulation patterns. METHODS: An observational clinical study was conducted in private OB/GYN clinics. Infertile women with regular menstrual cycles receiving intrauterine insemination (IUI) and/or in-vitro fertilization (IVF) had their ovulation patterns monitored in three consecutive spontaneous cycles receiving infertility treatment in the third cycle. Ovulation patterns were also observed in women with slight ovulation disorders during IUI and/or IVF in clomiphene citrate stimulated cycles. All the pregnant women's ages at conception and their respective offspring sex ratios were compared to various ovulation patterns. Statistical evaluation was performed using ANOVA, unpaired t test, χ2 test or Fisher's exact test, heterogeneity χ2 test, odds ratios at 95% confidence intervals and logistic regression. RESULTS: Contralateral ovulation (i.e. ovulation jumping from ovary to the other) was more often observed in relatively younger women, who showed a higher probability of having a boy than after ipsilateral ovulation. There was a significantly higher frequency of boys being conceived following three consecutive ovulations with a left-left-right (LLR) ovulation pattern, while three ovulations from the left ovary (LLL) were associated with a higher frequency of girls. We also found two consecutive menstrual cycles the left-right (LR) ovulation pattern showed a similar significant difference compared to the left-left (LL) ovulation. Both the infertile and infertile + fertile women groups showing right-sided ovulation, regardless of age, showed significantly higher offspring sex ratio compared to left-sided ovulation, which was not observed in the group of fertile women alone. CONCLUSIONS: LLR, LR and contralateral ovulation happens more often in younger women and favors male offspring in infertile women. Right-sided ovulation favors male offspring in infertile and infertile + fertile women, which was not observed in the group of fertile women.

It is of interest to evaluate whether ovulation patterns change with women's ages at conception and affect offspring sex ratios. An observational clinical study was conducted in private OB/GYN clinics. Infertile women with regular menstrual cycles receiving intrauterine insemination (IUI) and/or in-vitro fertilization (IVF) had their ovulation patterns monitored in three consecutive spontaneous cycles receiving infertility treatment in the third cycle. Ovulation patterns were also observed in women with slight ovulation disorder during IUI and/or IVF in clomiphene citrate stimulated cycles. Women's ages and offspring sex ratios were compared to various ovulation patterns. The contralateral ovulation was more often observed in relatively younger women, who showed a higher probability of having a boy than following a pregnancy after ipsilateral ovulation. There was a significantly higher frequency of boys being conceived following three consecutive ovulations with after a left-left-right (LLR) ovulation pattern, while three ovulations from the left ovary (LLL) were associated with a higher frequency of girls. Only considering two consecutive menstrual cycles the left-right (LR) ovulation pattern showed a similar significant difference compared to the left-left (LL) ovulation. Both infertile and infertile + fertile women showing right-sided ovulation, regardless of age, showed significantly higher offspring sex ratio compared to left-sided ovulation, which was not observed in the group of fertile women alone. LLR, LR and contralateral ovulation happens more often in younger women and favor male offspring in infertile women. Right-sided ovulation favors male offspring in infertile and infertile + fertile women, which was not observed in the group of fertile women.

Effects of earthquakes and other natural catastrophic events on the sex ratio of newborn infants.

Stress due to earthquakes and other natural catastrophic events may result in a decline in the male to female ratio of newborn infants. One reason may be an increased death of male fetuses 3-5 months earlier. Another reason may relate to reduced conception of males and/or early male embryo demise 8-10 months earlier. Almost all of the earthquakes and natural catastrophic events have caused declines in sex ratios at birth except the Hurricane Katrina which showed a rise in the birth sex ratio. We describe hypothetical immunological cause for the decline in the sex ratio at birth following periods of augmented stress levels.

The male to female ratio of newborn infants in Japan in relation to climate change, earthquakes, fetal deaths, and singleton male and female birth weights.

We have updated our work regarding climate extremes in Japan and the consequences of the huge earthquake in the Fukushima Prefecture in year 2011. We have interchangeably used the term sex ratio at birth, sex ratio of births. This ratio describes the secondary sex ratio, whereas the primary sex ratio designates the male/female ratio at fertilization. The underlying mechanisms of declines in sex ratios at birth may be related to decreased fertilization of XY embryos by reduced motility of Y spermatozoa from male factor approach and increased cortisol secretion prior to conception from a female factor approach. We have shown that the declines in sex ratio at birth were observed 9 months after the Kobe earthquake but 10 months after the Tohoku and Kumamoto earthquakes. The temperature difference may be associated positively with sex ratio of fetal deaths and negatively with sex ratio of births and with singleton male and female birth weights.

Ultrasound Assessment of Lower Uterine Segment Thickness During Pregnancy, Labour, and the Postpartum Period.

OBJECTIVES: To evaluate the normal ranges of lower uterine segment (LUS) thickness throughout pregnancy in women without a previous cesarean and to evaluate the relationship between ultrasound and intraoperative LUS thickness. METHODS: We assessed LUS thickness using transabdominal and transperineal longitudinal scan at each week of gestation, during labour, and in the postpartum period in 1000 pregnant women without previous CS. Secondly, we assessed LUS thickness immediately before CS (using ultrasound) and intraoperatively (using ophthalmic calipers) immediately before delivery of the fetus in 35 women with a previous CS and 29 women without previous CS undergoing elective CS before labour. RESULTS: We performed 20 307 LUS thickness measurements in between 119 and 944 women at each week of gestation, in 944 women during labour, and in 936 women after delivery. We observed a strong relationship between transabdominal and transperineal ultrasound (P < 0.001) and an inverse correlation between LUS thickness and gestational age (P < 0.001), with a mean thickness of 5.1 ± 1.4 mm at 20 weeks, 3.6 ± 1.3 mm at 30 weeks, and 2.3 ± 0.6 mm at 40 weeks of gestation. In women undergoing elective CS, we observed a strong relationship between antepartum and intraoperative LUS thickness (P < 0.001), with mean thicknesses of 2.2 ± 0.7 mm in 28 women without thinning of LUS; 0.8 ± 0.1 mm in four women with grade II uterine scar dehiscence; and 0.4 ± 0.1 mm in three women with grade III dehiscence. A LUS myometrial thickness less than 1.2 mm could have predicted all grade II and grade III uterine scar dehiscences without false-positive cases. CONCLUSION: LUS thickness decreases with gestational age and correlates strongly with the intraoperative LUS thickness in women with a previous CS.

Climate change is associated with male:female ratios of fetal deaths and newborn infants in Japan.

OBJECTIVE: To evaluate whether climate change is associated with male:female ratios (sex ratios) of fetal deaths and births in Japan. DESIGN: A population-based cohort study. SETTING: Not applicable. PATIENT(S): Newborn infants and fetuses spontaneously aborted after 12 weeks of gestation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Yearly sex ratios of fetal deaths and newborn infants and monthly fetal death rates and sex ratios of newborn infants. RESULT(S): A statistically significant positive association was found between yearly temperature differences and sex ratios of fetal deaths; a statistically significant negative association was found between temperature differences and sex ratios of newborn infants from 1968 to 2012, and between sex ratios of births and of fetal deaths. The sex ratios of fetal deaths have been increasing steadily along with temperature differences, whereas the sex ratios of newborn infants have been decreasing since the 1970s. Two climate extremes, a very hot summer in 2010 and a very cold winter in January 2011, showed not only statistically significant declines in sex ratios of newborn infants 9 months later in June 2011 and October 2011 but also statistically significant increases of fetal death rates immediately, in September 2010 and January 2011. CONCLUSION(S): The recent temperature fluctuations in Japan seem to be linked to a lower male:female sex ratio of newborn infants, partly via increased male fetal deaths. Male concepti seem to be especially vulnerable to external stress factors, including climate changes.

Paternal smoking habits affect the reproductive life span of daughters.

The present study assessed whether the smoking habits of fathers around the time of conception affected the period in which daughters experienced menstrual cycles (i.e., the reproductive life span). The study revealed that the smoking habits of the farther shortened the daughters' reproductive life span compared with daughters whose fathers did not smoke.

The sex ratio of offspring is associated with the mothers' age at menarche.

BACKGROUND: Early menarcheal age is a risk factor for breast and ovarian cancers and is also associated with an increased spontaneous abortion rate. The aim of this study was to investigate whether there is a link between early menarcheal age and the offspring sex ratio. METHODS: We recorded the sex of 21208 live born infants, all singletons, born to 10 847 premenopausal women (mean attending age: 37.5 ± 7.2 years, range 22-54) who attended our clinics for obstetrical and gynaecological assessment. We calculated the sex ratio of newborn infants in relation to the mothers' age of menarche (from 9 to 18 years) and to the number of infants per woman (i.e. fertility index). RESULTS: A low offspring sex ratio (males/females) of 0.800 was observed in mothers who entered menarche at the age of 9 years; the odds ratio (OR) (95% confidence intervals) compared with those of control group with menarche at age 14 was 0.72 (0.29-1.79). The sex ratio remained low, until the group of mothers who entered menarche at 12 years of age [1.009; OR: 0.90 (0.85-0.95)]. The highest sex ratio was observed in mothers with a menarcheal age of 14 years (1.118; OR: 1.00 control) and it gradually decreased until the menarcheal age of 17 years [1.000; OR: 0.89 (0.15-5.26)]. The fertility index was also low in women with menarche at the age of 9 to 11 years. CONCLUSIONS: Women entering menarche outside the normal range, especially those with earlier menarche, may have an increased chance of producing female offspring.

The ovulation pattern during three consecutive menstrual cycles has a significant impact on pregnancy rate and sex of the offspring.

Identification of the ovary at the time of ovulation during three consecutive menstrual cycles results in one of eight ovulation patterns, left-left-right, right-left-right, left-right-right, and right-right-right of right-sided ovulation and right-right-left, left-right-left, right-left-left, and left-left-left of left-sided ovulation. Our data suggest that IVF and IUI treatment in cycles in which development of the preovulatory follicle(s) occurs in the right-sided ovary-and ovulations took place from the left-sided ovary in the preceding two cycles (left-left-right)-is likely to show the best pregnancy potential and high offspring sex ratio.

Levels of the epidermal growth factor-like peptide amphiregulin in follicular fluid reflect the mode of triggering ovulation: a comparison between gonadotrophin-releasing hormone agonist and urinary human chorionic gonadotrophin.

OBJECTIVE: To detect differences in follicular fluid (FF) levels of amphiregulin (AR), depending on mode of triggering final oocyte maturation. DESIGN: Prospective randomized trial. SETTING: Three IVF units. PATIENT(S): Ninety-six patients undergoing IVF-intracytoplasmic sperm injection. INTERVENTION(S): Ovulation triggered with either urinary hCG or GnRH agonist (GnRH-a). CONTROLS: 15 FF samples from small antral follicles (3-9 mm) and 12 FF samples from natural cycle. MAIN OUTCOME MEASURE(S): Follicular fluid concentration of AR, P4, E2, vascular endothelial growth factor, and inhibin B. RESULT(S): Significantly lower levels of AR were found in FF from the GnRH-a group versus the hCG group, 51±3.5 versus 71±6.0 ng/mL. In FF from natural cycles, levels of AR were significantly higher than those of GnRH-a triggering but significantly lower than those of urinary hCG triggering. In small antral follicles only 5 out of 15 follicles contained measurable amounts of AR. When urinary hCG and GnRH-a triggering were compared, FF P4 was significantly higher after urinary hCG triggering, whereas no difference was seen regarding E2, vascular endothelial growth factor, and inhibin B. A total of 14% more metaphase II oocytes and 11% more transferable embryos were obtained after GnRH-a triggering. CONCLUSION(S): This study suggests that oocyte competence is linked to granulosa cell AR secretion.

Ovulation jumping from the left to the right ovary in two successive cycles may increase the chances of pregnancy during intrauterine insemination and/or in vitro fertilization natural cycles.

Identification of the ovary from which ovulation takes place in two consecutive menstrual cycles results in one of four ovulation patterns, contralateral and ipsilateral ovulations on the right or on the left ovary. Our data suggest that IVF and IUI treatment in cycles in which development of the dominant follicle occurs in the right-sided ovary--and ovulation took place from the left-sided ovary in the preceding cycle (contralateral right-sided ovulation)--is likely to show the best pregnancy outcome.

Do basal oestradiol and oestradiol:androgens and oestradiol:FSH ratios reflect pregnancy potential of women receiving intrauterine insemination during natural cycles?

The aim of this retrospective study was to evaluate whether basal hormone profiles could be related to the ability to achieve pregnancy in women receiving intrauterine insemination (IUI) treatment during their natural menstrual cycle. Serum hormone profiles on cycle day 3 of naturally menstruating women were assessed in a total of 163 treatment cycles (29 conceptional and 53 non-conceptional cycles of 27 women who became pregnant and 81 non-conceptional cycles of 33 women who did not become pregnant). Basal concentrations of LH, FSH and prolactin were similar between conceptional and non-conceptional cycles. In contrast, concentrations of oestradiol in conceptional cycles (38 +/- 26 pg/ml: mean +/- SD) were significantly higher than those in non-conceptional cycles (23 +/- 18 pg/ml) (P = 0.0003). Concentrations of androstenedione and testosterone were lower but not significantly so in conceptional cycles as compared with non-conceptional cycles. The ratios of oestradiol/androstenedione, oestradiol/testosterone and oestradiol/FSH were significantly higher in conceptional as compared with non-conceptional cycles (29, 2.3, 6.2 versus 17, 1.2, 3.6 respectively) (all P < 0.006). Thus, increased concentrations of oestradiol and increased oestradiol/androgens and oestradiol/FSH ratios already on day 3 of the natural menstrual cycle correlate with the likelihood of achieving conception during the following IUI treatment. Therefore, measurement of basal hormones, including androstenedione and testosterone, may be useful to assess the health status of the coming dominant follicle.

Pregnancy outcome of embryonic/fetal pleural effusion in the first trimester.

OBJECTIVE: To investigate the incidence of embryonic/fetal pleural effusion in the first trimester and its pregnancy outcome. METHODS: A total of 965 viable singleton pregnancies confirmed by sonography between 7 and 10 weeks were examined to estimate the incidence of embryonic/fetal pleural effusion. When initial transvaginal sonography showed pleural effusion, serial ultrasound examinations were performed. RESULTS: Pleural effusion was detected in 12 pregnancies (incidence, 1.2%; 95% confidence interval, 0.7-2.2), which involved bilateral thoracic cavities in all cases. The pregnancy outcome was assessed among 14 cases of pleural effusion, including 2 previously reported cases from the same institution. Among these, 12 pregnancies (86%) miscarried by 14 weeks' gestation. Karyotype was abnormal in 9 (82%) of 11 cases in which chromosomal analysis was successfully performed. Of these, 6 (67%) were 45,X. CONCLUSIONS: The results suggested that embryonic/fetal pleural effusion in early pregnancy was associated with poor pregnancy outcome such as spontaneous abortion and chromosomal abnormality.