Acute leukemias in pregnant women: Results of a retrospective study at a local tertiary-care hospital in Japan.

Leukemia may rarely develop in a woman during pregnancy, posing clinical challenges to the patient, fetus, family, and medical staff managing malignancy and pregnancy. We retrospectively analyzed cases of pregnancy-associated leukemia consecutively diagnosed and treated at a local tertiary-care hospital in Nagano, Japan, over the past 20 years. Five cases were identified among 377,000 pregnancies in the area (one in every 75,000 pregnancies), all involving acute leukemia (three acute myelogenous leukemia [AML] and two acute lymphoblastic leukemia [ALL]). The cases were diagnosed in the first trimester (n = 1), second trimester (n = 3), or third trimester (n = 1). There were no apparent pregnancy-associated delays in diagnosing and treating the cases. Three patients underwent induction chemotherapy during pregnancy, two of whom eventually delivered healthy babies. One of the five patients chose abortion before chemotherapy initiation. Two cases showing high-risk features at the diagnosis (AML with an FLT3-ITD mutation [n = 1] and relapsed ALL [n = 1]) eventually died despite consolidative allogeneic hematopoietic stem cell transplantation. Our results suggested that patients with pregnancy-associated acute leukemia can be treated similarly to nonpregnant patients, although pregnancy imposes particular clinical challenges that should be resolved with multidisciplinary care.

Anti-tumor effect of Wasabi component, 6-(methylsulfinyl) hexyl isothiocyanate, against endometrial carcinoma cells.

PURPOSE: Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. METHODS: The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. RESULTS: The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P < 0.05, 4 µmol/kg). Immunohistochemical staining of resected tumors revealed increased expression of Ki-67 and reduced cleaved-caspase3. Furthermore, 6-MITC treatment enhanced NK cell activity, especially when administered before tumor xenografting. CONCLUSION: These results indicate that 6-MITC has a marked anti-tumor effect against EMC cells and a novel effect to enhance NK cell activity. These effects suggest the therapeutic potential of 6-MITC.

PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium.

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.

Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

Clinical characteristics of a novel "Type 3" vasa previa: case series at a single center.

OBJECTIVE: Vasa previa is a condition in which fetal blood vessels are located on fetal membranes within 2 cm of the internal cervical os. Vasa previa has been classified into two types: Type 1, in which vessels connect a velamentous umbilical cord to the placenta, and Type 2, in which vessels connect the lobes of a bilobed placenta or the placenta to a succenturiate lobe. However, there are also atypical cases that cannot be classified into these two types. These cases are manifested by a center or marginal cord insertion with a normal shaped placenta, and fetal vessels were also located on membranes around the internal cervical os. These cases were recently proposed as Type 3 vasa previa. The present study investigated the incidence of Type 3 vasa previa and elucidated differences in clinical and ultrasonographical characteristics between traditional types and Type 3. METHODS: This was a single-center observational study using a cohort of all vasa previa cases between January 2010 and April 2020. RESULTS: Among 8,723 deliveries, there were 14 cases (0.16%) of vasa previa, all of which were diagnosed prenatally by US, not after vaginal delivery or CS. There were 9 (64%), 0, and 5 (36%) cases of Types 1, 2, and 3, respectively. All 5 Type 3 cases had only one fetal aberrant vessel of vasa previa, while 6 out of 9 Type 1 cases (67%) had two or more aberrant vessels. Seven Type 1 cases (78%) possessed two or more known risk factors, such as velamentous cord insertion, whereas all Type 3 cases only had one. Difficulties were associated with diagnosing two out of the 14 cases of vasa previa using routine transvaginal ultrasonography (TVUS). In these cases, the aberrant fetal vessel of vasa previa was only one vein with a thin wall that was not clearly visualized by gray-scale TVUS as well as slow flow that was easily misread by color-Doppler. These cases were ultimately diagnosed as vasa previa based on non-pulsatile flow detected by color and pulsed Doppler. CONCLUSIONS: The present results suggest that Type 3 may account for a large proportion of vasa previa cases. Most Type 3 cases may present with only one fetal aberrant vessel of vasa previa and fewer risk factors, suggesting that the diagnosis of vasa previa may be more challenging in Type 3 cases than in the other types. Vasa previa with a venous vasa previa needs to be considered because of the difficulties associated with an antenatal diagnosis due to unclear imaging of the vasculature or the lack of specific color Doppler flow patterns. Pulsed Doppler imaging may be helpful for the diagnosis of these cases.

Sawtooth fetal heart rate pattern associated with a favorable neurological outcome in an infant: a case report.

BACKGROUND: The sawtooth fetal heart rate pattern is rare, and has been reported as a possible indicator of neurological sequelae in newborns. However, we observed this fetal heart rate pattern in an infant with normal neurological function. CASE PRESENTATION: A 29-year-old primigravida Japanese woman presented to our hospital at 40 weeks and 1 day of gestation with marked vaginal bleeding. Since admission, fetal heart rate tracing consistently demonstrated a sawtooth-like pattern. There were 3-4 oscillations per minute, and their amplitude was 30-40 beats per minute. An emergency cesarean section was performed because of non-reassuring fetal status. Evidence of placental abruption was not observed. The newborn was a male weighing 2936 g, with an Apgar score of 1 and 3 at 1 minute and 5 minutes, respectively. The infant received brain cooling, but was discharged uneventfully. A follow-up examination at age 3 years demonstrated no developmental restriction. CONCLUSION: Although the Apgar score of the newborn was low, the infant had no neurological sequelae. Thus, the sawtooth fetal heart rate pattern may not be linked to in utero irreversible fetal central nervous system injury.

Clonality analysis suggests that STK11 gene mutations are involved in progression of lobular endocervical glandular hyperplasia (LEGH) to minimal deviation adenocarcinoma (MDA).

Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.

Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis.

Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.

Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene.

Hypoxia is known to play important roles in the development and progression of tumors. We previously demonstrated that S100A4, a critical molecule for metastasis, was upregulated in ovarian cancer cells. Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the increased binding of HIF-1α to a methylation-free HRE in ovarian carcinoma cells. These results indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the "metastatic phenotype."

Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin.

Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.