Clinicopathologic Features of NSCLC Diagnosed During Pregnancy or the Peripartum Period in the Era of Molecular Genotyping.

INTRODUCTION: Cancer will be diagnosed in one in 1000 women during pregnancy. The outcomes of NSCLC diagnosed during pregnancy are dismal, with most patients dying within 1 year. Actionable mutations are more likely to be found among younger patients with NSCLC. However, most previous reports of NSCLC diagnosed during pregnancy did not include molecular genotyping. METHODS: We performed a retrospective analysis of patients seen at our institution between 2009 and 2015 to identify women in whom NSCLC was diagnosed during pregnancy or the peripartum period and determined clinicopathologic features, including molecular genotype. RESULTS: We identified 2422 women with NSCLC, including 160 women of reproductive age. Among the women of reproductive age, eight cases of NSCLC diagnosed during pregnancy or the peripartum period were identified; all were diagnosed in minimal or never-smokers with metastatic adenocarcinoma. Six of these patients were found to have anaplastic lymphoma kinase gene (ALK) rearrangements, whereas the remaining two were EGFR mutation positive. We observed a borderline significant association between a diagnosis of NSCLC during pregnancy or the peripartum period and ALK positivity (p = 0.053). All eight women in whom NSCLC was diagnosed during pregnancy or the peripartum period received treatment with genotype-directed therapies after delivery. The median overall survival has not been reached at a median follow-up of 30 months. CONCLUSIONS: Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, diagnostic evaluation should not be delayed in pregnant women presenting with symptoms worrisome for lung cancer. Evaluation should include testing for targetable molecular alterations.

Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: short report from a single centre.

BACKGROUND: The aim of this work was to report on the outcome of pregnancy in patients with chronic myeloid leukaemia who were on tyrosine kinase inhibitor treatment. PATIENTS AND METHODS: We report the result of 22 pregnancies in 14 patients (9 female and 5 male) who conceived or their partner conceived while being on tyrosine kinase inhibitors for their CML. RESULTS: All pregnancies except one were uneventful. 25 newborns were born and except in one case where small atrial septal defect was diagnosed, all infants were healthy and showed normal development after birth. CONCLUSION: This small series does indicate that parents can most likely expect an uneventful outcome to a pregnancy despite exposure of either partner to TKIs. There is no consensus or guideline regarding the best practice in case of pregnancy. More reports of similar nature would certainly be beneficial to practitioners and patients alike. As such it is still recommended to practice effective contraception during the period of TKI treatment.

Placental steroidogenesis in pregnant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the placental activity of steroid sulfatase (STS), 3ß-hydroxysteroid dehydrogenase type 1 (3ß-HSD-1) and P450 aromatase (P450arom) in polycystic ovarian syndrome (PCOS) compared to normal pregnant women. DESIGN: Twenty pregnant women with PCOS and 30 control pregnant women who delivered at term were studied. Samples of placental tissue and cord blood were obtained after delivery. A maternal blood sample was obtained during the 34th week of gestation. In placental tissue, the activities of STS, 3ß-HSD-1 and P450arom were evaluated. In the blood samples, progesterone, DHEAS, DHEA, androstenedione, testosterone, estrone, estradiol and total estriol were determined. RESULT: In placental tissue from women with PCOS, higher 3ß-HSD-1 and lower P450 aromatase activities were observed compared to control women. Moreover, women with PCOS showed higher androstenedione and testosterone concentrations compared to normal pregnant women (p=0.016 and p=0.025, respectively). In cord blood, female newborns of women with PCOS exhibited lower androstenedione and higher estriol concentrations compared to daughters of control women (p=0.038; p=0.031, respectively). CONCLUSION: These data suggest that placental tissue from women with PCOS shows changes in the activities of two important enzymes for steroid synthesis, higher 3ß-HSD-1 and lower P450, which could increase androgen production during pregnancy.

Maternal smoking during pregnancy, genetic polymorphisms of metabolic enzymes, and childhood acute leukemia: the ESCALE study (SFCE).

PURPOSE: This study explored interactions between prenatal exposure to maternal smoking and polymorphisms in metabolic genes in the risk of childhood acute leukemia (AL). METHODS: The data were generated by the ESCALE study, which included 764 AL cases and 1,681 controls in 2003-2004. The data on maternal smoking during pregnancy were obtained by standardized telephone interview of the cases' and controls' mothers. The genotypes CYP1A1*2A/2B (rs4646903), CYP2E1*5 (rs2031920, rs3813867), NQO1*2 (rs1800566), NAT2*5 (rs1801280), and EPHX1 exon 3 (rs1051740) and exon 4 (rs2234922) were obtained using a high-throughput platform and imputation for untyped polymorphisms. The analyses were restricted to the 493 cases (433 cases of lymphoblastic (ALL) and 51 of myeloblastic (AML) leukemia) and 441 controls with at least 2 grandparents born in Europe, who were genotyped with individual call rates greater than 95%. Odds ratios were estimated by logistic regression in case-control analyses and, for gene-gene and gene-environment interactions, by case-only analyses. RESULTS: ALL and AML were not associated with either maternal smoking during pregnancy or candidate polymorphisms in CYP1A1, CYP2E1, EPHX1, and NQO1. Carrying two NAT2*5 alleles was significantly associated with ALL (OR = 1.8 [1.3-2.5]). The analyses also suggested an interaction between three genes involved in benzene metabolism CYP2E1, NQO1, and EPHX1. There was no interaction between maternal smoking and any of the polymorphisms under study. CONCLUSIONS: The ESCALE study did not evidence the interaction between CYP1A1*2A/2B and maternal smoking suggested previously. The association with NAT2*5 and the gene-gene interactions need to be replicated.

Pancreatic adenocarcinoma presenting as acute pancreatitis during pregnancy: clinical and radiologic manifestations.

Only seven cases of pancreatic adenocarcinoma diagnosed during pregnancy have been reported. In this article, we describe a case of pancreatic adenocarcinoma presenting clinically as acute pancreatitis in a pregnant patient. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) revealed a pancreatic mass with an inflammatory component and multiple hyperintense metastatic lesions in the liver. The patient was initially treated for biliary pancreatitis, and pancreatic cancer was not suspected given her young age and absence of risk factors. A diagnosis of pancreatic cancer in a pregnant patient requires a high index of suspicion, and pancreatitis can be a mode of presentation.

Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis.

Detoxification of ethanol can contribute to oxidative cellular and DNA damage and, thereby, to carcinogenesis. The potential relevance of this to breast carcinogenesis is suggested by evidence that alcohol consumption is a risk factor for breast cancer. It is, however, not known whether ethanol can be metabolized in breast parenchyma. The goal of this study was to determine whether class I and/or IV alcohol dehydrogenase (ADH), medium chain ADHs that can catalyze oxidation of ethanol, are expressed in human breast parenchyma. Normal and neoplastic human breast tissue specimens were examined for class I and IV ADH mRNA by reverse transcription-PCR, for protein by immunocytochemistry and Western analysis, and for their potential to catalyze NAD(+)-dependent oxidation of ethanol. Together, the findings provide evidence that: (a) class I ADH is the medium-chain ADH that is expressed in human breast parenchyma, specifically in the mammary epithelium; (b) human breast parenchyma can support ADH-mediated oxidation of ethanol; and (c) the expression of class I ADH is dramatically reduced or abrogated in invasive breast cancers. Expression of class I ADH in normal human breast parenchyma was confirmed by probing a multiple human tissue polyA(+)RNA. The unexpected finding of virtual abrogation of expression of class I ADH in invasive breast cancer suggests that the enzyme has some "tumor suppressor" function in the mammary epithelium. The one property of class I ADH fitting this designation is its potential to catalyze the oxidation of the micronutrient/prohormone retinol to retinal, the first step in the biosynthesis of retinoic acid, the principal known mediator of the actions of retinoids important for maintaining epithelia in a differentiated state.

Telomere length, telomerase activity and telomerase RNA expression during mouse mammary tumor progression.

To investigate the roles of telomere length (mean length of the terminal restriction fragments; TRFs), telomerase activity (TA) and telomerase RNA (mTR) expression in relation to mouse mammary tumor progression, we examined a pregnancy-dependent mouse mammary tumor line (TPDMT-4) and its four autonomous sublines (T4-OI320: non-metastatic; and T4-OI165, -OI96, and -OI145: artificial metastatic) of DDD/1 mouse origin, and an autonomous growing mammary tumor (JYG-MC) showing spontaneous lung metastasis developed in BALB/c mice infected with a Chinese feral mice (Sub-Jyg)-derived mouse mammary tumor virus (JYG-MTV). Compared with normal (pregnant) mammary tissue, the TA was elevated in the TPDMT-4 tumor and in the non-metastatic subline tumor (T4-OI320) (x10 fold, respectively), and was further increased (x13-15 fold) in parallel with the acquisition of metastatic potential (T4-OI165, -OI96, and -OI145). The mTR level was upregulated (x2.7-2.8 fold) in all autonomous growing tumors compared to the normal counter-part, but not in TPDMT-4. The TRF was shorter in accord with tumor progression (normal mammary tissue, 48 kb; TPDMT-4, 45 kb; T4-OI320, 37 kb; T4-OI165, -OI96 and -OI145, mean 37.7 kb; and JYG-MC, 21 kb). These results suggest that the activation of TA occurs as an early event at the stage of hormone-dependent tumorigenesis, followed by the up-regulation of mTR expression in accordance with the acquisition of autonomous growth, and then further activation of TA occurs when the tumor acquires metastatic potential. The TRF shortening was in parallel with the tumor progression.

Quantitative evaluation of human placental aromatase in abnormal pregnancy--anencephalus and hydatidiform mole.

To determine why estriol (E3) levels in the urine and serum are extremely low in pregnancies with anencephalus or hydatidiform mole, both the aromatase activity and the tissue P450arom concentration in solubilized fractions of placental or mole microsomes was measured. The aromatase activity was measured by tritiated water assay and the tissue P450arom concentration was determined by sandwich enzyme-linked immunosorbent assay (ELISA). Consequently, any tissue P450arom concentration was at a lower level than the regression line for that in normal placenta. The aromatase activity also showed a tendency to be lower than that in normal placenta. These results therefore suggest that a decrease of E3 in these abnormal pregnancies would result mainly in a lower level of tissue P450arom concentration.

Basal and interferon-induced 2',5'-oligoadenylate synthetase activity in human placental trophoblast and trophoblast-derived malignant cell lines.

Human placental trophoblasts produce interferon (tro-IFNs) when stimulated with viral inducers. Since the antiviral and cellular functions of IFNs are partly mediated by the 2',5'-oligoadenylate synthetase (2-5A synthetase) pathway, the aim of the present study was to determine the basal and IFN-induced levels of 2-5A synthetase in villous trophoblast cultures. A considerable basal level of 2-5A synthetase was observed in syncytiotrophoblast cultures from both first and third trimester. In contrast no basal activity was detectable in placental fibroblast- and trophoblast-derived malignant cell lines (Far, FEG-3, and BeWo). Stimulation with tro-IFN-beta, -alpha and leucocyte-IFN (leu-IFN)-alpha increased the enzyme activity in first and third trimester human syncytiotrophoblast cultures. Treatment with recombinant-IFN (rec-IFN)-gamma significantly enhanced 2-5A synthetase activity in first trimester syncytiotrophoblast, but had no effect on third trimester syncytiotrophoblast. Tro-IFN-beta, -alpha and leu-IFN-alpha induced high levels of 2-5A synthetase activity in placental fibroblast, BeWo and FEG-3 cell-lines, whereas rec-IFN-gamma treatment did not induce 2-5A synthetase activity in any of these cells. No detectable 2-5A synthetase activity was found in the Far cell line. The capability of cells deriving from the fetoplacental unit to raise an antiviral response by the induction of 2-5A synthetase may be important in defending the fetus against viral infection from the mother. Furthermore 2-5A synthetase in cells of the fetoplacental unit may play a role in their normal growth and development.

[The relation between granulocyte elastase activity in cervical mucus and gestational cervical polyp].

Granulocyte elastase activity in cervical mucus (elastase activity) was measured in pregnant women (10-20 gestational weeks) with cervical polyp and controls (gravida with no cervical polyp). Elastase activity in the cervical polyp group was 86 +/- 44 U/l, and that in the control group was 22 +/- 13 (p less than 0.01). Elastase activity after polypectomy was 44 +/- 24. It decreased significantly compared with prepolypectomy (p less than 0.05). A high level of elastase activity continued in cases without polypectomy. Immunohistochemical staining of elastase for cervical polyps was also performed. In the low elastase staining group there was low elastase activity (46 +/- 26 U/l). Elastase activity in the moderate staining group was 89 +/- 31, and that in the intense staining group was 114 +/- 31. As for the prognosis of patients with cervical polyps, the occurrence rate of chorioamnionitis is 9% in the control group, 14% in the polyp with polypectomy group and 40% in the polyp without polypectomy group. There was a significant difference between the polyp without polypectomy group and other groups (p less than 0.01). These data suggest that cervical polyp is a focus of inflammation and that it may cause chorioamnionitis. We conclude that cervical polyp during pregnancy should be removed. If polypectomy could not be performed, local anti-inflammatory and anti-infectious therapy would be needed.

[N-acetyltransferase activity during growth of the transplantable Pliss lymphosarcoma and during pregnancy in rats]. / Izuchenie aktivnosti N-atsetiltransferazy v dinamike rosta transplantiruemoi limfosarkoma Plissa i pri beremennosti u krys.

Study of the distribution of female noninbred rats according to N-acetyltransferase activity has permitted the conclusion to be derived that the animals may have a "slow", "intermediate" and "fast" phenotype of acetylation. It was discovered that the rate of N-acetyltransferase activity increased 1.5-2-fold on days 12 and 15 after transplantation of Pliss's lymphosarcoma. The time course of changes in N-acetyltransferase activity was characterized by individual features. The pattern of changes in N-acetyltransferase activity in pregnancy was dependent on the initial acetylation phenotype: in animals with a "slow" and "intermediate" phenotype of acetylation, the activity ascended by the 21st day of pregnancy, whereas in animals with a "fast" phenotype of acetylation, it declined.