Incidence of Neonatal Neutropenia and Leukopenia After In Utero Exposure to Chemotherapy for Maternal Cancer.

OBJECTIVE: The main purpose of this article was to report the incidence of neonatal neutropenia or leukopenia after chemotherapy exposure during pregnancy according to the time elapsed between treatment during pregnancy and birth. BACKGROUND: A single study reports 33% of infants exposed to chemotherapy within the last month of pregnancy are born with neutropenia, which can place the newborn at risk for nosocomial infections. On the basis of this report, chemotherapy is typically stopped by 34 weeks of pregnancy to avoid maternal or neonatal myelosuppression at delivery. Such a pause in treatment may affect maternal health. Determining the true incidence of neutropenia after chemotherapy in relation to the time of this lapse in treatment is important to support this practice. MATERIALS AND METHODS: Complete blood counts are collected for newborn whose mothers were treated for cancer during pregnancy and enrolled in the Cancer and Pregnancy Registry. Neutropenia was defined as absolute neutrophil count<1000 mm3 and leukopenia was defined as white blood cells <5000 cells/µL. Incidence of neutropenia was calculated according to the time elapsed from last chemotherapy treatment until birth. Fisher's exact test is used to determine if neutropenia or leukopenia is related to the time elapsed between chemotherapy during pregnancy and newborn birth. A Bayesian analysis evaluated the occurrence of neutropenia and leukopenia according to the number of days between the initiation of chemotherapy and birth. RESULTS: A total of 135 infants exposed to chemotherapy in utero with a complete blood count collected at birth were identified from the database. Only 7.3% and 2.9% of infants were born with neutropenia or leukopenia, respectively. The highest incidence of newborn neutropenia occurred in infants delivered 22 to 28 days after chemotherapy. CONCLUSIONS: The incidence of neutropenia peaks when chemotherapy is given 22 to 28 days before birth, while leukopenia is highest if delivery is <7 days from chemotherapy.

Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice.

The cytochrome P450 (CYP) 1 family is active toward numerous environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs). Utilizing a mouse model, null for Cyp1b1 and expressing human CYP1B1, we tested the hypothesis that hCYP1B1 is important for dibenzo[def,p]chrysene (DBC) transplacental carcinogenesis. Wild-type mCyp1b1, transgenic hCYP1B1 (mCyp1b1 null background), and mCyp1b1 null mice were assessed. Each litter had an equal number of siblings with Ahrb-1/d and Ahrd/d alleles. Pregnant mice were dosed (gavage) on gestation day 17 with 6.5 or 12 mg/kg of DBC or corn oil. At 10 months of age, mortality, general health, lymphoid disease and lung tumor incidence, and multiplicity were assessed. hCYP1B1 genotype did not impact lung tumor multiplicity, but tended to enhance incidence compared to Cyp1b1 wild-type mice (P = 0.07). As with Cyp1b1 in wild-type mice, constitutive hCYP1B1 protein is non-detectable in liver but was induced with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Wild-type mice were 59% more likely to succumb to T-cell Acute Lymphoblastic Leukemia (T-ALL). Unlike an earlier examination of the Ahr genotype in this model (Yu et al., Cancer Res, 2006;66:755-762), but in agreement with a more recent study (Shorey et al., Toxicol Appl Pharmacol, 2013;270:60-69), this genotype was not associated with lung tumor incidence, multiplicity, or mortality. Sex was not significant with respect to lung tumor incidence or mortality but males exhibited significantly greater multiplicity. Lung tumor incidence was greater in mCyp1b1 nulls compared to wild-type mice. To our knowledge, this is the first application of a humanized mouse model in transplacental carcinogenesis. © 2016 Wiley Periodicals, Inc.

Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.

We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50.

Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case-control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed.

Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to pesticides.

OBJECTIVE: To ascertain whether there was an association between parental occupational exposure to pesticides and increased risk of acute lymphoblastic leukaemia (ALL) in the offspring. METHOD: A population-based case-control study of childhood ALL was conducted in Australia. Information about the occupational pesticide exposure of mothers and fathers was collected using job-specific modules. Information on the types and extent of pesticide exposure was collected for mothers and fathers before and around the time of conception, and also for mothers during pregnancy for the index case or control and for 1 year after birth. RESULTS: Paternal occupational exposure to pesticides before or around conception was not related to increased risk of childhood ALL. There was a low prevalence of occupational exposure to pesticides among women that reduced after birth. CONCLUSIONS: Paternal occupational exposure to pesticides was not found to be associated with an increased risk of acute lymphoblastic leukaemia in the offspring. The study was underpowered with respect to maternal exposure to pesticides.

Impact of cancer therapies on ovarian reserve.

OBJECTIVE: To determine whether measures of ovarian reserve differ between females exposed to cancer therapies in a dose-dependent manner as compared with healthy controls of similar age and late reproductive age. DESIGN: Cross-sectional analysis of data from a prospective cohort study. SETTING: University medical center. PATIENT(S): Seventy-one cancer survivors aged 15-39 years; 67 healthy, similarly aged unexposed subjects; and 69 regularly menstruating women of late reproductive age (40-52 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Early follicular-phase hormones (FSH, E(2), inhibin B, antimüllerian hormone [AMH]) and ovarian ultrasound measurements (ovarian volume and antral follicle counts [AFC]) were compared using multivariable linear regression. RESULT(S): In adjusted models, FSH, AMH, and AFC differed between exposed vs. unexposed subjects (FSH 11.12 mIU/mL vs. 7.25 mIU/mL; AMH 0.81 ng/mL vs. 2.85 ng/mL; AFC 14.55 vs. 27.20). In participants with an FSH <10 mIU/mL, survivors had lower levels of AMH and AFC compared with controls. Alkylating agent dose score was associated with increased levels of FSH and decreased levels of AMH. Exposure to pelvic radiation was associated with impairment in FSH, AMH, AFC, and ovarian volume. Antimüllerian hormone was similar in women previously exposed to high-dose cancer therapy and 40-42-year-old controls. CONCLUSION(S): Measures of ovarian reserve are impaired in a dose-dependent manner among cancer survivors compared with unexposed females of similar age. Reproductive hormone levels in menstruating survivors exposed to high-dose therapy are similar to those in late-reproductive-age women. The predictive value of measures for pregnancy and menopause must be studied. CLINICALTRIALS.GOV IDENTIFIER: NCT01143844.

Do hormones influence melanoma? Facts and controversies.

The issue of whether hormones influence malignant melanoma (MM) has been controversial for many years. Although early case reports demonstrated a negative effect of hormones, recent evidence has not supported a potential role for hormones in MM. We address whether exogenous and endogenous hormones influence a woman's risk for MM or affect her prognosis if diagnosed with MM. Multiple epidemiologic studies show the use of oral contraceptives or hormone replacement therapy does not appear to increase a woman's risk for MM. Pregnancy does not appear to influence a woman's risk of MM, nor does pregnancy appear to affect prognosis in the woman diagnosed with MM. When counseling the woman who is diagnosed with MM during pregnancy or during the childbearing years, future use of oral contraceptives or hormone replacement therapy is not contraindicated; counseling concerning future pregnancies should be done on a case-by-case basis, with emphasis placed on established prognostic factors for MM.

CML in pregnancy and childhood.

With the improved survivals offered by the tyrosine kinase inhibitors has come the necessity to address issues relating to quality of life and one such area is that of fertility and parenting. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult males or females but human data remain limited. Children born to men who are actively taking imatinib at the time of conception appear healthy and current advice is not to discontinue treatment. In contrast the data relating to children born to women exposed to imatinib during pregnancy are less encouraging. Although numbers are small there has been a disturbing cluster of rare congenital malformations such that imatinib cannot be safely recommended, particularly during the period of organogenesis. The appropriate management of children with CML has also been radically changed by the advent of imatinib. The features of the disease at presentation, the natural history and the response to therapy seem to be identical in children to that seen in adults. Now that imatinib has been in clinical use for almost ten years without severe long-term side effects, most physicians are now comfortable advising a trial of imatinib prior to consideration of transplant. Data relating to the efficacy and safety of second generation tyrosine kinase inhibitors in childhood is entirely absent and transplant remains the first choice for patients failing imatinib and perhaps also for young patients with sub-optimal responses.

Malformations in the offspring of women with thyroid cancer treated with radioiodine for the ablation of thyroid remnants.

RATIONALE: Since ovarian function is only temporarily compromised by radioiodine therapy, many women with thyroid cancer treated with radioiodine can become pregnant. The present study evaluated the evolution of these pregnancies and the consequences for the offspring. PATIENTS AND METHODS: We retrospectively analyzed 78 pregnancies of 66 women submitted to total thyroidectomy, followed by radioiodine therapy 3.75-5.5 GBq (131)I, mean 4.64 GBq). In all patients, conception occurred one year after ablative therapy (mean of 30 months). Age ranged form 19 to 36 years (mean of 30.6 years) at the time of radioiodine treatment and from 23 to 39 years (mean of 32.8 years) at the time of conception. RESULTS: Four (5.1%) of the 78 pregnancies resulted in spontaneous abortions. Three (4%) of the 74 deliveries were preterm and there was no case of stillbirth. The birthweight was > 2500 g in 94.6% of the children (+/- SD: 3350 +/- 450 g) and only one infant (1.3%) presented an apparent malformation at birth (intraventricular communication). No difference in the age at the time of radioiodine therapy or conception or in radioiodine dose was observed between pregnancies with an unfavorable outcome and those with a favorable outcome. CONCLUSION: We conclude that pregnancies that occur 12 months after ablative therapy are safe.

Malformations in the offspring of women with thyroid cancer treated with radioiodine for the ablation of thyroid remnants / Malformações na prole de mulheres com câncer de tireóide tratadas com radioiodo para ablação de remanescentes tireoideanos

RATIONALE: Since ovarian function is only temporarily compromised by radioiodine therapy, many women with thyroid cancer treated with radioiodine can become pregnant. The present study evaluated the evolution of these pregnancies and the consequences for the offspring. PATIENTS AND METHODS: We retrospectively analyzed 78 pregnancies of 66 women submitted to total thyroidectomy, followed by radioiodine therapy (3.7­5.5 GBq 131I, mean 4.64 GBq). In all patients, conception occurred one year after ablative therapy (mean of 30 months). Age ranged form 19 to 36 years (mean of 30.6 years) at the time of radioiodine treatment and from 23 to 39 years (mean of 32.8 years) at the time of conception. RESULTS: Four (5.1 percent) of the 78 pregnancies resulted in spontaneous abortions. Three (4 percent) of the 74 deliveries were preterm and there was no case of stillbirth. The birthweight was > 2500 g in 94.6 percent of the children (mean ± SD: 3350 ± 450 g) and only one infant (1.3 percent) presented an apparent malformation at birth (intraventricular communication). No difference in the age at the time of radioiodine therapy or conception or in radioiodine dose was observed between pregnancies with an unfavorable outcome and those with a favorable outcome. CONCLUSION: We conclude that pregnancies that occur 12 months after ablative therapy are safe.

ARRAZOADO: Uma vez que a função ovariana está apenas temporariamente comprometida pela terapia com radioiodo, muitas mulheres com câncer de tireóide tratadas com radioiodo podem engravidar. O presente estudo avaliou a evolução dessas gravidezes e suas conseqüências para a prole. PACIENTES E MÉTODOS: Analisamos retrospectivamente 78 gravidezes de 66 mulheres submetidas a tiroidectomia total seguida de radioiodoterapia (3,7­5,5 GBq 131I, média 4,64 GBq). Em todas, a concepção ocorreu um ano após a terapia ablativa (média de 30 meses). A idade variou de 19 a 36 anos (media de 30,6) à época do tratamento com radioiodo e de 23 a 39 anos (média de 32,8) na época da concepção. RESULTADOS: Quatro (5,1 por cento) das 78 gravidezes resultaram em abortamento espontâneo. Três (4 por cento) dos 74 partos foram pré-termo, mas não houve nenhum natimorto. O peso ao nascer foi >2.500 g em 94,6 por cento das crianças (média ± DP: 3.350 ± 450 g) e somente uma delas (1,3 por cento) apresentou uma malformação aparente ao nascimento (comunicação intraventricular). Nenhuma diferença quanto à idade na época da radioiodoterapia ou na concepção ou na dose de radioiodo foi observada entre as gravidezes com ou sem um desfecho favorável. CONCLUSÃO: Gravidezes que ocorrem 12 meses após terapia ablativa com radioiodo são seguras.

Fibrolamellar hepatocellular carcinoma arising in a background of focal nodular hyperplasia: a report of 2 cases.

BACKGROUND: Fibrolamellar carcinoma, a rare variant of hepatocellular carcinoma, and focal nodular hyperplasia, a benign lesion, are rare hepatic lesions that are known to occur in young women with noncirrhotic livers. Some have suggested that fibrolamellar carcinoma might be the malignant counterpart of focal nodular hyperplasia. The coexistence of the 2 lesions is very rare. CASES: Two cases of fibrolamellar hepatocellular carcinoma arising in a background of focal nodular hyperplasia followed long-term oral contraception, and 1 of the 2 occurred during pregnancy. CONCLUSION: Distinguishing fibrolamellar carcinoma from focal nodular hyperplasia has important implications for treatment and prognosis. One should be aware of such conditions, especially in patients with a long history of oral contraception.

Diethylstilbestrol (DES) update: recommendations for the identification and management of DES-exposed individuals.

Diethylstilbestrol (DES) was etiologically linked to clear cell adenocarcinoma of the vagina in 1971. This article reviews on-going research and emerging information relevant to DES-related health risks, thereby enabling women's health care providers to maintain an evidence-based practice for their DES-exposed patients. To accomplish these goals, the Center for Disease Control and Prevention (CDC) has initiated a national education campaign. This article describes the reasons for this new initiative, the target audiences, the DES historical framework (including major studies and findings), and populations that are affected. Clinical steps for the identification and management of the DES-exposed individual and resultant implications for midwifery and women's health practices are reviewed.

Role of iron-dextran on 7,12-dimethylbenz(a) anthracene-initiated and croton oil-promoted cutaneous tumorigenesis in normal and pregnant mice.

Skin chemical carcinogenesis has been divided into the process of initiation, promotion and progression. Earlier, we showed the role of iron overload in the promotion stage of skin carcinogenesis. In this communication, we report that iron overload does not augment croton oil-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated pregnant mice skin tumorigenesis. Virgin female Swiss mice were given 1 mg iron/mouse/day parenterally for 2 weeks to induce iron overload. After the last injection, a group of mice was left with male mice for 10 days. These animals showed an increase in cutaneous iron concentration as compared to normal mice. Papillomas were induced in mice skin by a single topical application of DMBA as initiator. A week after the initiation, promoting agent, croton oil was applied twice per week for 20 weeks. The appearance of the first tumor (papilloma), number of tumors/mouse and percentage incidence were recorded. When compared to the iron unloaded control and iron overload pregnant groups, the iron overload virgin animals showed an increased incidence of tumors. In iron overload virgin animals, tumors appeared earlier and also the numbers of tumors/mouse were significantly higher. However, in iron overload pregnant animals, diminished tumor incidence was observed and the numbers of tumors matched the result of normal pregnant animals. Our results show that iron overload in pregnant mice does not participate in the augmentation of DMBA- and croton oil-induced skin tumorigenesis.

Breast cancer risk in rats fed a diet high in n-6 polyunsaturated fatty acids during pregnancy.

BACKGROUND: Women who took the synthetic estrogen diethylstilbestrol during pregnancy exhibit an elevated risk of breast cancer, whereas those who suffered from preeclampsia, which is associated with low circulating pregnancy estrogens, exhibit a reduced risk. Since a high-fat diet may increase circulating estrogen levels and possibly breast cancer risk, dietary factors during pregnancy could influence the risk of developing this disease. PURPOSE: We tested the hypothesis that consumption of a high-fat diet during pregnancy increases carcinogen-induced mammary tumor incidence in rats. METHODS: Pregnant or virgin female Sprague-Dawley rats that had been previously treated with 10 mg 7, 12-dimethylbenz[a]anthracene (DMBA) by oral gavage when 55 days old were assigned to one of two isocaloric diets containing either 16% calories from fat (low-fat) or 43% calories from fat (high-fat) for the length of pregnancy or for the equivalent time of approximately 21 days. There were 20 pregnant and 10 nonpregnant DMBA-treated rats per group. Ten additional pregnant animals (not previously treated with DMBA) per group were used for hormone analysis. The fat source used was corn oil, which is high in n-6 polyunsaturated fatty acids, primarily linoleic acid. The animals were checked for tumors at least once per week by palpation. The tumor size, number, and latency to appearance after carcinogen exposure were recorded. The statistical significance of observed differences was tested by use of appropriate two-sided tests. RESULTS: Female rats on different diets had virtually identical food intakes and weight gains during pregnancy. On gestation day 19, serum estradiol levels were approximately twofold higher in rats fed a high-fat diet than in rats fed a low-fat diet (P < .02). The serum insulin levels and insulin/glucose ratios (an index of insulin resistance) in rats fed the high-fat diet were approximately twofold lower than in rats fed the low-fat diet, but the differences did not reach statistical significance (P < .09 and P < .09, respectively). On week 18 following DMBA administration, the number of rats developing mammary tumors was significantly higher in the group exposed to a high-fat diet (40% of animals) than in the group exposed to a low-fat diet (10% of animals) during pregnancy (P < .05). Tumor multiplicity, latency to tumor appearance, and size of tumors upon first detection were similar among the dietary groups. No intergroup differences in the mammary tumor incidence were noted in virgin animals that were exposed to the high- or low-fat diets for an equivalent period of time. CONCLUSIONS: Our findings indicate that consumption of a diet high in fat (primarily in the form of n-6 polyunsaturated fatty acids) during pregnancy increases the risk of developing carcinogen-induced mammary tumors, possibly by increasing the pregnancy levels of circulating estrogens. IMPLICATIONS: If further studies find that the results from animal model studies are applicable to humans, some human breast cancers may be preventable by dietary manipulations during pregnancy.

Refractoriness to mammary carcinogenesis in the parous mouse is reversible by hormonal stimulation induced by pituitary isografts.

We have previously reported that mouse mammary epithelial cells transformed in vitro yield tumors which vary qualitatively and quantitatively as a function of the mitogenic environment in which the cells are propagated at the time of carcinogen treatment. One milieu supportive of transformation in vitro was medium supplemented with progesterone and prolactin as the mitogens. We have performed parallel studies in which virgin mice were isografted with pituitaries resulting in elevated serum titers of progesterone and prolactin. After carcinogen treatment, these mice developed mammary tumors which included those identical genotypically and phenotypically to tumors induced in vitro in cells grown in progesterone and prolactin during carcinogen exposure. Our current working hypothesis is that the mitogenic environment around the time of carcinogen administration can modulate the incidence and phenotype of the resultant tumors. To further test this hypothesis, we have evaluated the susceptibility of hormonally-stimulated parous mice to chemically induced mammary carcinogenesis since parity is known to significantly reduce the susceptibility of the mouse mammary gland to carcinogenesis. Virgin or multiparous BALB/c mice were isografted with two pituitaries. Five weeks after surgery, the mice were injected with N-methyl-N-nitrosourea (MNU; 50 micrograms/g i.v.). Mammary carcinomas arose in 85% (11/13) with a median latency of 22.8 weeks and 1.9 tumors per virgin mouse and 80% (24/30) with a median latency of 22.1 weeks at a frequency of 1.9 tumors per parous mouse. Only 14% (2/14) of the non-isografted, age-matched parous controls developed tumors when injected with MNU. Fourteen parous mice receiving only pituitary isografts (no MNU), did not develop mammary carcinomas within the 7-month period of the study. These results demonstrate that parous BALB/c mice are refractory to MNU-induced mammary carcinogenesis and that this refractoriness is not permanent, but can be overcome by hormonal stimulation mediated by pituitary isografts.

Promotive effects of diethylstilbestrol, its metabolite (Z,Z-dienestrol) and a stereoisomer of the metabolite (E,E-dienestrol) in tumorigenesis of rat mammary glands pregnancy-dependently initiated with radiation.

Wistar-MS rats received whole body irradiation with 260 cGy gamma-rays at day 20 of pregnancy and then were treated with diethylstilbestrol (DES), E,E-dienestrol (E,E-DIES) or Z,Z-dienestrol (Z,Z-DIES) for 1 year. DES administration caused the highest incidence of mammary tumors with a concomitant reduction of gain in body weight. When E,E-DIES or Z,Z-DIES in pellet form was implanted, the incidence of tumors was significantly lower than that observed in rats treated with DES. To clarify the increased susceptibility to mammary tumorigenesis after DES administration we measured hormone levels in the serum of rats implanted with pellets containing derivatives of the synthetic estrogens. The serum prolactin concentration was significantly increased by DES administration. When E,E-DIES or Z,Z-DIES pellets were implanted the prolactin level was markedly reduced to 4.5% and 0.7% of that observed in DES-treated rats, respectively. In addition, the serum concentrations of estradiol-17 beta and progesterone in rats with Z,Z-DIES pellets were higher than those of rats with DES or E,E-DIES pellets. A large number of DES-induced mammary tumors were positive for both estrogen and progesterone receptors, but no tumors negative for both receptors were obtained. The findings suggest that DES acts directly on radiation-initiated mammary cells via binding with estrogen receptors and/or stimulates the secretion of prolactin from the pituitary glands.