An autopsy case of lung cancer in a young adult dwarf

A 31-year-old man with peripheral squamous cell carcinoma is reported. By nature he was very small. On admission he was 140 cm tall, weighed 28 kg, and was complaining of chest pain of five years duration. A giant tumor in the right lung was found to be moderately differentiated squamous cell carcinoma. He also had congenital anomalies, such as crossed ectopic kidney with fusion, café-au-lait spots, inguinal hernia, simian line, etc. He had never been exposed to cancer-causing agents. In conclusion, genetic factors related to intrauterine growth retardation might have been linked to his oncodevelopmental mechanisms.     

Neonatal congenital leukemia caused by several missense mutations and AFF1-KMT2A fusion: A case report

Neonatal leukemia, a congenital form of leukemia, is a rare and fatal disease occurring in the neonatal period. Its etiology and pathogenesis have remained to be fully elucidated and the clinical manifestations differ due to age variability. Acute myeloid leukemia (AML) occurring after birth indicates genetic abnormalities and possibly intrauterine exposure to radiation, drugs or other toxins. The present report described the case of a premature neonate without phenotypic signs of Down syndrome, but with an elevated white blood cell count, mainly pertaining to the monocytes of peripheral blood. At 31 weeks of gestation, delivery by Caesarean section was performed due to fetal distress; however, the infant died three days after birth. Further laboratory examination indicated pediatric myeloid leukemia. The present case report described a case of fetal AML. According to the results of peripheral blood smear and targeted-panel sequencing, 5 missense mutations with clinical significance and a novel AFF1-KMT2A fusion gene were detected, which may be the main causes of AML and death.     

Modulation of benzo[a]pyrene-induced covalent DNA modifications in adult and fetal mouse tissues by gestation stage

In these studies, we investigated the influence of gestation age on the induction of covalent DNA modifications by benzo[a]pyrene (B[a]P). Timed-pregnant ICR mice were given a single treatment of B[a]P (80 mg/kg, p.o.) on different days of gestation, killed 24 h later and analyzed for the presence of B[a]P-induced DNA adducts using the P1 nuclease version of the 32P-postlabeling method. Our results showed that B[a]P bound to embryonic, placental, fetal and maternal DNA throughout gestation with gestation-stage dependency. Overall, B[a]P bound less to maternal DNA during organogenesis and placentation compared to other stages of gestation and to the non-pregnant stage. The ontogenesis of B[a]P-induced DNA adducts in fetal tissues exhibited organ specificity that had two different types of profiles. With advancing gestation age, one type (lung, carcass and placenta) exhibited a steady linear increase, and the other type [gastrointestinal tract (GIT) and skin] a biphasic increase. In the fetal and maternal organs, adduct levels peaked 2 days before parturition. Over the course of gestation, fetal adduct levels were 70-100% of adult levels in the skin, 7-12% in the GIT, 25-40% in the liver and 15-80% in the lung. The adduct levels in many fetal organs exhibited little relationship to placental adduct levels throughout gestation. Collectively, our results indicate that: (i) transplacental DNA damage induced by B[a]P is determined mainly by fetal competence in metabolic activation and/or detoxification of B[a]P; and (ii) events occurring during placentation and organogenesis inhibit B[a]P binding to maternal tissues.     

Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: This study was undertaken to determine the effect, if any, of prior treatment with radiation therapy or chemotherapy for Wilms tumor diagnosed during childhood or adolescence on live births, birthweight, and the frequency of congenital malformations. PATIENTS AND METHODS: We reviewed pregnancy outcomes among survivors of Wilms tumor treated with or without irradiation to the flank or tumor bed on National Wilms Tumor Studies 1, 2, 3, and 4 using a maternal questionnaire and review of both maternal and offspring medical records. RESULTS: We received reports regarding 427 pregnancies with duration of 20 weeks or longer, including 409 liveborn singletons for whom 309 sets of medical records were reviewed. Malposition of the fetus and early or threatened labor were more frequent among irradiated women. Both were more frequent among women who received higher radiation therapy doses. The offspring of the irradiated female patients were more likely to weigh less than 2,500 g at birth and to be of less than 36 weeks gestation, with both being more frequent after higher doses of radiation. An increased percentage of offspring of irradiated females had one or more congenital malformations. CONCLUSION: Women who receive flank radiation therapy as part of their treatment for Wilms tumor are at increased risk of fetal malposition and premature labor. The offspring of these women are at risk for low birthweight, premature (< 36 weeks gestation) birth, and the occurrence of congenital malformations. These risks must be considered in the obstetrical management of female survivors of Wilms tumor.     

Radiation therapy in pregnancy: risk calculation and risk minimization

The benefits of radiation therapy (RT) as part of a treatment regimen for cancer must be weighed against the potential risk of harm to the patient and in the pregnant patient, the risk to the developing fetus. Information necessary for determining the potential effects of RT on the developing fetus include the gestational age, absorbed fetal dose-equivalent, and dose-rate. The risk periods in humans for RT-induced prenatal or neonatal death, congenital anomalies, severe mental retardation (SMR), temporary (TGR) or permanent growth retardation (PGR), carcinogenesis, sterility, and germ cell mutations have been elicited directly from the study of Japanese victims of the atomic bombs and unintentional medical exposures, and indirectly from animal experiments. The wide range of congenital anomalies elicited from animal studies have not occurred in the Japanese atomic bomb victims exposed in utero. The major congenital anomaly observed in the Japanese cohort has been microcephaly. The highest risk period for SMR correlates with the proliferation, differentiation, and, most importantly, migration of neurons from their proliferative zones. PGR was apparent 17 years after ionizing radiation (IR) exposure at Hiroshima in children who were within 1,500 meters of the hypocenter. Children were on average 2.25 cm shorter, 3 kg lighter, and had head diameters 1.1 cm smaller than age-matched children. The projected lifetime risk of cancer mortality in the Japanese cohort is 14% per gray. The risk of a radiation-induced hereditary disorder is reported to be approximately 1% per gray. RT plays a major role in the definitive treatment of cervical and breast carcinomas, Hodgkin's disease, and non-Hodgkin's lymphoma. With appropriate abdominal shielding in place, the estimated fetal dose can be reduced by 50% or greater in most cases. In certain clinical situations, RT may be administered during pregnancy.     

Unclassified Osteochondrodysplasia in a 21-Year-Old Woman

A 21-year-old woman with unusual bone changes is described. The disease may have been present at birth but only facial abnormalities were recognised in infancy. Later, bilateral hip dislocation and stunted growth became apparent. X-ray examination during childhood showed microepiphyses of all the long bones, small round bones, dislocation of the hips and kyphoscoliosis. These changes showed little variability with growth. Unusual changes in the shape of the vertebral bodies took place during late childhood or adolescence. In the authors' opinion this is a previously undescribed type of spondyloepiphyseal dysplasia or an allied disorder.     

Apoptosis and human placenta: expression of proteins belonging to different apoptotic pathways during pregnancy

Apoptosis occurs during normal development and it is important for the right balance between the loss of old, non-functional cells and the formation of new cells in different organs and tissues. Apoptosis is triggered by different cell-type-specific signals which involve several pathways, such as mitochondrial and receptor-mediated pathways, resulting in caspase cascade activation. Several studies have suggested that apoptosis plays an important role in the normal development, remodelling and aging of the placenta. Moreover, it has been demonstrated that apoptosis increases as pregnancy progresses suggesting that it is a normal physiological phenomenon throughout gestation. In the last years, it has been hypothesized that the process known as syncytial fusion is directly or indirectly related to apoptotic events. In particular, it has been suggested that cytotrophoblast cells early express most important apoptotic proteins that translocate in the syncytiotrophoblast with the fusion. This suggests that apoptosis has a central role in the villous trophoblast turnover. Recently, another important involvement of apoptotic processes in human placenta has been demonstrated. In particular, the apoptosis, mainly through Fas-FasL or TRAIL-R-TRAIL signalling, may be a defence mechanism against rejection of the fetal allograft by maternal immune system. The whole data suggest that regulation of apoptotic events is important to allow a correct development, differentiation and function of the placenta throughout pregnancy and that an unbalance of this process leads to severe pathologies such as pre-eclampsia and intrauterine growth retardation. Therefore, due to its extensive proliferation and invasive properties, the placenta mimics a malignant tumor and represents an interesting model to evaluate those processes leading to carcinogenesis.     

Non-Endemic Burkitt's Lymphoma in a Patient with Bloom's Syndrome

Bloom's syndrome is an autosomal recessive disorder characterized by intrauterine growth retardation, typical physical signs, immunodeficiency and an increased risk of developing neoplasms at a young age, compared to the general population. Factors possibly involved in the pathogenesis of non-endemic Burkitt's lymphoma in a five year old girl with Bloom's syndrome are discussed. These include immunodeficiency, upregulated c-myc expression and an Epstein-Barr viral infection.     

Alpha-fetoprotein subfractions in amniotic fluid identified by a modification of the method of concanavalin A, lentil lectin or phytohemagglutinin-E affinity crossed-line immunoelectrophoresis

Using a modified method of concanavalin A (Con A), lentil lectin (LCH) or phytohemagglutinin-E (PHA-E) affinity crossed-line immunoelectrophoresis, alpha-fetoprotein (AFP) subfractions were studied in 33 samples of human amniotic fluid obtained between 41 and 287 days of gestation. Fetal tissues (yolk sac, liver, stomach and small intestine) obtained from a fetus of 68 days' gestation were incubated for 24 hours and AFP subfractions in the culture fluid examined. AFP in control amniotic fluids yielded two subfractions (types a and b) with Con A, three subfractions (types A, B and C) with LCH, and four subfractions (types W, X, Y and Z) with PHA-E. Serial changes of AFP subfractions in the amniotic fluid, as well as in the incubation study, indicated that the yolk sac and the gastrointestinal tract were responsible for the production of the Con A non-reactive subfraction (type b), the LCH weakly-reactive subfraction (type B) and the PHA-E reactive subfraction (types W and X), at an early stage of gestation. The Con A reactive subfraction (type a), LCH reactive subfraction (type A), PHA-E weakly-reactive subfraction (type Y) and PHA-E non-reactive subfraction (type Z) were assumed to be produced mainly by yolk sac, liver or gastrointestinal tract. We also found that the LCH non-reactive subfraction (type C) was synthesized either by liver or by the gastrointestinal tract at an early stage of gestation. At term, type a of Con A, type C of LCH and types Y and Z of PHA-E were the main subfractions in amniotic fluid, assumed to be produced by the fetal liver.     

Urodynamics of the lower urinary tract of the fetus during physiological pregnancy

To evaluate urodynamic parameters of the fetal lower urinary tracts in physiological pregnancy and without malformations, a monitoring of filling and voiding of fetal urinary bladder was made by the results of ultrasonic study of 76 fetuses at getation term 20-40 weeks. All the infants of the first year of life have undergone clinical examination of urination, 24-h monitoring of spontaneous voiding rhythms, ultrasonic measurements of residual urine. Normal urodynamic parameters of fetal lower urinary tract depending on gestation duration were obtained. These parameters can be used as prognostic criteria in diagnosis of intrauterine urinary disorders.     

Soft tissue and bone sarcomas in association with pregnancy

The occurrence of cancer in a pregnant woman is a relatively infrequent event. The influence of pregnancy on the initiation, promotion and development of sarcomas is yet unclear. The medical approach is strongly influenced by the type and site of the primary tumor, its growth rate and associated symptoms, and by the need to treat the woman while minimizing fetal toxicity. The medical files of seven pregnant women in whom sarcomas were diagnosed during gestation or 3-4 months after delivery were reviewed. Three had bone sarcomas, and four had soft tissue sarcomas. In five cases there were various reasons for the delayed diagnosis and treatment, including lack of any signs or symptoms during gestation, clinical misdiagnosis, religious attitude and refusal of the patients. Ancillary tests such as magnetic resonance imaging (MRI) and ultrasound, and biopsy, are safe during gestation. Adriamycin, ifosfamide and granisetron were administered in one case during the third trimester, without remarkable toxicity. Whenever a pregnant woman is diagnosed as having a malignant tumor, serious medical, ethical, emotional, religious and philosophical dilemmas arise. The mother's well-being and the risk to the fetus by introducing early diagnostic tests and treatment should be weighed against the risk to the mother and the well-being of the fetus in carrying on an uninterrupted gestation.     

Sarcoma of the Ewing Family in Pregnancy: A Case Report of Intrauterine Fetal Death after Induction of Chemotherapy

Ewing''s sarcoma is an ultra-orphan disease (2/1,000,000/year) which requires a multimodal therapy approach in high-volume centers. Treatment consists of pre-operative therapy followed by surgery and post-operative combination of chemo-radiotherapy. Experience with diagnosis and therapy of Ewing''s sarcoma in pregnancy is very limited. We herein report the case of an atypical Ewing''s sarcoma detected in the second trimester of gestation. Neoadjuvant chemotherapy was initiated and resulted in substantial tumor shrinkage and intrauterine fetal death. The rare nature of this condition underlines once more the need for a multidisciplinary team to improve the quality of care for this highly special patient collective.Key words: Ewing''s sarcoma, Pregnancy, Neoadjuvant chemotherapy, Intrauterine fetal death, Multidisciplinary team approach     

The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome

The autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) was first described in 1981 in patients living in Nijmegen, Holland. NBS patients display a characteristic facial appearance, microcephaly and a range of symptoms including immunodeficiency, increased cancer risk and growth retardation. In addition, NBS patient cells were found to have elevated levels of chromosomal damage and to be sensitive to ionizing irradiation (IR). This radiosensitivity had fatal consequences in some undiagnosed patients. The most dangerous DNA lesion caused by IR is considered to be the double-strand break (DSB) and indeed, NBS patient cells are sensitive to all mutagens that produce DSBs directly or indirectly. We discuss here our current understanding of how a deficiency in DSB repair manifests as the particular symptom complex of NBS.     

Differential effect of gestation stage on benzo(a)pyrene-induced micronucleus formation and/or covalent DNA modifications in mice

Benzo(a)pyrene (BP), an environmental carcinogen, binds ubiquitously to the DNA of maternal and fetal tissues (Lu et al., Cancer Res., 46: 3046-3054, 1986). These studies further investigated the effect of gestation age on the induction of genetic damage by BP. Timed-pregnant ICR mice were treated with one dose of BP on various days of gestation and sacrificed 24-120 h after treatment. At the molecular level, BP covalently bound to the DNA of adult bone marrow and fetal liver of mice at all gestation ages. Compared to the nonpregnant mice (adduct level = 15 adducts/10(8) bases), the adduct levels in the pregnant adult bone marrow were decreased up to 50% during early gestation (days 3-9) and then increased steadily to a 4-fold excess over nonpregnant values during late gestation (days 15-18). In the fetal liver, adduct levels exhibited little variation (3-4 adducts/10(8) bases) between days 11 and 15 of gestation and then increased sharply to 14 adducts/10(8) bases after day 16. At the cellular level, a higher percentage of polychromatic RBCs from adult and fetal mice after BP treatment contained micronuclei (MN) than controls (solvent or untreated). Bone marrow from pregnant mice exhibited greater increases in the formation of MN during early gestation (days 3-9) relative to late gestation (days 15-18), compared to the nonpregnant mice. In the fetuses, the amounts of MN formed were higher than those found in the adult nonpregnant or maternal mice, but these amounts decreased with gestation progression. Thus, MN induction with gestation progression differed from DNA adduction in adults and fetuses. In addition, the dose and time responses of MN formation also differed from those of covalent DNA modifications, when analyzed in the bone marrow of pregnant mice treated on gestation day 5. Collectively, our results showed that pregnancy and development modulate different types of genetic damage in different ways. Fetal tissues may be more sensitive than maternal tissues to genetic damage. Factors in addition to DNA adduct formation may be responsible for MN induction.     

Perinatal and familial risk factors for soft tissue sarcomas in childhood through young adulthood: A population-based assessment in 4 million live births

Perinatal factors have been associated with soft tissue sarcomas (STS) in case-control studies. However, (i) the contributions of factors including fetal growth remain unknown, ( ii ) these factors have not been examined in cohort studies and (iii) few assessments have evaluated risk in specific STS subtypes. We sought to identify the role of perinatal and familial factors on the risk of STS in a large population-based birth cohort. We identified 4,023,436 individuals in the Swedish Birth Registry born during 1973–2012. Subjects were linked to the Swedish Cancer Registry, where incident STS cases were identified. We evaluated perinatal and familial factors obtained from Statistics Sweden, including fetal growth, gestational age, and presence of a congenital malformation. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for associations between perinatal factors and STS overall, as well as by common subtypes. There were 673 individuals diagnosed with STS in 77.5 million person-years of follow-up. Having a congenital malformation was associated with STS (IRR = 1.70, 95% CI: 1.23–2.35). This association was stronger (IRR = 2.90, 95% CI: 1.25–6.71) in recent years (2000–2012). Low fetal growth was also associated with STS during the same time period (IRR = 1.86, 95% CI: 1.05–3.29). Being born preterm was associated with rhabdomyosarcoma (IRR = 1.74, 95% CI: 1.08–2.79). In our cohort study, those with congenital malformations and other adverse birth outcomes were more likely to develop a STS compared to their unaffected contemporaries. These associations may point to disrupted developmental pathways and genetic factors influencing the risk of STS.     

含铜宫内节育器的致畸作用评价

目的：评价含铜宫内节育器对SD大鼠的致畸作用。方法：试验设4组,分别为溶剂对照组（生理盐水）、给药组含铜宫内节育器浸提液,浸提比例分别为0.1、0.3和0.9g/ml）,每组24只孕鼠。各组于妊娠期第6～15天静脉注射给予受试物,于孕第20天时处死孕鼠,观察孕鼠一般状况、体质量、活胎数、胎鼠外观、骨骼及内脏等。结果：受试组孕鼠孕期的体质量增长、窝质量、黄体数、着床数、活胎数、胎鼠的身长、尾长等指标与溶剂对照组相比,差异均无统计学意义（P〉0.05）。但0.9g/ml组的吸收胎率（7.3%）较对照组（3.4%）明显升高（P〈0.05）。胎鼠外观、内脏及骨骼检查均未见畸形。结论：在本实验条件下,SD大鼠静脉注射含铜宫内节育器样品浸提液（0.1～0.9g/ml）,仅0.9g/ml时有早期胚胎发育毒性,各浓度均未见母体毒性与致畸性。     

Ethylnitrosourea-induced transplacental carcinogenesis in the mouse: tumor response, DNA binding, and adduct formation

We have confirmed previous results which suggest that transplacental exposure of fetal mice to carcinogens does not cause an increase in tumor incidence as they mature unless treatment occurs after midorganogenesis. In C3HeB/FeJ mice we found a negligible increase in tumor incidence and multiplicity following transplacental exposure to the direct-acting carcinogen ethylnitrosourea (ENU) on gestation day 10, but significant increases in lung and liver tumor incidence following exposure on days 13 or 15 or in adults. To explore the possibility that this observed difference is due to differences in the biodistribution of the carcinogen or its interaction with cellular macromolecules, the level of covalent binding between ENU and fetal and maternal DNA following an i.p. injection of a dose of 50 mg/kg of tritium-labeled ENU was measured 30 min after its injection into pregnant females on days 10, 13, and 15 of gestation. The DNA from fetal and maternal lung, liver, and brain was isolated and the amount of covalent binding estimated from the dpm/mg DNA recovered. Samples of DNA were hydrolyzed and chromatographed to determine that the bound tritium was associated with ENU-DNA adducts and not as a product of DNA synthesis. The level of binding of ENU to fetal DNA was equivalent at all gestation days studied but was significantly less than maternal tissues. Binding to the DNA of maternal liver was 4-fold greater than to fetal DNA while maternal lung and brain DNA were bound at intermediate levels. We conclude that the lack of carcinogenic response to ENU documented here, in fetal mice exposed early in gestation (day 10), is not due to differences in ENU binding to fetal DNA during development.     

Analyses of transplacentally induced sister chromatid exchanges and micronuclei in mouse fetal liver cells following maternal exposure to cigarette smoke

The effect of maternal exposure to cigarette smoke on the fetus was studied by analyses of sister chromatid exchange (SCE) and formation of micronuclei with fetal liver cells. Fetal tissues were obtained from pregnant ICR/Jcl mice at the 16th day of gestation. Mice were exposed to mainstream or sidestream cigarette smoke with or without passage through filter (gas phase smoke or whole smoke). Each stream of smoke was used for three exposure schedules, i.e., short-term (two exposures at 15th and 16th day of gestation), long-term (exposure started at 4 wk before mating and stopped at 16th day of gestation), and prepregnant term (exposed for 4 wk before mating). The number of SCEs of fetal liver cells was significantly increased in all exposed groups. In the mainstream experiments, the long-term group showed a significant increase in the number of SCEs in comparison with that in the short-term group. Exposure to sidestream smoke increased the number of SCEs more than in groups exposed to mainstream smoke. This tendency was also recognized in the experiments with filtered smoke. On the contrary, no significant changes were observed by the micronucleus test. The transplacental genotoxic effect of maternally inhaled cigarette smoke was accurately detected by analysis of SCEs with fetal liver cells.     

Cranial base surgery. Results in 183 patients

Objective To learn about the effects of cranial base surgery.Design Cohort study with a mean follow-up of 30 months.Setting Population-based.Patients A consecutive sample of 183 patients who underwent cranial base surgery; 118 patients had malignant skull base tumors, majority were previously treated; 50 had benign tumors, 9 patients had congenital malformations of the skull base; 3 patients had inflammatory lesions, and 3 had traumatic defects of the skull base.Main outcome measures Disease-free interval and overall survival as well as rate of complications and functional statusIntervention Cranial base surgery was followed by radiotherapy (in previously untreated patients).Results After completion of follow-up (30 months, mean), 30 (25.4%) patients had died of their malignant tumors and 8 (6.8%) had died of other causes. One patient (0.84%) was lost to follow-up. The overall cancer survival without regard to histologic type was 67% (63% with no evidence of disease). Among the patients who were treated for benign neoplasm 72% were NED at a mean 39 months of follow-up. The group of patients with congenital malformations, inflammatory, and traumatic lesions demonstrated successful correction of their pre-surgical problem with skull base surgery. One patient (invasive aspergillosis) died of disease. The overall surgical/medical mortality was 2%, complication rate was 33% and Karnofsky performance scale was improved or unchanged postoperatively in 83% of patients. The average duration of surgery, number of blood transfusions used and the length of the hospital stay was 10 hours, 3 units, and 15 days respectively.Conclusions Cranial base surgery is a valid surgical technique for cranial base afflictions. In this study it was found to be beneficial in controlling benign as well as malignant disease and be the treatment of choice in selected congenital malformations, trauma, and inflammatory lesions.This article is reprinted with permission from Otolaryngology-Head/Necksurgery (MOSBY Publish.)     

Peptidyl proline hydroxylase in adult, developing, and neoplastic rat tissues.

A sensitive assay system, optimally supplemented with tritiated protocollagen substrate and cofactors, is described which is suitable for determining the peptidyl proline hydroxylase (PPH) content of a wide spectrum of rat tissues. In most tissues, less than 50 percent of the total activity was soluble; the particulate portion of the activity (concentrated in the mitochondrial and microsomal fractions) was doubled by pretreatment with Triton X-100. Among normal adult tissues, lung had the highest total PPH activity (2.4 times that of liver) and small intestine had the lowest (25 percent that of liver). In brain and lactating mammary gland, the activity was similar to that in skin (60 percent of that in liver). Fetal tissues contained 3 to 8 times more PPH than the corresponding adult tissues, and a much lower portion of the total activity was soluble. In four tissues studied in detail (lung, liver, kidney, and brain), the total PPH declined rapidly during the last few days of gestation; brain attained its low adult value before term, whereas the other three tissues continued to decrease in the course of postnatal development. An injection of cortisol to fetal rats enhanced the decline of PPH in lung, liver, and skull. These experiments suggest that during normal differentiation the decline in collagen synthesis is initiated by fetal glucocorticoid secretion which is maximal on the 19th gestational day. PPH activity appears to be a sensitive indicator of neoplastic growth. In renal, mammary, muscle, and hepatic tumors, the PPH activities were 4 to 10 times higher than in the cognate adult tissue. Even in well-differentiated, slowgrowing tumors, the activity was considerably higher than in any normal, mature, or immature tissue, with the exception of the skull and lung of the 19-day-old fetus.