Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos.

BRCA1 associated protein-1 (BAP1) germline mutations define a novel hereditary cancer syndrome, namely BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by an increased susceptibility to develop different cancer types, including mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and basal cell and squamous cell carcinoma. Currently, the role of BAP1 germline mutations in intrahepatic cholangiocarcinoma (iCCA) pathogenesis is less known. Here we report the first clinical case of a female patient who developed an iCCA when she was 47-years-old and was found to carry a novel germline mutation at a splicing site of exon 4 in BAP1 gene (NM_004656.4: c.255_255+6del). An accurate anamnesis revealed the absence of risk factors linked to iCCA development, except for a low occupational exposure to asbestos. In tumor tissue, BAP1 sequencing, multiplex ligation-dependent probe amplification and immunoistochemistry showed the loss of heterozygosity and lack of nuclear expression, suggesting that BAP1 wild-type allele and functional protein were lost in cancer cells, in line with the classical two-hit model of tumor suppressor genes. Further studies are needed to confirm whether iCCA may be included into BAP1-TPDS cancer phenotypes and whether minimal asbestos exposure may facilitate the development of this malignancy in individuals carrying BAP1 germline mutations.

Searching for novel multimodal treatments in oligometastatic pancreatic cancer.

BACKGROUND: Metastatic pancreatic cancer has a median overall survival of less than 12 months, even if treated with chemotherapy. Selected patients with oligometastatic disease could benefit from multimodal treatments connecting chemotherapy and surgical treatment or radiofrequency ablation (RFA) of metastases. CASE PRESENTATION: We present a patient with oligometastatic pancreatic cancer recurrence who was successfully treated with a multimodal therapeutic approach. A 57-year-old male initially presenting with resectable pancreatic cancer underwent pancreatoduodenectomy. The histopathological diagnosis revealed ductal pancreatic adenocarcinoma with positive surgical resection margins and negative lymph nodes. He completed six cycles of adjuvant therapy with gemcitabine (1000 mg/mq 1,8,15q 28), followed by external radiotherapy (54 Gy in 25 fractions) associated with gemcitabine 50 mg/mq twice weekly. Three years later, the patient developed multiple liver metastases, and he started FOLFIRINOX (oxaliplatin 85 mg/mq, irinotecan 180 mg/mq, leucovorin 400 mg/mq and fluorouracil 400 mg/mq given as a bolus followed by 2400 mg/mq as a 46 h continuous infusion,1q 14) as a first-line treatment. The CT scan showed a partial response after 6 cycles. After multidisciplinary discussion, the patient underwent a laparotomic metastasectomy of the three hepatic lesions. After additional postsurgical chemotherapy with 4 cycles of the FOLFIRINOX schedule, the patient remained free of recurrence for 12 months. A CT scan showed a new single liver metastasis, which was treated with radiofrequency ablation (RFA). A second radiofrequency ablation was performed when the patient developed another single liver lesion 12 months after the first RFA; currently, the patient is free from recurrence with an overall survival of 6 years from the diagnosis. CONCLUSIONS: Our case has benefited from successful multimodal treatment, including surgical and local ablative techniques and systemic chemotherapy. A multimodal approach may be warranted in selected patients with oligometastatic pancreatic cancer and could improve overall survival. Further research is needed to investigate this approach.

Membrane human equilibrative nucleoside transporter 1 is associated with a high proliferation rate and worse survival in resected intrahepatic cholangiocarcinoma patients not receiving adjuvant treatments.

Human equilibrative nucleoside transporter 1 (hENT-1) is a membrane nucleoside transporter mediating the intracellular uptake of nucleosides and their analogues. hENT-1 was recently reported to have a predictive role in intrahepatic cholangiocarcinoma (iCC) patients receiving adjuvant gemcitabine-based chemotherapy, but its biological and clinical significance in iCC remains unsettled. This study investigated the role of hENT-1 in regulating tumour growth and predicting the survival of 40 resected iCC patients not receiving adjuvant treatments. hENT-1 expression was found to be significantly higher in iCC than in the matched non-tumoural liver. Patients harbouring hENT-1 localised on the tumour cell membrane had a worse overall survival than membrane hENT-1-negative patients (median 21.2 months vs 30.3 months, p = 0.031), with an adjusted hazard ratio of 2.8 (95% confidence interval 1.01-7.76). Moreover, membrane hENT-1-positive patients had a higher percentage of Ki67-positive cells in tumour tissue than membrane hENT-1-negative patients (median 23% vs 5%, p < 0.0001). Functional analyses in iCC cell lines revealed that hENT-1 silencing inhibited cell proliferation and induced apoptosis in HUH-28 cells expressing hENT-1 on the cell membrane, but not in SNU-1079 cells expressing the transporter only in the cytoplasm. Overall, these findings suggest that membrane hENT-1 is involved in iCC proliferation and associated with worse survival in resected iCC patients. Further prospective studies on larger cohorts are required to confirm these results and better define the potential prognostic role of membrane hENT-1 in this setting of patients.

The relationship between chronic stress, hair cortisol and hypertension.

Inconsistencies in studies of chronic psychosocial stress and hypertension may be explained by the use of stress markers greatly influenced by circadian rhythm and transient stressors. We assessed whether hair cortisol, a marker that captures systemic cortisol over months, was independently associated with hypertension. We measured hair cortisol and blood pressure in 75 consecutive participants in the Survey of the Health of Wisconsin, using an ELISA test. Individuals with values â€‹≥ â€‹median (78.1 â€‹pg/mg) were considered exposed. We used approximate Bayesian logistic regression, with a prior odds ratio of 1.0-4.0, to quantify the multivariate-adjusted hair cortisol-hypertension association. Participants' average age was 46.9 years; 37.3% were male; and 25.3% were hypertensive. Hypertension prevalence was 2.23 times higher in exposed (95% CI: 1.69-3.03). This finding was unlikely explained by differential measurement errors, since we conducted blinded measurements of exposure and outcome. Sensitivity analyses showed the association was unlikely explained by an unmeasured confounder, survival bias, or reverse causality bias. Findings suggest elevated hair cortisol is a risk factor for hypertension. Although feasible, the clinical value of hair cortisol as a tool for hypertension risk stratification or for monitoring the effect of chronic psychosocial stress management interventions is still uncertain.

Bone metastases in biliary cancers: A multicenter retrospective survey.

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

Una escala psicométrica breve para evaluar el estado cognitivo de hispanoparlantes de edad mayor / A short psychometric scale to evaluate the cognitive status of aged Spanish speakers

During the last ten years there has been an interest for determining the prevalence and incidence of dementia among older adults and for cognitive tests that do to discriminate by level of education. This article revolves around the validation of a minimental exam, the Cabán minimental, to measure the cognitive capacity of Spanish-speaking adults 60 years of age and older; a test that is not affected by level of education. The factors measured in the Cabán minimental are: orientation, visual and motor coordination, learning, recent memory and abstraction. The validation process underwent two phases. During the first one, the Cabán test was subjected to construct validation and internal and predictive consistency tests. The second stage comprised a comparison between the Cabán and Folstein minimentals. The Cabán showed a statistically significant difference to discriminate for subjects with dementia. Results also suggest that the Cabán is not as much affected as the Folstein by differences in education.

Interpreting the paradoxical in the hispanic paradox: demographic and epidemiologic approaches.

This paper discusses problems that are common to both the epidemiologic risk-factor approach and the demographic variable-based approach to studying population health. We argue that there is a shared reluctance to move away from a narrow variable-based thinking that pervades both disciplines, and a tendency to reify the multivariate linear procedures employed in both disciplines. In particular, we concentrate on the difficulties generated by classical variable-based approaches that are especially striking when one neglects selection processes and the use of strategies to minimize its effects. We illustrate these difficulties in terms of the so-called "Hispanic Paradox", which refers to comparative health advantages that some Hispanic groups appear to have. We find that much of what is conceived by demographers and epidemiologists as a paradox may not be paradoxical at all.

The effects of infant mortality on fertility revisited: new evidence from Latin America.

In this paper, we examine empirical evidence for a relation between infant and child mortality and fertility in Latin American countries from 1920 to 1990. We investigate the relation at several levels of aggregation and evaluate the extent to which evidence at one level is consistent with evidence at other levels. We first examine aggregate cross-country information over several decades, a type of data typically used in past research on the topic. We also examine yearly series of births, deaths, infant deaths, and socioeconomic indicators for selected countries to track the association between short-term fluctuations in fertility and infant mortality. Finally, we use micro-level data from the Demographic and Health Surveys (DHS) to assess the relation between fertility and child mortality from individual reproductive histories. The evidence we assemble from these different data sets is remarkably consistent and suggests small positive effects of infant mortality on fertility. These effects, however, may be too small to support the hypothesis that changes in child mortality are of more than modest importance in the process of fertility decline in Latin America in the late twentieth century.

Economic swings and demographic changes in the history of Latin America.

In this paper we study the effects of short-term fluctuations in indicators of economic well-being on selected demographic response such as births, marriages and deaths at age intervals in eleven Latin American countries between 1910 and 1990. We use conventional distributed lag models to assess the magnitude and direction of effects and test a variety of hypotheses some of which have been posed to hold in Western Europe and others that are more specific and tailored to the Latin American context. We also compare the magnitude and direction of effects obtained among these countries with those obtained for pre-industrial Europe and uncover the existence of broadly similar patterns.

Determinants of mortality among Cameroonian children: are the effects of breastfeeding and pace of childbearing artifacts?

"We analyse a rich data source, the Yaounde round of surveys [conducted] by IFORD (Institut de Formation et de Recherche Demographiques) during the late seventies and early eighties in several African urban centers. We argue that despite important limitations, these surveys are potentially very useful as a source of verification of hypotheses that have been heretofore improperly tested with retrospective surveys. Using the Yaounde round we obtain fine-tuned estimates of the effects of lactation and timing of following conception on infant and child mortality. We are able to identify the role played by birthweight, types of breastfeeding, and antecedent illnesses and thus control for important variables that are not normally recorded in conventional demographic surveys. We show that potential biases associated with losses to follow-up and selection processes are of little significance." (SUMMARY IN ITA AND FRE)

The effects of breast-feeding and the pace of childbearing on early childhood mortality in Mexico.

Using data from Mexico's Demographic and Health Survey, the authors examine the effects of breast-feeding and the pace of childbearing on early childhood mortality in a sample of 2,665 children born between 1982 and 1986. From a family planning perspective, they seek to assess the impact that changes in childbearing patterns and associated changes in breast-feeding patterns may have on infant and childhood mortality. This is done by integrating breast-feeding models with variables influencing the pace of childbearing. The analysis indicates that the effects of breast-feeding on infant mortality were strong, consistently negative, and statistically significant until at least the sixth month of life, after which they were considerably diluted. Among the other variables analyzed, the effects of a following conception on mortality were found to be very strong among infants 3-5 months old; and maternal age at delivery appeared to have some importance among infants 1-2 months old and among children in the second year of life. To examine likely interactions between family planning, breast-feeding, and mortality, an integrated model was applied that simultaneously considered these and a range of other variables. The results suggest that the effects of improved birth spacing and maternal age at delivery associated with family planning are powerful enough to cause 20-40% reductions in infant mortality. However, the effects of reduced breast-feeding associated with family planning are great enough to offset more than 60% of these benefits. Limitations of the model make it necessary to emphasize that all of these conclusions need to be accepted with caution.

Demographic responses to economic shocks: the case of Latin America.

PIP: People have long studied the relationship between economic trends and demographic parameters. However, in so doing, it is important to distinguish between the direct and usually short-term effects of economic change on demographic variables and longer-term, generally indirect, associations between economic and demographic conditions. This paper discusses the mechanisms through which economic recession and adjustment programs may affect demographic outcomes; implements a simple procedure to assess the magnitudes of the short-term economic effects of the recession on nuptiality, fertility, and mortality; and applies a technique using successive census age distributions to estimate the magnitude of past fertility and mortality fluctuations. To provide additional evidence of demographic responses to past crises, those indirect estimates are then compared with more direct ones obtained from historical records.^ieng

Changes in the family status of elderly women in Korea.

As a result of sharp declines in fertility and mortality, the aging of the Korean population has proceeded rapidly and is likely to continue in full force for some time. In societies such as Korea, where families traditionally have been the only efficient source of support for the elderly, an aging population poses a threat because families have fewer descendants available to care for increasing numbers of surviving elderly persons. The exact magnitude of the reduction in the supply of kin depends on details of the demographic trends and cannot be evaluated a priori. In this paper we use family-status life tables to assess the effects of changes in demographic processes on the family status of elderly women and to project trends in elderly women's family status.

Some aspects of the social context of HIV and its effects on women, children and families.

PIP: The effects of the HIV/AIDS epidemic on women and children in African countries are perpetrated by heterosexual contact. Women's multiple role as sexual companions, wives, daughters, and mothers impact on the spread of the virus and also on the social and economic effects of the epidemic on family members. If premarital sex is tolerated and the age at onset of sexual activity is indistinguishable from the age at menarche, young females will become exposed to HIV very early in their lives. The probability of not becoming infected between ages 15 and 25 in 3 HIV infectivity regimes (assuming the age of 15 for onset of sexual activity) indicated proportionately larger gains in HIV regimes of higher infectivity. A reduction of 15 years in the age gap between partners in a regime with an intermediate infectivity leads to an increase of about 24% in the probability of avoiding infection. In contrast, in the regime with highest infectivity, the gains multiply the probability of remaining uninfected more than 10-fold. Although the growing incidence of orphanhood should affect male and female children alike, if mortality and female children are excessive in fosterage arrangements female children may be inflicted disproportionately. Unless massive social remedies mitigate the growing orphanhood, the rates of school dropout, child-labor participation and outright abandonment will increase. Increased adult mortality will also raise the incidence of widow(er)hood. Women can reduce the risk of HIV sexual partners. Increased adult mortality could induce and overhaul of family arrangements where female children, mothers, and grandmothers are likely to bear the bulk of the personal, social, and economic burden in the absence of social interventions.^ieng

Formal models and methods for the analysis of kinship and household organization.

PIP: This paper discusses the use of formal models for analyzing kin-group and household organization. The authors begin by presenting a conceptual framework that relates the supply of kin to rules of household formation, demographic constraints, and observed household structure. This framework is used to evaluate an array of techniques and models of kinship and households. Kin relations and household structures can be described using a unifying model designed to identify the dynamic of a system of states out of and into which the units of analysis can move. The behavior of the system is identified through knowledge of transition rates. It is then possible to link such transition rates to coarse indicators of the system, such as proportions occupying a state and distribution of the units by state. Analytic, macro-, and microsimulation models are just alternative ways of linking a state-space and measures of transition rates to final indicators or outcomes. No model can avoid addressing the independence, homogeneity, and time-invariance assumptions, or the 2-sex problem.^ieng

The effects of breastfeeding and pace of childbearing on mortality at early ages.

The effects of the pace of childbearing and breastfeeding practices on infant mortality have rarely been considered together. In this paper, we design and use a set of methodological tools to test a variety of hypotheses postulating the effects of breastfeeding and pace of childbearing on mortality in infancy and early childhood, the mechanisms through which those effects operate, and the contingencies that strengthen or weaken them. The strong effects of both length of breastfeeding and the pace of childbearing on the risks of child death suggest that neither of them exerts an impact on mortality totally mediated by the other. Social and demographic factors (such as age of child, education of mother, and region of residence) also condition the impact of breastfeeding and pace of childbearing on mortality.

Re-estimation of structural parameters to obtain estimates of mortality in developing countries.

PIP: The introduction of new models of mortality is intended to provide a representation of age/sex patterns of mortality which are closer to those underlying the mortality experience of developing countries. With the publication of new model life tables for developing countries by the UN, it is now possible to provide more reliable formulations for indirect mortality measurements. This paper provides improved regression equations for transforming survivorship of kin statistics into measures of infant, early childhood and adult mortality. After a short description of the mortality models upon which the new methods are based, the 1st section covers the treatment of estimation of mortality in infancy and childhood. The 2nd section is devoted to transformations of orphanhood data into conditional probabilities of surviviorship for adults. Finally the 3rd section provides an illustrative application of the new equations to the case of Peru (1960-1978). Emphasized throughout the paper is the quite different issue of not just selecting between appropriate mortality models but also between appropriate techniques.^ieng

Assessing the effects of intermediate variables on birth interval-specific measures of fertility.

PIP: This paper proposes a technique to simultaneously assess the effect of selected intermediate variables on the dynamics of birth intervals and to aggregate such effects across births of different order. The essentials, virtues and limitations of other approaches are 1st summarized. A method to link measures of birth interval dynamics to aggregated measures of fertility such as the age-specific fertility rates and total fertility is explained. A set of operations is suggested, required to translate estimates of birth interval-specific effects of intermediate variables into aggregate effects (e.g., effects at the level of fertility rates). These operations effectively permit the synthesis of results from multivariate procedures and those of techniques aimed at decomposing the effects of intermediate variables. Discussed are estimation and measurement procedures to deal with deal available from retrospective interviews carried out as part of the World Fertility Survey (WFS) program. The effects of marriage pattern are not considered. The effects of lactation are measured by using a dichotomous variable with a value of 1 if the preceding child was breast fed for at least as long as 9 months less than the beginning of the segment of interest and 0 otherwise. Following the assignment of a measure of effectiveness, 3 groups are distinguished in measuring contraceptive use: non-contraceptors, those using an ineffective method, and effective contraceptors. With respect to measuring the effects of induced abortion and spontaneous fetal losses, a variable is created indicating whether or not a birth leading to a fetal loss or the fetal loss itself had occurred within the segment being examined. 2 indicators, 1 a binary variable and the other aimed at measuring gradations of sterility are introduced to measure exposure to intercourse and sterility. Logit regression coefficients for selected intermediate variables are presented for Peru. The tables reveal the power of the variables measuring contraception. The evidence offers strong indications to support the contention that some form of birth control makes a difference as it does to confirm a priori expectations about success of different types of users. The inhibiting effects of breast feeding are generally in the direction expected but they are not always statistically significant. They appear to be stronger at higher parities and more intense in the earlier parts of the birth intervals. The effects of the variable representing continuity of marital union are surprisingly strong and significant for all segments of 10 months of width and for all births of order higher than 1.^ieng