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.

How Diet and Lifestyle Can Fine-Tune Gut Microbiomes for Healthy Aging.

Many physical, social, and psychological changes occur during aging that raise the risk of developing chronic diseases, frailty, and dependency. These changes adversely affect the gut microbiota, a phenomenon known as microbe-aging. Those microbiota alterations are, in turn, associated with the development of age-related diseases. The gut microbiota is highly responsive to lifestyle and dietary changes, displaying a flexibility that also provides anactionable tool by which healthy aging can be promoted. This review covers, firstly, the main lifestyle and socioeconomic factors that modify the gut microbiota composition and function during healthy or unhealthy aging and, secondly, the advances being made in defining and promoting healthy aging, including microbiome-informed artificial intelligence tools, personalized dietary patterns, and food probiotic systems.

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.

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.

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.

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.

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.

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

Comments on R. H. Gray's 'The decline in mortality in Ceylon and the demographic effects of malaria control'.

Abstract With his article 'The Decline in Mortality in Ceylon and the Demographic Effects of Malaria Control', R. H. Gray has added a new contribution to the long discussion of the effects of malaria eradication on the abrupt mortality decline experienced by Ceylon immediately after World War II. He has used new information and at the same time introduced slight modifications in the statistical procedures designed to evaluate the validity of the hypothesis. However, certain aspects of his article need to be clarified; they are related to the methodology employed and to the theoretical approach used.

A new technique to estimate infant mortality with an application for El Salvador and Colombia.

The paper presents new estimates of infant mortality for Colombia and El Salvador for the years 1950--1970. These estimates are obtained by using a technique which improves on Brass's method in that it suppresses the assumption of constant mortality and introduces instead assumptions about linear and nonlinear changes in mortality risks affecting various cohorts of individuals.

Estimating infant and childhood mortality under conditions of changing mortality.

Summary It is well known that estimates of infant mortality obtained using Brass's technique are very accurate. Biases are introduced, however, when one or more of the assumptions on which it relies are violated. Departures from the assumption of constant fertility may be handled by using a variant of the technique which depends on information on the age distribution of surviving children, rather than on indexes of the fertility function. Violations of the assumption of constant mortality - an increasingly common situation in most developing societies - produce upward biases in the estimates. The amount of bias is a function of the speed of mortality decline, the characteristics of the fertility pattern and, finally, of the age of the mother. This paper presents a simple technique which corrects these biases, and in addition, generates estimates of the parameters of the mortality trend. It differs from others in that it uses a cohort definition of mortality decline and relies on knowledge of the age structure of surviving children rather than on indexes of the fertility pattern.

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

Estimation of adult mortality using forward and backward projections.

Summary In this paper it is shown that, contrary to our intuitive understanding of the nature of population projection, the estimation of adult intercensal mortality leads to different results depending on whether forward or backward projection of the population is used. From this result a simple procedure is developed that yields estimates of the completeness of adult mortality registration. Finally, the nature and performance of a variety of methods that have recently been developed to estimate adult mortality in the absence of accurate data are compared.

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

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

Mortality decline in Latin America: changes in the structure of causes of deaths, 1950-1975.

PIP: Some of the characteristics of the process of mortality decline in Latin America were studied for the 1955-73 period. General characteristics of mortality decline were examined and total and cause specific standardized death rates were examined in an effort to uncover the contribution of changes in the incidence of some diseases to the rate of decline in the initial stages of the process. The relationship between socioeconomic factors and total and cause-specific levels of mortality were also examined. Data on deaths by age groups and causes on various Latin American countries were collected from regular publications of the World Health Organization (WHO). Only those countries for which information was available at least at 1 point during the 1950s and at least once during the 1960s were included. Adult deaths (above age 5) were adjusted for completeness using techniques by Brass (1975) and Preston (1979). Causes of deaths were grouped into categories that allowed the comparability of the 6th, 7th, and 8th revisions of the International Classification of Diseases. Death rates specific for 5-year age groups were computed. The analysis supports the idea that the major contributors to the rapid process of mortality decline were, in this order: infectious diseases, influenza-pneumonia-bronchitis, and diarrhea. Respiratory tuberculosis and other diseases of early infancy were responsible for about 12% of the total decline. Of late there has been an apparent increase in deaths due to cardiovascular diseases and neoplasms, but cardiovascular diseases (probably of infectious origin) may have contributed positively to mortality decline, perhaps as much as 28% of the total decline (net of the effects of changes in the category of "ill defined" deaths). The association between the decline in malaria and the concomitant decline in other infectious diseases points to a confirmation of the hypothesis which attributed substantial weight to medical innovations because of the synergism among the diseases themselves. The source of the changes in mortality were found to correspond in almost equal measure to rising standards of living and to the contribution of exogenous factors: about 45% of the changes between 1955-73 were due to rising standards of living. Exogenous factors seemed to have left a more decisive imprint among countries in which malaria was endemic and within categories of such diseases (such as infections) which were most likely to be controlled without imposing the necessity of substantial transformations in standards of living.^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.

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.

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