Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study.

BACKGROUND: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce. PATIENTS AND METHODS: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded. RESULTS: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009). CONCLUSIONS: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment.

Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy.

Since the MOSAIC study, oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer. Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival (OS) and reduced the risk of recurrence in patients with resected stage III colon cancer. However, only 20% of patients really benefit from adjuvant chemotherapy, exposing 80% of patients to unnecessary toxicity. Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease. Indeed, clinical and pathological prognostic factors, although important, are not sufficient to decide which stage III patients will benefit from adjuvant therapy, and biomarkers will help select patient that need adjuvant treatment. Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored, and molecular signatures have been identified as promising prognostic factor for OS. Furthermore, recent studies have highlighted the prognostic value of immune infiltration. This review focuses on pathologic, immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach.

Anaesthetists' experiences with the early labour epidural recommendation for obese parturients: a qualitative study.

Caring for obese pregnant women presents challenges for all medical professionals. Despite a lack of supporting evidence, expert opinion and international guidelines suggest early labour epidural insertion for obese women. Anecdotally this is not supported by all anaesthetists. This qualitative study explored the experiences of anaesthetists regarding early epidural analgesia in obese parturients, to answer the research question: Are anaesthetists consistent in how they apply early epidural analgesia in obese parturients? Personal in-depth interviews with 42 specialist anaesthetists working in south-east Queensland, Australia, were completed between February and April, 2015. Leximancer™ text analysis software applied a validated algorithm to the data to identify themes and concepts. The major themes were explored by the first author to answer the research question. Three major themes were identified: the demands associated with caring for obese women; concern regarding the anaesthetic technique used in obese women; and the importance of communication with obstetric staff. Disagreement regarding interpretation and application of early epidural analgesia was identified within this group of anaesthetists. These anaesthetists were inconsistent in how they interpreted and applied early epidural analgesia for obese parturients, with some questioning the validity of the practice. The combination of uncertainty, urgency and technical difficulty presented by obese parturients provoked anxiety in these clinicians, particularly the anticipation of unplanned general anaesthesia. Consistent anaesthetic practice could improve the implementation of early epidural analgesia in obese parturients.

Methylator phenotype in colorectal cancer: A prognostic factor or not?

Colorectal cancer (CRC) is due to different types of genetic alterations that are translated into different phenotypes. Among them, CpG island methylator phenotype (CIMP+) is the most recently involved in carcinogenesis of some CRC. The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes. CIMP+ are reported to be more frequently found in the elderly and in women. The tumors are more frequently located in the proximal part of the colon, BRAF mutated and are associated with microsatellite instability (MSI) phenotype. All sporadic MSI CRC belong to the methylator phenotype, however some non MSI CRC may also harbor a methylator phenotype. The prognostic value of CIMP is not well known. Most studies show a worse prognosis in CIMP+ CRC, and adjuvant treatments seem to be more efficient. We review here the current knowledge on prognostic and predictive values in CIMP+ CRC.

Women's attitudes towards the use of complementary and alternative medicine products during pregnancy.

The aim of this study was to analyse women's attitudes towards the use of complementary and alternative medicine (CAM) products during pregnancy. The study sample was obtained via the Australian Longitudinal Study on Women's Health or ALSWH. A response rate of 79.2% (n = 1,835) was attained. Women who use herbal medicines (34.5%, n = 588) view CAM as a preventative measure, are looking for something holistic and are concerned about evidence of clinical efficacy when considering the use of these products during pregnancy. Women who use aromatherapy (17.4%, n = 319) and homoeopathy (13.3%, n = 244) want more personal control over their body and are concerned more about their own personal experience of the efficacy of CAM than clinical evidence of efficacy. As CAM use in pregnancy appears to be increasingly commonplace, insights into women's attitudes towards CAM are valuable for maternity healthcare providers.

Fatal necrotizing fasciitis due to necrotic toxin-producing Escherichia coli strain.

We report a fatal case of necrotizing soft tissues infection caused by an Escherichia coli strain belonging to phylogenetic group C and harbouring numerous virulence factors reported to be part of a pathogenicity island (PAI) such as PAI IIJ96 and conserved virulence plasmidic region.

Older adults' trait ratings of three age-groups around the Pacific rim.

In this paper, we assess the traits that older adults associate with younger, middle-aged, and older adults in five Pacific Rim nations from Western and Eastern cultural traditions (Australia, People's Republic of China (PRC), Hong Kong, Philippines, Thailand). We find cross-cultural trends which replicate patterns found in the US context. In most cultures, attractiveness, strength, activity, liberalism, health, and flexibility are seen to decline with increasing age. Kindness assessments are positively associated with age across cultures. Mixed patterns are found with assessments of wisdom and generosity, with respondents from the PRC and Hong Kong being notably more negative about increasing age than other respondents. Implications for the aging process across cultures are discussed, and suggestions made for future research.

Antiproliferative properties of sphingosine 1-phosphate in human hepatic myofibroblasts. A cyclooxygenase-2 mediated pathway.

Proliferation of hepatic myofibroblasts (hMF) is central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with growth-regulating properties, either via Edg receptors or through intracellular actions. In this study, we examined the effects of S1P on the proliferation of human hMF. Human hMF expressed mRNAs for the S1P receptors Edg1, Edg3, and Edg5. These receptors were functional at nanomolar concentrations and coupled to pertussis toxin-sensitive and -insensitive G proteins, as demonstrated in guanosine 5'-3-O-(thio)triphosphate binding assays. S1P potently inhibited hMF growth (IC(50) = 1 microm), in a pertussis toxin-insensitive manner. Analysis of the mechanisms involved in growth inhibition revealed that S1P rapidly increased prostaglandin E(2) production and in turn cAMP, two growth inhibitory messengers for hMF; C(2)-ceramide and sphingosine, which inhibited hMF proliferation, did not affect cAMP levels. Production of cAMP by S1P was abolished by NS-398, a selective inhibitor of COX-2. Also, S1P potently induced COX-2 protein expression. Blocking COX-2 by NS-398 blunted the antiproliferative effect of S1P. We conclude that S1P inhibits proliferation of hMF, probably via an intracellular mechanism, through early COX-2-dependent release of prostaglandin E(2) and cAMP, and delayed COX-2 induction. Our results shed light on a novel role for S1P as a growth inhibitory mediator and point out its potential involvement in the negative regulation of liver fibrogenesis.

Attachment style as a piedictor of sexual attitudes and behavior in late Adolescence.

Abstract This research applied attachment theory to the study of sexual attitudes and behaviors in a sample of late adolescents. Four hundred and seventy heterosexual undergraduate students completed questionnaires assessing attachment (discomfort with closeness; anxiety over relationships). relationship history, communication about sex. sexual self-efficacy and locus of control, and attitudes to condoms. Eight weeks later, participants reported on sexual behaviors occurring during the eight-week interval. and perceived risk of these activities. Both discomfort with closeness and anxiety over relationships were associated with external locus of control for sexual outcomes, and with use of drugs before sexual contact. Anxiety over relationships was linked to unsafe sex and to negative attitudes to condoms, but discomfort with closeness was associated with a more cautious approach to sexual risk-taking. Some results were qualified by gender differences. and by differences between the full sample and those who were sexually active. The findings arc discussed in terms of attachment style and its links with communication and affect regulation. SUMMARY AND CONCLUSIONS This study indicates that attachment dimensions are reliably related to many aspects of sexual attitudes and behaviors among late adolescents. Insecure attachment was linked to increased drug use before sexual contact. Anxiety over relationships was also linked to less safe sexual practice, but discomfort with closeness was associated with a tendency for males to be cautious about sexual risk-taking. The results support the utility of the attachment perspective on adolescent sexuality, but also highlight the complex relations between attachment dimensions and sexual outcomes. Future research would benefit from more detailed investigations of the attitudes, emotions, and cognitions which may mediate the link between attachment style and sexual behavior. For example, those who are highly anxious about their relationships may engage in more risky sexual practices because they fear that non-compliance with partners' wishes will jeopardize their relationship; the tendency to engage in drug use before sexual cpntact may reflect their attempts to boost self-confidence or to manage negative mood states. Research into these issues has the potential to explain how attachment insecurity is played out in patterns of sexual activity.

Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells.

During chronic liver diseases, hepatic stellate cells (HSC) acquire a myofibroblastic phenotype, proliferate, and synthetize fibrosis components. Myofibroblastic HSC (mHSC) also participate to the regulation of intrahepatic blood flow, because of their contractile properties. Here, we examined whether human mHSC express natriuretic peptide receptors (NPR). Only NPR-B mRNA was identified, which was functional as demonstrated in binding studies and by increased cGMP levels in response to C-type natriuretic peptide (CNP). CNP inhibited mHSC proliferation, an effect blocked by the protein kinase G inhibitor 8-(4 chlorophenylthio)-cGMP and by the NPR antagonist HS-142-1 and reproduced by analogs of cGMP. Growth inhibition was associated with a reduction of extracellular signal-regulated kinase and c-Jun N-terminal kinase and with a blockade of AP-1 DNA binding. CNP and cGMP analogs also blunted mHSC contraction elicited by thrombin, by suppressing calcium influx. The relaxing properties of CNP were mediated by a blockade of store-operated calcium channels, as demonstrated using a calcium-free/calcium readdition protocol. These results constitute the first evidence for a hepatic effect of CNP and identify mHSC as a target cell. Activation of NPR-B by CNP in human mHSC leads to inhibition of both growth and contraction. These data suggest that during chronic liver diseases, CNP may counteract both liver fibrogenesis and associated portal hypertension.

Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors.

Proliferation of myofibroblastic hepatic stellate cells (HSC) in response to growth factors is essential for the development of liver fibrosis. We have reported that prostaglandins (PG) and cyclic AMP (cAMP) inhibit growth of human HSC. This PG/cAMP pathway transduces the endothelin (ET) B-mediated antiproliferative effect of endothelin-1 (ET-1) and up-regulates ETB receptors. Here, we show that platelet-derived growth factor (PDGF)-BB and thrombin, although mitogenic, generate growth inhibitory PGE2 in myofibroblastic human HSC. The two peptides elicit early PGE2 and cAMP synthesis, and also promote delayed induction of cyclooxygenase (COX)-2. Both early and delayed production of PGE2 counteract the mitogenic effect of PDGF-BB and thrombin because: (i) pretreatment with the COX inhibitor ibuprofen markedly enhances the mitogenic effect of both peptides; (ii) blocking early synthesis of PGE2 greatly enhances extracellular signal-regulated kinase (ERK) activation by both growth factors; (iii) enhancement of DNA synthesis by ibuprofen is only lost when the inhibitor is added after COX-2 induction has occurred. Finally, PDGF-BB and thrombin raise ETB receptors through the PG pathway. Thus, ibuprofen blunts growth factor-induced increase in ETB receptors. Up-regulation of the growth inhibitory ETB receptors by both mitogens may enhance the antiproliferative effect of ET-1 and thereby establish a negative feedback of their mitogenic effect. Our results shed light on novel growth inhibitory signals evoked by two mitogenic growth factors expressed during liver injury.

Role of NF-kappaB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2.

During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype and proliferate and synthesize fibrosis components. Endothelin-1 (ET-1), which inhibited the growth of human myofibroblastic HSC, increased the formation of two NF-kappaB DNA binding complexes; this effect was also observed with tumor necrosis factor-alpha (TNF-alpha). The complexes were identified as the p50/p50 and p50/p65 NF-kappaB dimers. Activation of NF-kappaB was associated with the degradation of the inhibitory protein IkappaB-alpha; no IkappaB-beta was detected. Activation of NF-kappaB and degradation of IkappaB-alpha were prevented by the NF-kappaB inhibitors sodium salicylate and MG-132. In addition to cyclooxygenase-1 (COX-1), COX-2 is also constitutively expressed in human HSC, and the use of dexamethasone and of SC-58125, a selective COX-2 inhibitor, revealed that COX-2 accounts for basal COX activity. Moreover, COX-2 mRNA and protein were up-regulated by ET-1 and TNF-alpha, whereas COX-1 was unaffected. Induction of COX-2 and stimulation of COX activity by ET-1 and TNF-alpha were prevented by sodium salicylate and MG-132, suggesting that activation of NF-kappaB by either factor is needed for stimulation of COX-2. Finally, SC-58125 and dexamethasone reduced the growth inhibitory effect of ET-1 and TNF-alpha, indicating that activation of COX-2 is required for inhibition of HSC proliferation. Taken together, our results suggest that NF-kappaB, by inducing COX-2 expression, may play an important role in the negative regulation of human myofibroblastic HSC proliferation.

Nurturing communication by health professionals toward patients: a communication accommodation theory approach.

This study explores the role of nurturing communication in distinguishing interpersonal and intergroup interactions between health professionals and patients, from the perspective of communication accommodation theory (CAT). Participants (47 men and 87 women) rated videotapes of actual hospital consultations on 12 goal and 16 strategy items derived from CAT. Health professionals in interpersonal interactions were perceived to pay more attention to relationship and emotional needs and to use more nurturant discourse management and emotional expression. These results point the way toward elucidating the perceived optimal balance in accommodative behavior, both group based and interpersonal, in these contexts, and they highlight the importance of nurturant communication to this process.

Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.

During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype, proliferate, and synthetize fibrosis components. We have shown that endothelin-1 (ET-1) inhibits the proliferation of activated human HSC via endothelin B (ETB) receptors. We now investigate the transduction pathway involved in the growth inhibitory effect of ET-1 in activated HSC. Endothelin-1 and the ETB receptor agonist, sarafotoxin-S6C, increased synthesis of PGI2 and PGE2, leading to elevation of cAMP. The cyclooxygenase inhibitor ibuprofen and the adenylyl cyclase inhibitor SQ22536 both blunted the growth inhibitory effect of ET-1. Analysis of early steps associated with growth inhibition indicated that: (a) similar to ET-1, forskolin decreased c-jun mRNA induction without affecting c-fos and krox 24 mRNA expression; (b) ET-1, sarafotoxin-S6C, as well as forskolin, reduced activation of both c-Jun kinase and extracellular signal-regulated kinase. Finally, forskolin, PGI2, and PGE2 raised by fivefold the number of ET binding sites after 6 h, and increased the proportion of ETB receptors from 50% in control cells to 80% in treated cells. In conclusion, ET-1 inhibits proliferation of activated HSC via ETB receptors, through a prostaglandin/cAMP pathway that leads to inhibition of both extracellular signal-regulated kinase and c-Jun kinase activities. Upregulation of ETB receptors by prostaglandin/cAMP raises the possibility of a positive feedback loop that would amplify the growth inhibitory response. These results suggest that ET-1 and agents that increase cAMP might be of interest to limit proliferation of activated HSC during chronic liver diseases.

Gay and lesbian identity development: a social identity perspective.

This paper critically examines models of identity development from the perspective of social identity theory. It is argued that recent perspectives on homosexual identity development have focused upon psychological processes of the individual and that a shift toward a more social psychological perspective is required. Extant models of homosexual identity development and associated relevant evidence are described, and criticisms of these models are discussed. Next, social identity theory is outlined, illustrating how such an approach can address the criticisms of the dominant approach to gay and lesbian identity development. An extension of social identity theory is then offered in an attempt to explain some of the identities which homosexuals have developed in reaction to being members of an oppressed group.

A needs analysis of Brisbane lesbians: implications for the lesbian community.

This study examined the needs of lesbians in Brisbane, a state capital city of Australia, and the importance of lesbian "community" in meeting those needs. The extent to which a lesbian community can meet the needs of individual lesbians is dependent on what those needs are, the prevailing social climate, and the resulting degree of access by lesbians to the community. This study examined lesbians' perceptions of their individual needs and the extent to which they looked to their community to meet those needs. Overall, the results indicated that lesbians in Brisbane had many unmet needs which, in many instances, cut across the demographic spectrum of age, politics, stage of identity development, religious beliefs, occupation, and educational achievements. These can be broadly categorized as needs that related to the lesbian community itself and external needs that related to changes needed in heterosexual society. The results of this study indicated that characteristics of community do exist within the Brisbane lesbian subculture. There were distinct, identifiable, interacting small groups and social networks in existence. However, a common need was for an identifiable, accessible, lesbian community that could provide stable, long-term services and cultural and social activities. In Brisbane lesbians also needed a focus that superseded the needs of individual lesbians and their small interacting social networks. This study highlighted the need for further research into the area of lesbian community identity formation.

College students' trait ratings of three age groups around the Pacific Rim.

In this paper, the traits which younger adults associate with younger, middle-aged, and older adults in a number of Pacific Rim nations were assessed. Two dependent variables ('personal vitality' and 'benevolence') emerged from factor analyses of a series of trait adjectives. Cross cultural trends emerged which replicated patterns found in the US context. Main effects indicated declines in ratings of personal vitality and increases in ratings of benevolence with increasing target-age. However, interesting variations on this pattern emerged in different cultures. In particular, very negative evaluations of aging in Hong Kong, and a lack of differentiation between middle-aged and older adults in the Philippines and New Zealand were found. Little evidence emerged supporting the notion of particular positive evaluations of older adults in Asian cultures.

The theory of reasoned action and cooperative behaviour: it takes two to use a condom.

The applicability of the Theories of Reasoned Action and Planned Behaviour to the cooperative behaviour of condom use were examined. Seventy-one male and 78 female students, all sexually active unmarried heterosexuals aged 17 to 21 years, gave information about their intentions for the next sexual encounter, as well as their attitude, subjective norm, expectancy-value attitude and subjective norm (including normative beliefs for their sexual partner), and their past behaviour with respect to condom use. After their next sexual encounter, they completed a questionnaire on their actual condom use. Results indicated that when behavioural conditions including the availability of a condom and an agreement with the partner to use it were satisfied, intention interacted with past behaviour to predict actual behaviour. These results imply that intentions which are consistent with past behaviour are stable enough to be carried out in the face of the interpersonal dynamics of a sexual encounter. Further, normative belief for the sexual partner had a direct influence on attitudes, subjective norm and intention. Neither the Theory of Reasoned Action nor the Theory of Planned Behaviour can fully explain these results, which point to the need for further theoretical inquiry into the dynamics of cooperative behaviour.

The psychological well-being of infertile women after a failed IVF attempt: the effects of coping.

One hundred infertile women and 73 female controls completed three measures of psychological well-being (depression, self-esteem and self-confidence) on two occasions (Times 1 and 2), coinciding with the beginning and end of a failed IVF attempt by the infertile women. At Time 2, the IVF women were also asked to indicate whether they had used a number of different coping responses, in relation to dealing with their failed IVF attempt. As predicted, IVF women were more depressed and had lower self-esteem than controls prior to the treatment cycle, and both before and after the treatment cycle they were less self-confident. After the failed IVF procedure, IVF women were more depressed and had lower levels of self-esteem than they did prior to the treatment cycle. In terms of the effects of coping on the post-attempt well-being of the IVF women, the use of problem-focused coping was associated with high levels of well-being, while the use of avoidance coping and seeking social support was associated with low levels of well-being.