Palliative care in the context of immune and targeted therapies: A qualitative study of bereaved carers' experiences in metastatic melanoma.

BACKGROUND: Immune and targeted therapies continue to transform treatment outcomes for those with metastatic melanoma. However, the role of palliative care within this treatment paradigm is not well understood. AIM: To explore bereaved carers' experiences of immune and targeted therapy treatment options towards end of life for patients with metastatic melanoma. DESIGN: An interpretive, qualitative study using a social constructivist framework was utilised. Interviews were recorded, transcribed and analysed using grounded theory methods. SETTING/PARTICIPANTS: Participants (n = 20) were bereaved carers of patients who had received some form of immune and/or targeted therapy at one of three Australian metropolitan melanoma treatment centres. RESULTS: Carers struggled to reconcile the positive discourse around the success of immune and targeted therapies in achieving long-term disease control, and the underlying uncertainty in predicting individual responses to therapy. Expectations that immune and targeted therapies necessarily provide longer-term survival were evident. Difficulty in prognostication due to clinical uncertainty and a desire to maintain hope resulted in lack of preparedness for treatment failure and end of life. CONCLUSION: Immune and targeted therapies have resulted in increased prognostic challenges. There is a need to engage, educate and support patients and carers to prepare and plan amid these challenges. Educational initiatives must focus on improving communication between patients, carers and clinicians; the differences between palliative and end-of-life care; and increased competency of clinicians in having goals-of-care discussions. Clinicians must recognise and communicate the benefit of collaborative palliative care to meet patient and family needs holistically and comprehensively.

FLAT REACTION NORMS AND "FROZEN" PHENOTYPIC VARIATION IN CLONAL SNAILS (POTAMOPYRGUS ANTIPODARUM).

The Frozen Niche-Variation hypothesis (FNV) suggests that clones randomly sample and "freeze" the genotypes of their ancestral sexual populations. Hence, each clone expresses only a fraction of the total niche-use variation observed in the sexual population, which may lead to selection for ecological specialization and coexistence of clones. A generalized form of the FNV model suggests that the same is true for life-history (as well as other) traits that have important fitness consequences, but do not relate directly to niche use. We refer to the general form of the model as the Frozen Phenotypic Variation (FPV) model. A mixed population of sexual and parthenogenetic snails (Potamopyrgus antipodarum) in a New Zealand lake allowed us to examine the phenotypic variation expressed by coexisting clones in two benthic habitats, and to compare that variation to the sexual population. Three clones were found primarily in an aquatic macrophyte zone composed of Isoetes kirkii (1.5-3.0 m deep), and three additional clones were found in a deeper macrophyte zone composed of Elodea canadensis (4.0-6.0 m deep). These clones showed significant variation between habitats, which mirrored that observed in the sexual population. Specifically, clones and sexuals from the deeper habitat matured at a larger size and had larger broods. There was also significant among-clone variation within habitats; and as expected under the FPV model, the within-clone coefficients of variation for size at maturity were low in both habitats when compared to the sexual population. In addition, we found four clones that were common in both macrophyte zones. The reaction norms of these clones were flat across habitats, suggesting little phenotypic plasticity for morphology or life-history traits. Flat reaction norms, high among-clone variation, and low coefficients of variation (relative to the sexual population) are in accordance with the FPV model for the origin of clonal lineages. We also measured the prevalence of infection by trematode larvae to determine whether clones are inherently more or less infectable, or whether they are freezing phenotypic variation for resistance from the sexual population. We did this in the deep habitats of the lake where recycling of the parasite by the vertebrate host is unlikely, thereby reducing the complications raised by frequency-dependent responses of parasites to host genotypes. We found no indication that clones are either more or less infectable than the resident sexual population. Taken together, our results suggest that phenotypic variation for both life-history traits and resistance to parasites is frozen by clones from the local sexual population.

GENETIC STRUCTURE OF COEXISTING SEXUAL AND CLONAL SUBPOPULATIONS IN A FRESHWATER SNAIL (POTAMOPYRGUS ANTIPODARUM).

We examined clonal diversity and the distribution of both clonal and sexual genotypes in a single population of freshwater snails (Potamopyrgus antipodarum) in which diploid sexual individuals and triploid parthenogens coexist. A genetic analysis of individuals from three habitat zones in Lake Alexandrina, New Zealand revealed extremely high clonal diversity: 165 genotypes among 605 clonal individuals. The frequency of triploid clonal individuals increased with increasing depth in the lake, and most of the individual clones were habitat specific, suggesting that differences among habitats are important in structuring the clonal subpopulation. There were also high levels of clonal diversity within habitats, suggesting frequent origins of habitat-specific clones. In contrast, diploid sexual individuals were proportionately more common in the shallow regions of the lake (where infection by trematode larvae is highest), and there was no significant spatial structure in the sexual subpopulation. We suggest that habitat specialization by clones, as well as parasite-mediated selection against common clones, are important factors affecting the structure of this mixed population of sexual and clonal snails.