The convivial and the pastoral in patient-doctor relationships: a multi-country study of patient stories of care, choice and medical authority in cancer diagnostic processes.

Experiences of cancer diagnosis are changing in light of both the increasingly technological-clinical diagnostic processes and the socio-political context in which interpersonal relations take place. This has raised questions about how we might understand patient-doctor relationship marked by asymmetries of knowledge and social capital, but that emphasise patients' empowered choices and individualised care. As part of an interview study of 155 participants with bowel or lung cancer across Denmark, England and Sweden, we explored participants' stories of the decisions made during their cancer diagnostic process. By focusing on the intersections of care, choice and medical authority - a convivial pastoral dynamic - we provide a conceptual analysis of the normative ambivalences in people's stories of their cancer diagnosis. We found that participants drew from care, choice and medical authority to emphasise their relationality and interdependence with their doctors in their stories of their diagnosis. Importantly negotiations of an asymmetrical patient-doctor relationship were part of an on-going realisation of the healthcare processes as a human endeavour. We were therefore able to draw attention to the limitations of dichotomising emancipatory-empowerment discourses and argue for a theorisation of the patient-doctor relationship as a contextually bounded and relationally ambivalent humanity.

Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19.

PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19-, and mixed CD19+/CD19-B-cell lymphoma. CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.

Coordinating objects of care: Exploring the role of case managers as brokers in cancer patient pathways.

OBJECTIVE: Healthcare systems increasingly make use of case managers to handle organisational complexity. In Danish cancer patient pathways, case managers handle the complexities of cancer diagnostics and treatment while adhering to pathway guidelines. This article explores how case managers handle their various responsibilities and focuses on the micro-politics of case management. METHODS: An ethnographic study was carried out in three Danish cancer patient pathways. Interactions between patients and healthcare professionals were observed, including professionals with case management tasks. We interviewed 13 cancer diagnostic patients in their homes and 26 healthcare professionals during work hours, among other things about case management. RESULTS: We found that the work of case managers differs between cancer patient pathways and settings but overall emphasises coordination of patient trajectories and being contact person. We argue that case managers, embodying the figure of the broker, handle their responsibilities by coordinating the following co-existing objects of care, each with different goals: the diseased body, the person, the organisation and the cancer patient pathway. CONCLUSION: We conclude that case managers, in addition to being a response to the complexity of healthcare services, impact the implementation of cancer patient pathways and influence cancer diagnostic activities.

Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells.

In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

Neoantigen landscape dynamics during human melanoma-T cell interactions.

Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.

Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.

SSX cancer/testis antigens are frequently expressed in melanoma tumors and represent attractive targets for immunotherapy, but their role in melanoma tumorigenesis has remained elusive. Here, we investigated the cellular effects of SSX2 expression. In A375 melanoma cells, SSX2 expression resulted in an increased DNA content and enlargement of cell nuclei, suggestive of replication aberrations. The cells further displayed signs of DNA damage and genomic instability, associated with p53-mediated G1 cell cycle arrest and a late apoptotic response. These results suggest a model wherein SSX2-mediated replication stress translates into mitotic defects and genomic instability. Arrest of cell growth and induction of DNA double-strand breaks was also observed in MCF7 breast cancer cells in response to SSX2 expression. Additionally, MCF7 cells with ectopic SSX2 expression demonstrated typical signs of senescence (i.e. an irregular and enlarged cell shape, enhanced ß-galactosidase activity and DNA double-strand breaks). Since replication defects, DNA damage and senescence are interconnected and well-documented effects of oncogene expression, we tested the oncogenic potential of SSX2. Importantly, knockdown of SSX2 expression in melanoma cell lines demonstrated that SSX2 supports the growth of melanoma cells. Our results reveal two important phenotypes of ectopic SSX2 expression that may drive/support tumorigenesis: First, immediate induction of genomic instability, and second, long-term support of tumor cell growth.

Towards a clinically useful diagnosis for mild-to-moderate conditions of medically unexplained symptoms in general practice: a mixed methods study.

BACKGROUND: Symptoms that cannot be attributed to any known conventionally defined disease are highly prevalent in general practice. Yet, only severe cases are captured by the current diagnostic classifications of medically unexplained symptoms (MUS). This study explores the clinical usefulness of a proposed new diagnostic category for mild-to-moderate conditions of MUS labelled 'multiple symptoms'. METHODS: A mixed methods approach was used. For two weeks, 20 general practitioners (GPs) classified symptoms presented in consecutive consultations according to the International Classification of Primary Care (ICPC) supplemented with the new diagnostic category 'multiple symptoms'. The GPs' experiences were subsequently explored by focus group interviews. Interview data were analysed according to ethnographic principles. RESULTS: In 33% of patients, GPs classified symptoms as medically unexplained, but applied the category of 'multiple symptoms' only in 2.8%. The category was described as a useful tool for promoting communication and creating better awareness of patients with MUS; as such, the category was perceived to reduce the risk of unnecessary tests and referrals of these patients. Three main themes were found to affect the clinical usefulness of the diagnostic category of 'multiple symptoms': 1) lack of consensus on categorisation practices, 2) high complexity of patient cases and 3) relational continuity (i.e. continuity in the doctor-patient relationship over time). The first two were seen as barriers to usefulness, the latter as a prerequisite for application. The GPs' diagnostic classifications were found to be informed by the GPs' subjective pre-formed concepts of patients with MUS, which reflected more severe conditions than actually intended by the new category of 'multiple symptoms'. CONCLUSIONS: The study demonstrated possible clinical benefits of the category of 'multiple symptoms', such as GPs' increased awareness and informational continuity in partnership practices. The use of the category was challenged by the GPs' conceptual understanding of MUS and was applied only to a minority of patients. The study demonstrates a need for addressing these issues if sub-threshold categories for MUS are to be applied in routine care. The category of 'multiple symptoms' may profitably be used in the future as a risk indicator rather than a diagnostic category.

Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers.

The use of fluorescently labeled major histocompatibility complex multimers has become an essential technique for analyzing disease- and therapy-induced T-cell immunity. Whereas classical major histocompatibility complex multimer analyses are well-suited for the detection of immune responses to a few epitopes, limitations on human-subject sample size preclude a comprehensive analysis of T-cell immunity. To address this issue, we developed a combinatorial encoding strategy that allows the parallel detection of a multitude of different T-cell populations in a single sample. Detection of T cells from peripheral blood by combinatorial encoding is as efficient as detection with conventionally labeled multimers but results in a substantially increased sensitivity and, most notably, allows comprehensive screens to be performed. We obtained proof of principle for the feasibility of large-scale screening of human material by analysis of human leukocyte antigen A3-restricted T-cell responses to known and potential melanoma-associated antigens in peripheral blood from individuals with melanoma.