Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition.

BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.

Incidence and risk factors of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients having undergone autologous stem cell transplantation.

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy. Due to their long survival and subsequently high cumulative doses of bisphosphonates, multiple myeloma patients have the highest risk of developing BRONJ of all patients treated with bisphosphonates. The purpose of the present study was to evaluate the incidence and risk factors for BRONJ in multiple myeloma patients after high-dose chemotherapy and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: We retrospectively analyzed the data of 120 multiple myeloma patients after high-dose chemotherapy and ASCT treated with bisphosphonates and assessed the incidence and risk factors of BRONJ. RESULTS: Of the 120 patients, 23 (19%) developed BRONJ. 6 patients suffered several BRONJ events, resulting in a total incidence of 23%. The risk for BRONJ was significantly higher for patients with rheumatism and recent dental manipulations. Furthermore, the number of previous bisphosphonate rotations, the duration of bisphosphonate therapy, and the type and cumulative dose of bisphosphonate used were associated with the incidence of BRONJ. CONCLUSION: Our study is the first to determine the risk of BRONJ in a homogeneous group of multiple myeloma patients treated with high-dose chemotherapy and ASCT.

Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells.

Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2'-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G(1) cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma.

Tumor patients in psychodynamic psychotherapy including daydreaming: can imagery enhance primary process and positive emotions?

This therapy process study investigates the use of guided affective imagery for tumor patients. The therapeutic access to tumor patients is generally described as complex and challenging because of a disturbed emotion regulation and a defensive focus on reality. After autologous blood stem cell transplantation, 29 patients were treated with psychotherapy, including two daydreaming imagery sessions. Three text-analytical measures--Affective Dictionary Ulm, Regressive Imagery Dictionary, and Computerized Referential Activity for verbatim session transcripts--as well as the Quality of Life Questionnaire and the Karnofsky Performance Status were administered. Results show that guided affective imagery was able to enhance the psychotherapeutic process in tumor patients by activating the primary process, decreasing anxiety, and increasing referential activity. The positive emotional shift during imagery was achieved by the patients irrespective of their oncological severity status. Study limitations and future directions for research are discussed.

Inhibition of lymphocyte function associated antigen 1 by LFA878 induces apoptosis in multiple myeloma cells and is associated with downregulation of the focal adhesion kinase/phosphatidylinositol 3 kinase/Akt pathway.

Multiple myeloma (MM) is still an incurable disease and adhesion of MM cells to bone marrow stromal cells is one of the hallmarks of the disease. Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule that mediates lymphocyte adhesion, but its role in MM is only poorly understood. The aim of the presented study was to improve knowledge on LFA-1 and associated pathways in MM for the development of molecular targeted therapies. We demonstrate that LFA-1 is expressed in U266, RPMI-8226, OPM-2, and NCI-H929 MM cell lines and in primary cells of eight tested patients. The LFA-1 inhibitor LFA878 induces apoptosis in all four cell lines as revealed by annexin V staining and caspase 3 cleavage. Apoptosis is not hampered by adhesion to stromal cells. Additionally, the soluble ligand, intracellular adhesion molecule 1 (ICAM-1), which is increased in the serum of MM patients, does not protect from melphalan-induced apoptosis. Western blots demonstrate downregulation of FAK, PI3-K, and Akt upon LFA878 treatment. Additionally, sequential inhibition of the pathway by simultaneous application of Src family kinase or PI3-K inhibitors significantly increases LFA878 induced apoptosis. We conclude that LFA-1/FAK/PI3-K/Akt is a survival pathway in MM and that targeted inhibition may provide new therapeutic options.

First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma.

In vitro statins overcome cell adhesion-mediated drug resistance at non-toxic concentrations that are achievable in humans by standard dose simvastatin. A pilot phase-II trial was initiated to determine feasibility and antimyeloma efficacy. In six myeloma patients refractory to two cycles of bortezomib or bendamustine simvastatin was concomitantly administered during further two cycles. The therapy was well tolerated without grade 3/4 toxicity. Intrapatient (cycles I/II vs. III/IV) and interpatient comparison (vs. ten patients without simvastatin) showed reduction of drug resistance by inhibition of HMG-CoA-reductase. In summary, this is the first phase II experience to study antimyeloma activity of statins in humans.

Social support and quality of life of patients prior to stem cell or bone marrow transplantation.

OBJECTIVES: To determine the positive and detrimental aspects of social support prior to allogeneic or autologous bone marrow transplantation/stem cell transplantation. DESIGN: Cross-sectional. METHODS: Patients completed the German version of the Illness-specific Social Support Scale (ISSS) and the Quality of Life (QoL) Questionnaire Core 30 (EORTC QLQ-C30). RESULTS: Participants were 282 patients (62% autologous SCT, 39% women, 97% haematological malignancies, 72% with partner). We found satisfactory reliability values for both ISSS scales: positive support (Cronbach's alpha=.91) and problematic support (=.73). Patients living with a partner displayed higher scores in positive interaction than patients living alone (p<.001). Analysis showed a significant main effect of partnership, p<.001; F(1)=8.345, and better scores for women, p<1; F(1)=2.758. Furthermore, we determined a negative correlation between problematic interaction and emotional/social function (p<.001) and a positive correlation with insomnia, but no correlation between positive interaction, QLQ-C30, and Karnofsky's index. CONCLUSIONS: We could distinguish between helpful and harmful support, and determine clinically important associations of problematic support. Partnership seems to be a major source of positive interaction.

Social support, affectivity, and the quality of life of patients and their support-givers prior to stem cell transplantation.

PURPOSE: To determine differences and interdependencies between patients and their support-givers prior to PBSCT. METHOD: Patients and their principal support-givers completed the Illness- Specific Social Support Scale (ISSS), the Profile of Mood States, and the EORTC QLQ-C30. RESULTS: One hundred fifty-five of 200 eligible patients replied. They nominated spouse/partner (70.6%), friends, and children as principal support source. Patients receiving social support from spouses reported a better HRQoL than patients who nominated other persons as the principal source of social support. Patients perceived more positive (p < .01) and more problematic (p < .05) social interactions than support-givers. The support-givers nominated: children (25.8%), spouse/partner, and siblings. Analysis showed an additional effect of gender and support-giving role (female patients scored worst in overall QoL, male support- givers best). CONCLUSION: Psychotherapeutic interventions should not only address the patients' problems but also the support-givers' questions, needs, and psychosocial burdens.