Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors.

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

Revisiting treatment-related cardiotoxicity in patients with malignant lymphoma-a review and prospects for the future.

Treatment of malignant lymphoma has for years been represented by many cardiotoxic agents especially anthracyclines, cyclophosphamide, and thoracic irradiation. Although they are in clinical practice for decades, the precise mechanism of cardiotoxicity and effective prevention is still part of the research. At this article we discuss most routinely used anti-cancer drugs in chemotherapeutic regiments for malignant lymphoma with the focus on novel insight on molecular mechanisms of cardiotoxicity. Understanding toxicity at molecular levels may unveil possible targets of cardioprotective supportive therapy or optimization of current therapeutic protocols. Additionally, we review novel specific targeted therapy and its challenges in cardio-oncology.

Emergency medicine pharmacotherapy compromises accuracy of plasma creatinine determination by enzyme-based methods: real-world clinical evidence and implications for clinical practice.

Background: Assessment of kidney function in emergency settings is essential across all medical subspecialties. Daily assessment of patient creatinine results from emergency medical services showed that some deviated from expected values, implying drug-related interference. Methods: Real-time clinical evaluation of an enzyme method (Roche CREP2) in comparison with the Jaffé gen. 2 method (Roche CREJ2) was performed. During the period of December 2022 and January 2023, we analyzed 8,498 patient samples, where 5,524 were heavily medicated STAT patient specimens, 500 were pediatric specimens, and 2,474 were from a distant general population in a different region using the same methods. Results: In 109 out of 5,524 hospital specimens (1.97%, p < 0.001), the CREP2 value was apparently (25% or more) lower than CREJ2. Suspect interfering medication was found in a sample of 43 out of 46 reviewed patients where medication data were available. This phenomenon was not observed in the general population. Conclusion: In a polymedicated urgent care hospital population, a creatinine enzyme method produces unreliable results, apparently due to multiple drug-related interferences.

Sunitinib-Induced Elevation of Mean Corpuscular Volume (MCV)-Exploring Its Possible Clinical Relevance in Cancer Patients.

Sunitinib is a broad-spectrum multitargeted tyrosine kinase inhibitor mainly used as second-line therapy for non-resectable gastrointestinal stromal or first-line treatment option of metastatic renal cell carcinoma (mRCC), and as an "off-label" option in pediatric oncology. It has been previously reported that sunitinib elevates the mean corpuscular volume of erythrocytes (MCV) in treated subjects. The aim of this study was to assess time-dependent changes of this effect and evaluate its possible clinical relevance. In this study, 179 adult and 21 pediatric patients with solid tumors treated with sunitinib were retrospectively analyzed. The laboratory and treatment-related data were collected for each treatment period. The regression model with a broken-line relationship was used to fit time dependence of the MCV. In the adult group, the MCV was increasing during the first 21.6 weeks (median) of treatment in a median level of 99.8 fL, where it stabilized. MCV increase was faster in the patients who suffered from treatment-related adverse events (21.3 vs. 24.6 weeks, p = 0.010). In the pediatric cohort, the MCV dynamics were similar to adults. In conclusion, MCV changes during sunitinib treatment in pediatric and adult patients may be of clinical utility in monitoring sunitinib treatment course.

The Clinical Significance of DJ1 and L1CAM Serum Level Monitoring in Patients with Endometrial Cancer.

Circulating tumor markers are not routinely used in patients with endometrial cancer (EC). This pilot study evaluated the role of monitoring new biomarkers DJ1 and L1CAM, in correlation with CA125 and HE4, for the effects of anticancer treatment and preoperative management in EC patients. Serial serum levels of DJ1, L1CAM, CA125 and HE4 were collected in 65 enrolled patients. Serum DJ1, L1CAM, CA125 and HE4 levels were significantly higher at the time of diagnosis compared to those measured during follow-up (FU). In patients with recurrent disease, serum DJ1, CA125 and HE4 levels were significantly higher at the time of recurrence compared to levels in disease-free patients. Serum L1CAM levels were also higher in patients with recurrence but without reaching statistical significance. While DJ1 levels were not affected by any of the observed patient-related characteristics, L1CAM levels were significantly higher in patients with age ≥60 years who were overweight. At the time of EC diagnosis, DJ1 and L1CAM serum levels did not correlate with stage, histological type or risk of recurrence. This is a preliminary description of the potential of serial DJ1 and L1CAM serum level measurement for monitoring the effects of treatment in EC patients.

N-Glycome changes reflecting resistance to platinum-based chemotherapy in ovarian cancer.

A number of studies have reported aberrant glycosylation in connection with malignancy. Our investigation further expands on this topic through the examination of N-glycans, which could be associated with the resistance of advanced stage, high-grade non-mucinous ovarian cancer to platinum/taxane based chemotherapy. We used tissue samples of 83 ovarian cancer patients, randomly divided into two independent cohorts (basic and validation). Both groups involved either cases with/without postoperative tumor residue or the cases determined either resistant or sensitive to this chemotherapy. In the validation cohort, preoperative serum samples were also available. N-glycans released from tumors and sera were permethylated and analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The MS analysis yielded a consecutive detection of 68 (tissue) and 63 (serum) N-glycan spectral signals. Eight of these were found to be differentially abundant in tissues of both independent cohorts including the cases with a postoperative cancer residue. One of these glycans was detected as differentially abundant in sera of the validation cohort. No statistically significant differences in intensities due to the same N-glycans were found in the cases without postoperative macroscopic residues in either the basic or validation cohort. From the biochemical point of view, the statistically significant N-glycans correspond to the structures carrying bisecting (terminal) GlcNAc residue and tetra-antennary structures with sialic acid and/or fucose residues. Among them, six tissue N-glycans could be considered potential markers connected with a resistance to chemotherapy in ovarian cancer patients. The prediction of primary resistance to standard chemotherapy may identify the group of patients suitable for alternative treatment strategies. SIGNIFICANCE: Drug resistance has become a major impediment to a successful treatment of patients with advanced ovarian cancer. The glycomic measurements related to cancer are becoming increasingly popular in identification of the key molecules as potential diagnostic and prognostic indicators. Our report deals with identification of differences in N-glycosylation of proteins in tissue and serum samples from the individuals showing sensitivity or resistance to platinum/taxane-based chemotherapy. The detection sensitivity to chemotherapy is vitally important for these patients.

Interpretive discrepancies caused by target values inter-batch variations in chemiluminescence immunoassay for SARS-CoV-2 IgM/IgG by MAGLUMI.

Plasma specimens from coronavirus disease 2019 patients were double-tested for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies by two different batches of MAGLUMI 2019-nCov immunoglobulin M/immunoglobulin G (IgM/IgG) assays to evaluate IgM/IgG levels, qualitative interpretation, antibody kinetics, and linearity of diluted specimen. Here we show that (i) high-level IgM specimens need to be diluted with negative human plasma but not kit diluents and (ii) measured anti-SARS-CoV-2 IgM/IgG concentrations are substantially higher with later marketed immunoassay batch leading to (iii) the change of qualitative interpretation (positive vs. negative) in 12.3% of specimens measured for IgM, (iv) the informative time-course pattern of antibody production only when data from different immunoassay batches are not combined.

Enhanced Antiproliferative Effect of Combined Treatment with Calcitriol and All-Trans Retinoic Acid in Relation to Vitamin D Receptor and Retinoic Acid Receptor α Expression in Osteosarcoma Cell Lines.

The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.

BBMRI-ERIC's contributions to research and knowledge exchange on COVID-19.

During the COVID-19 pandemic, the European biobanking infrastructure is in a unique position to preserve valuable biological material complemented with detailed data for future research purposes. Biobanks can be either integrated into healthcare, where preservation of the biological material is a fork in clinical routine diagnostics and medical treatment processes or they can also host prospective cohorts or material related to clinical trials. The paper discussed objectives of BBMRI-ERIC, the European research infrastructure established to facilitate access to quality-defined biological materials and data for research purposes, with respect to the COVID-19 crisis: (a) to collect information on available European as well as non-European COVID-19-relevant biobanking resources in BBMRI-ERIC Directory and to facilitate access to these via BBMRI-ERIC Negotiator platform; (b) to help harmonizing guidelines on how data and biological material is to be collected to maximize utility for future research, including large-scale data processing in artificial intelligence, by participating in activities such as COVID-19 Host Genetics Initiative; (c) to minimize risks for all involved parties dealing with (potentially) infectious material by developing recommendations and guidelines; (d) to provide a European-wide platform of exchange in relation to ethical, legal, and societal issues (ELSI) specific to the collection of biological material and data during the COVID-19 pandemic.

Assessment of Immune Response Following Dendritic Cell-Based Immunotherapy in Pediatric Patients With Relapsing Sarcoma.

Monocyte-derived dendritic cell (DC)-based vaccines loaded with tumor self-antigens represent a novel approach in anticancer therapy. We evaluated DC-based anticancer immunotherapy (ITx) in an academic Phase I/II clinical trial for children, adolescent, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors. The primary endpoint was safety of intradermal administration of manufactured DCs. Here, we focused on relapsing high-risk sarcoma subgroup representing a major diagnosis in DC clinical trial. As a part of peripheral blood immunomonitoring, we evaluated quantitative association between basic cell-based immune parameters. Furthermore, we describe the pattern of these parameters and their time-dependent variations during the DC vaccination in the peripheral blood immunograms. The peripheral blood immunograms revealed distinct patterns in particular patients in the study group. As a functional testing, we evaluated immune response of patient T-cells to the tumor antigens presented by DCs in the autoMLR proliferation assay. This analysis was performed with T-cells obtained prior to DC ITx initiation and with T-cells collected after the fifth dose of DCs, demonstrating that the anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens. Finally, we present clinical and immunological findings in a Ewing's sarcoma patient with an interesting clinical course. Prior to DC therapy, we observed prevailing CD8+ T-cell stimulation and low immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSC) and regulatory T-cells (Tregs). This patient was subsequently treated with 19 doses of DCs and experienced substantial regression of metastatic lesions after second disease relapse and was further rechallenged with DCs. In this patient, functional ex vivo testing of autologous T-cell activation by manufactured DC medicinal product during the course of DC ITx revealed that personalized anticancer DC-based vaccine stimulates a preexisting immune response against self-tumor antigens and that the T-cell reactivity persisted for the period without DC treatment and was further boosted by DC rechallenge. Trial Registration Number: EudraCT 2014-003388-39.

Dendritic Cell-Based Immunotherapy in Advanced Sarcoma and Neuroblastoma Pediatric Patients: Anti-cancer Treatment Preceding Monocyte Harvest Impairs the Immunostimulatory and Antigen-Presenting Behavior of DCs and Manufacturing Process Outcome.

Despite efforts to develop novel treatment strategies, refractory and relapsing sarcoma, and high-risk neuroblastoma continue to have poor prognoses and limited overall survival. Monocyte-derived dendritic cell (DC)-based anti-cancer immunotherapy represents a promising treatment modality in these neoplasias. A DC-based anti-cancer vaccine was evaluated for safety in an academic phase-I/II clinical trial for children, adolescents, and young adults with progressive, recurrent, or primarily metastatic high-risk tumors, mainly sarcomas and neuroblastomas. The DC vaccine was loaded with self-tumor antigens obtained from patient tumor tissue. DC vaccine quality was assessed in terms of DC yield, viability, immunophenotype, production of IL-12 and IL-10, and stimulation of allogenic donor T-cells and autologous T-cells in allo-MLR and auto-MLR, respectively. Here, we show that the outcome of the manufacture of DC-based vaccine is highly variable in terms of both DC yield and DC immunostimulatory properties. In 30% of cases, manufacturing resulted in a product that failed to meet medicinal product specifications and therefore was not released for administration to a patient. Focusing on the isolation of monocytes and the pharmacotherapy preceding monocyte harvest, we show that isolation of monocytes by elutriation is not superior to adherence on plastic in terms of DC yield, viability, or immunostimulatory capacity. Trial patients having undergone monocyte-interfering pharmacotherapy prior to monocyte harvest was associated with an impaired DC-based immunotherapy product outcome. Certain combinations of anti-cancer treatment resulted in a similar pattern of inadequate DC parameters, namely, a combination of temozolomide with irinotecan was associated with DCs showing poor maturation and decreased immunostimulatory features, and a combination of pazopanib, topotecan, and MTD-based cyclophosphamide was associated with poor monocyte differentiation and decreased DC immunostimulatory parameters. Searching for a surrogate marker predicting an adverse outcome of DC manufacture in the peripheral blood complete blood count prior to monocyte harvest, we observed an association between an increased number of immature granulocytes in peripheral blood and decreased potency of the DC-based product as quantified by allo-MLR. We conclude that the DC-manufacturing yield and the immunostimulatory quality of anti-cancer DC-based vaccines generated from the monocytes of patients were not influenced by the monocyte isolation modality but were detrimentally affected by the specific combination of anti-cancer agents used prior to monocyte harvest.

Individualization of Treatment Improves the Survival of Children With High-Risk Solid Tumors: Comparative Patient Series Analysis in a Real-Life Scenario.

Introduction: The individualization of treatment is attractive, especially in children with high-risk cancer. In such a rare and very heterogeneous group of diseases, large population-based clinical randomized trials are not feasible without international collaboration. We therefore propose comparative patient series analysis in a real-life scenario. Methods: Open cohort observational study, comparative analysis. Seventy patients with high-risk solid tumors diagnosed between 2003 and 2015 and in whom the treatment was individualized either empirically or based on biomarkers were analyzed. The heterogeneity of the cohort and repeated measurements were advantageously utilized to increase effective sample size using appropriate statistical tools. Results: We demonstrated a beneficial effect of empirically given low-dose metronomic chemotherapy (HR 0.46 for relapses, p = 0.017) as well as various repurposed or targeted agents (HR 0.15 for deaths, p = 0.004) in a real-life scenario. However, targeted agents given on the basis of limited biological information were not beneficial. Conclusions: Comparative patient series analysis provides institutional-level evidence for treatment individualization in high-risk pediatric malignancies. Our findings emphasize the need for a comprehensive, multi omics assessment of the tumor and the host as well whenever molecularly driven targeted therapies are being considered. Low-dose metronomic chemotherapy or local control of the disease may be a more rational option in situations where targeted treatment cannot be justified by robust evidence and comprehensive biological information. "Targeted drugs" may be given empirically with a realistic benefit expectation when based on robust rationale.

Circulating T cell subsets are associated with clinical outcome of anti-VEGF-based 1st-line treatment of metastatic colorectal cancer patients: a prospective study with focus on primary tumor sidedness.

BACKGROUND: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. METHODS: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high. CONCLUSIONS: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.

High prevalence of severe hypovitaminosis D in patients with advanced gastric cancer treated with first-line chemotherapy with or without anti-EGFR-directed monoclonal antibody (EXPAND trial) showing no prognostic impact.

PURPOSE: The goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab. METHODS: Six hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms. RESULTS: Majority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. CONCLUSIONS: Although majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy.

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities.

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

Comprehensive Molecular Profiling for Relapsed/Refractory Pediatric Burkitt Lymphomas-Retrospective Analysis of Three Real-Life Clinical Cases-Addressing Issues on Randomization and Customization at the Bedside.

In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma. SUMMARY: The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.

Myeloid-derived suppressor cells (MDSCs) in patients with solid tumors: considerations for granulocyte colony-stimulating factor treatment.

Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor escape from host immune surveillance and to cancer progression by production of tumor-promoting soluble factors. Granulocyte colony-stimulating factor (G-CSF) is a principle cytokine controlling granulocyte number. Recombinant human G-CSF (rhG-CSF) has become the main therapeutic agent for the treatment of neutropenia and prophylaxis of febrile neutropenia in cancer patients. However, we show here that rhG-CSF triggers accumulation of granulocytic and monocytic subsets. Consequently, we discuss the pharmacological use of granulopoiesis stimulating factors not only in the context of febrile neutropenia but also from the perspective of MDSC-dependent and MDSC-independent mechanisms of immunosuppression and cancer angiogenesis.

Host-dependent variables: The missing link to personalized medicine.

Individualized medicine has the potential to tailor anticancer therapy with the best response and highest safety margin to provide better patient care. However, modern targeted therapies are still being tested through clinical trials comparing preselected patient cohorts and assessed upon behaviour of group averages. Clinically manifesting malignant disease requires identification of host- and tumour-dependent variables such as biological characteristics of the tumour and its microenvironment including immune response features, and overall capacity of the host to receive, tolerate and efficiently utilize treatment. Contemporary medical oncology including clinical trial design need to refocus from assessing group averages to individuality taking into consideration time dependent host-associated characteristics and reinventing outliers to be appreciated as naturally occurring variables collectively determining the ultimate outcome of malignant disease.