216 research outputs found
Living with Advanced Kidney Cancer and Treatment with Cabozantinib: Through the Eyes of the Patient and the Physician
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Immunomonitoring and prognostic relevance of neutrophils in clinical trials
No full textAbstractThe clinical relevance of the interaction between human cancer and neutrophils has recently begun to emerge. This review will focus on recently published articles regarding immunomonitoring of neutrophils in blood and tumor tissue in clinical trials comprising the main human tumor types, with a strong emphasis on independent prognostic relevance assessed by multivariate analyses.The prognostic role of tumor-infiltrating neutrophils, elevated blood neutrophils and elevated blood neutrophil/lymphocyte ratio has been associated with poor clinical outcome in several human cancers, most notably in renal cell carcinoma, melanoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, GIST, gastric, esophageal, lung, ovarian and head and neck cancer. A striking finding is the notion that high baseline neutrophil count in either tumor or blood, or both, was identified as strong, independent risk factor for poor outcome in multivariate analyses, and the negative prognostic impact of neutrophils was not eliminated by increasing the dose of cytokines, chemotherapy, or targeted therapy. For several cancers, patients benefit most from therapy if baseline neutrophil was low. Thus, baseline neutrophils over-ride nadir counts in prognostic significance.In summary, a proportion of patients who do not experience benefit from surgery or medical intervention may be associated with a worst prognosis because they are characterized by baseline tumor-related neutrophilia protecting them from benefit from therapy. Further research to unraveling the cancer biology and new treatment options is encouraged
The database of the Danish Renal Cancer Group
No full textAstrid Christine Petersen,1 Mette Søgaard,2 Frank Mehnert,2 Erik Højkjær Larsen,3 Frede Donskov,4 Nessn H Azawi,5 Bjarne Kromann-Andersen6 1Department of Pathology, Aalborg University Hospital, Aalborg, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3Department of Urology, Odense University Hospital, Odense, 4Department of Oncology, Aarhus University Hospital, Aarhus, 5Department of Urology, Zealand University Hospital, Roskilde, 6Department of Urology, Herlev and Gentofte Hospital, Copenhagen, Denmark Aim of the database: The main purpose of the database of the Danish Renal Cancer Group (DaRenCaData) is to improve the quality of renal cancer treatment in Denmark and secondarily to conduct observational research. Study population: DaRenCaData includes all Danish patients with a first-time diagnosis of renal cancer in the Danish National Pathology Registry since August 1, 2010. Main variables: DaRenCaData holds data on demographic characteristics, treatments, and pathology collected through linkage to central registries and online registration of a few clinical key variables. Eight quality indicators have been selected for monitoring treatment quality and outcome after renal cancer. Descriptive data: The incidence of renal cancer in Denmark has increased from 12.7 per 100,000 population-years in 2010–2011 to 15.9 per 100,000 population-years in 2014–2015. A total of 3,977 Danish patients with renal cancer have been enrolled in the database in the period August 1, 2010–July 31, 2015. The completeness of data registration has increased substantially since the first years of the database. A tendency toward smaller and less advanced tumors, less invasive surgery, and a shorter hospital stay was observed, while the postoperative morbidity and mortality remained stable. Concurrently, the 1-year survival has improved and was 84.1% in 2014–2015. Conclusion: DaRenCaData provides valuable information on quality of and outcome after renal cancer treatment. Efforts to improve collection and registration of data are ongoing. Keywords: kidney cancer, database, clinical quality, indicators, incidence, survival, observational researc
Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium
No full textThe benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.sponsorship: Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Daniel Y.C. Heng is a consultant for Pfizer, Novartis, and Bayer/Onyx. Brian A. Rini is a consultant for Pfizer, GlaxoSmithKline, Aveo, and Bayer/Onyx. He receives research funding from GlaxoSmithKline and Pfizer. Jennifer J. Knox is a consultant for Aveo and receives research funding from Pfizer. Georg A. Bjarnason is a consultant and receives research funding and honoraria from Pfizer. Christian K. Kollmannsberger is a consultant for Pfizer, Novartis, and GlaxoSmithKline. He receives honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sandy Srinivas is a consultant for Pfizer, Novartis, and Genentech. Frede Donskov receives research funding from Novartis. Lori A. Wood is a consultant for Pfizer and Novartis; she receives research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka Vaishampayan receives honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun Young Rha is a consultant for Pfizer, Novartis, and GlaxoSmithKline, and receives research funding from Novartis and Bayer Korea. Toni K. Choueiri is a consultant for Aveo, Pfizer, Novartis, GlaxoSmithKline, Genentech, and Bayer/Onyx, and receives research funding from Pfizer. (GlaxoSmithKline, Pfizer, Novartis, Bayer Korea)status: Publishe
The presentation of death in L. N. Tolstoy's prose.
No full textThis study treats in detail one of the significant themes of world literature in the narratives of the Russian writer L. N. Tolstoy. The theme of death, its modalities, motifs and related aspects, occur frequently in all of Tolstoy's artistic and philosophical writings. He presents this theme in connection with other dominant themes such as appearance and reality, falsity and truth, the attempts and failures to materialize individuals' objectives, all in various contexts of life--both private and public, and especially military life. The selection of themes such as sexuality, violence, or the transgression of moral laws, also affects the presentation of the theme of death. Instead of focusing on one pair of dominant semantic fields, Tolstoy (in the majority of his narratives) connects several of them equally. There are very few of his works in which one semantic field dominates. In accordance with Realist poetics, Tolstoy presents the theme of death directly; references to death on an allegorical or symbolic level occur in only a few of his narratives. In his early works, Tolstoy varies not only the fundamental modalities, but also the basic modes of violent and natural death. The presentation of a theme in a narrative differs depending on the length of the narrative. In his shorter prose fiction, Tolstoy concentrates the theme of death into specific passages, while its presentation in the longer narratives is distributed throughout the texts. In presenting the various characters, his narrators reveal their philosophies of life, which are particularly apparent in the borderline situation of death and dying. Members of different social classes display, as a rule, contrasting philosophies in revealing their attitudes and reactions--a trend which is again noticeable both in Tolstoy's major prose and in his late narratives. The author's focus on introspection (although in his early prose members of the lower classes are excluded from this technique) continues to play an important role in his late work as well. The author uses typical narrative devices such as anticipation, retrospection, association and paradox in the depiction of this complex theme as he attempts to 'de-romanticize', 'de-sensationalize' and 'de-dramatize' this topic. Despite the general tendency to omit the actual moment of death, there are a few works in which the horror of violent death shocks the reader. As for artistic development in presenting this theme, Tolstoy continues to employ a basic stock of devices and techniques already manifest in his early works
The presentation of death in L. N. Tolstoy's prose.
No full textThis study treats in detail one of the significant themes of world literature in the narratives of the Russian writer L. N. Tolstoy. The theme of death, its modalities, motifs and related aspects, occur frequently in all of Tolstoy's artistic and philosophical writings. He presents this theme in connection with other dominant themes such as appearance and reality, falsity and truth, the attempts and failures to materialize individuals' objectives, all in various contexts of life--both private and public, and especially military life. The selection of themes such as sexuality, violence, or the transgression of moral laws, also affects the presentation of the theme of death. Instead of focusing on one pair of dominant semantic fields, Tolstoy (in the majority of his narratives) connects several of them equally. There are very few of his works in which one semantic field dominates. In accordance with Realist poetics, Tolstoy presents the theme of death directly; references to death on an allegorical or symbolic level occur in only a few of his narratives. In his early works, Tolstoy varies not only the fundamental modalities, but also the basic modes of violent and natural death. The presentation of a theme in a narrative differs depending on the length of the narrative. In his shorter prose fiction, Tolstoy concentrates the theme of death into specific passages, while its presentation in the longer narratives is distributed throughout the texts. In presenting the various characters, his narrators reveal their philosophies of life, which are particularly apparent in the borderline situation of death and dying. Members of different social classes display, as a rule, contrasting philosophies in revealing their attitudes and reactions--a trend which is again noticeable both in Tolstoy's major prose and in his late narratives. The author's focus on introspection (although in his early prose members of the lower classes are excluded from this technique) continues to play an important role in his late work as well. The author uses typical narrative devices such as anticipation, retrospection, association and paradox in the depiction of this complex theme as he attempts to 'de-romanticize', 'de-sensationalize' and 'de-dramatize' this topic. Despite the general tendency to omit the actual moment of death, there are a few works in which the horror of violent death shocks the reader. As for artistic development in presenting this theme, Tolstoy continues to employ a basic stock of devices and techniques already manifest in his early works
Prognostic Utility of Parameters Derived From Pretreatment Dual-Layer Spectral-Detector CT in Patients With Metastatic Renal Cell Carcinoma
No full textBACKGROUND. New therapies have emerged for metastatic renal cell carcinoma (mRCC), though corresponding imaging markers are lacking. Dual-layer spectral-detector CT (DLCT) can quantify iodine concentration (IC) and effective atomic number (Zeffective), providing information beyond attenuation that may indicate mRCC prognosis. OBJECTIVE. The purpose of our study was to assess the utility of the DLCT-derived parameters IC and Zeffective for predicting mRCC treatment response and survival. METHODS. This prospective study enrolled 120 participants with mRCC from January 2018 to January 2020 who underwent DLCT, with reconstruction of IC and Zeffective maps, before treatment initiation. Final analysis included 115 participants (86 men, 29 women; median age, 65.1 years), incorporating 313 target lesions that were clinically selected using RECIST version 1.1 on arterial phase acquisitions of the chest and abdomen. Semiautomatic volumetric segmentation was performed of the target lesions. Voxels from all lesions were combined to a single histogram per patient. The median IC and Zeffective of the combined histograms were recorded. Measurements above and below the cohort median values were considered high and low, respectively. Univariable associations were explored between IC and Zeffective with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Multivariable associations were explored between IC and ORR, PFS, and OS, adjusting for treatment (tyrosine kinase inhibitor vs checkpoint immunotherapy) and significant univariable predictors (including tumor histology and International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk factors). RESULTS. At baseline, median IC was 2.26 mg/mL, and median Zeffective was 8.49. In univariable analysis, high IC and high Zeffective were associated with better ORR (both, odds ratio [OR] = 4.35; p = .001), better PFS (both, hazard ratio [HR] = 0.51; p = .004), and better OS (both, HR = 0.38; p < .001). In multivariable models, high IC independently predicted better ORR (OR = 4.35, p = .001), better PFS (HR = 0.51, p = .004), and better OS (HR = 0.37, p < .001); neutrophilia independently predicted worse PFS (HR = 2.10, p = .004) and worse OS (HR = 2.28, p = .003). The estimated C-index for predicting OS using IMDC risk factors alone was 0.650 versus 0.687 when incorporating high attenuation and 0.692 when incorporating high IC or high Zeffective. CONCLUSION. High IC and high Zeffective are significant predictors of better treatment response and survival in mRCC. CLINICAL IMPACT. Baseline DLCT parameters may improve current mRCC prognostic models. TRIAL REGISTRATION. ClinicalTrials.gov NCT03616951.</p
Development and Methodological Validation of a Modified Staging System for de Novo Metastatic Breast Cancer
No full textImportance Validation of a new method for prognostication of de novo metastatic breast cancer (dnMBC) to better reflect the heterogenecity of the disease.Objective To perform external methodological validation of the Plichta staging system, a novel prognostic system for de novo metastatic breast cancer (dnMBC).Design, Setting, and Participants This retrospective cohort study used a multicenter, nationwide, population-based Danish Breast Cancer Group database to validate the new method. Participants were patients with dnMBC diagnosed between 2010 and 2019. Data were analyzed from April to June 2023.Main outcomes and measures A recursive partitioning analysis (RPA) was performed, as demonstrated by Plichta and colleagues, to group patients with similar overall survival (OS) based on clinical factors. The main outcome was to group patients into 4 prognostic groups based on 3-year OS as stage IVa, greater than 70%; stage IVb, 50% to 70%; stage IVc, 25% to less than 50%; or stage IVd, less than 25%. Bootstrapping was applied for 1000 iterations, with final stage assignments based on the most commonly occurring assignment.Results A total of 1859 women were included with a median (IQR) age of 69 (57-77) years. With a median potential follow-up of 89.9 (95% CI, 86.4-95.1) months and a median OS of 31.7 (95% CI, 29.5-34.1) months, the RPA stratified patients into 10 groups, with organ sites, estrogen receptor status, and human epidermal growth factor receptor 2 status as the key clinical factors. Three-year survival rates ranged from 62% (95% CI, 56%-69%) to 8% (95% CI, 3%-21%), which were further combined into 3 stage groups: IVb, 59.4% (95% CI, 56.2%-62.8%); IVc, 39.4% (95% CI, 36.2%-43.0%); and IVd, 15.4% (95% CI, 11.2%-21.3%) (P < .001). Following bootstrapping, an IVa group emerged, resulting in 4 stage groups with separate 3-year OS rates identified as IVa, 75.8% (95% CI, 67.8%-84.7%); IVb, 58.8% (95% CI, 55.5%-62.3%); IVc, 39.2% (95% CI, 35.8%-43.0%); and IVd, 14.4% (95% CI, 10.8%-19.4%) (P < .001).Conclusions and relevance These findings provide external and independent validation of the methods applied in the novel Plichta staging system for dnMBC. This could guide future revisions of the current American Joint Committee on Cancer staging guidelines and may be incorporated as a stratification factor in clinical trials.Importance: Validation of a new method for prognostication of de novo metastatic breast cancer (dnMBC) to better reflect the heterogenecity of the disease. Objective: To perform external methodological validation of the Plichta staging system, a novel prognostic system for de novo metastatic breast cancer (dnMBC). Design, Setting, and Participants: This retrospective cohort study used a multicenter, nationwide, population-based Danish Breast Cancer Group database to validate the new method. Participants were patients with dnMBC diagnosed between 2010 and 2019. Data were analyzed from April to June 2023. Main outcomes and measures: A recursive partitioning analysis (RPA) was performed, as demonstrated by Plichta and colleagues, to group patients with similar overall survival (OS) based on clinical factors. The main outcome was to group patients into 4 prognostic groups based on 3-year OS as stage IVa, greater than 70%; stage IVb, 50% to 70%; stage IVc, 25% to less than 50%; or stage IVd, less than 25%. Bootstrapping was applied for 1000 iterations, with final stage assignments based on the most commonly occurring assignment. Results: A total of 1859 women were included with a median (IQR) age of 69 (57-77) years. With a median potential follow-up of 89.9 (95% CI, 86.4-95.1) months and a median OS of 31.7 (95% CI, 29.5-34.1) months, the RPA stratified patients into 10 groups, with organ sites, estrogen receptor status, and human epidermal growth factor receptor 2 status as the key clinical factors. Three-year survival rates ranged from 62% (95% CI, 56%-69%) to 8% (95% CI, 3%-21%), which were further combined into 3 stage groups: IVb, 59.4% (95% CI, 56.2%-62.8%); IVc, 39.4% (95% CI, 36.2%-43.0%); and IVd, 15.4% (95% CI, 11.2%-21.3%) (P <.001). Following bootstrapping, an IVa group emerged, resulting in 4 stage groups with separate 3-year OS rates identified as IVa, 75.8% (95% CI, 67.8%-84.7%); IVb, 58.8% (95% CI, 55.5%-62.3%); IVc, 39.2% (95% CI, 35.8%-43.0%); and IVd, 14.4% (95% CI, 10.8%-19.4%) (P <.001). Conclusions and relevance: These findings provide external and independent validation of the methods applied in the novel Plichta staging system for dnMBC. This could guide future revisions of the current American Joint Committee on Cancer staging guidelines and may be incorporated as a stratification factor in clinical trials.</p
Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma
No full textUdgivelsesdato: 2009-Feb-1PURPOSE: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown. EXPERIMENTAL DESIGN: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival. RESULTS: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells. CONCLUSION: Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma
Outcomes for International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Groups in Contemporary First-line Combination Therapies for Metastatic Renal Cell Carcinoma
No full textImmunotherapy; Prognostication; Metastatic renal cell carcinomaImmunoteràpia; Pronòstic; Carcinoma de cèl·lules renals metastàticInmunoterapia; Pronóstico; Carcinoma de células renales metastásicoBackground
The combination of immuno-oncology (IO) agents ipilimumab and nivolumab (IPI-NIVO) and vascular endothelial growth factor targeted therapies (VEGF-TT) combined with IO (IO-VEGF) are current standard of care first-line treatments for metastatic renal cell carcinoma (mRCC).
Objective
To establish real-world clinical benchmarks for IO combination therapies based on the International mRCC Database Consortium (IMDC) criteria.
Design, setting, and participants
Patients with mRCC who received first-line IPI-NIVO, IO-VEGF, or VEGF-TT from 2002 to 2021 were identified using the IMDC database and stratified according to IMDC risk groups.
Outcome measurements and statistical analysis
Overall survival (OS), time to next treatment (TTNT), and treatment duration (TD) were calculated using the Kaplan-Meier method and compared between IMDC risk groups within each treatment cohort by the log-rank test. The overall response rate (ORR) was calculated by physician assessment of the best overall response. The primary outcome was OS at 18 mo.
Results and limitations
In total, 728 patients received IPI-NIVO, 282 IO-VEGF, and 7163 VEGF-TT. The median follow-up times for patients remaining alive were 14.3 mo for IPI-NIVO, 14.9 mo IO-VEGF, and 34.4 mo for VEGF-TT. OS at 18 mo for favorable, intermediate, and poor risk was, respectively, 90%, 78%, and 50% for those receiving IPI-NIVO; 93%, 83%, and 74% for IO-VEGF; and 84%, 64%, and 28% for VEGF-TT. ORRs in favorable-, intermediate-, and poor-risk groups were 41.3%, 40.6%, and 33.0% for those receiving IPI-NIVO; 60.3%, 56.8%, and 40.9% for IO-VEGF; and 39.3%, 33.5%, and 20.9% for VEGF-TT, respectively. The IMDC model stratified patients into statistically distinct risk groups for the three endpoints of OS, TTNT, and TD within each treatment cohort. Limitations of this study were the retrospective design and short follow-up.
Conclusions
This study demonstrated that the IMDC model continues to risk stratify patients with mRCC treated with contemporary first-line IO combination therapies and provided real-world survival benchmarks
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