The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients ...with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results (SEER) Research Data (2000–2017) were analyzed using the SEER*Stat software. The Kaplan–Meier method and Cox regression were used. Patients with de novo mPCa were allocated to three cohorts based on the year of diagnosis: A (2000–2003), B (2004–2010), and C (2011–2014). The maximum follow-up was fixed to 5 years. Overall, 26,434 patients were included. Age, race, and metastatic stage (M1) significantly affected OS and CSS. After adjustment for age and race, patients in Cohort C showed a 9% reduced risk of death (hazard ratio (HR): 0.91 (95% confidence interval CI 0.87–0.95), p < 0.001) and an 8% reduced risk of cancer-specific death (HR: 0.92 (95% CI 0.88–0.96), p < 0.001) compared with those in Cohort A. After adjustment for age, race, and metastatic stage, patients in Cohort C showed an improvement in OS and CSS compared with Cohort B (HR: 0.94 (95% CI 0.91–0.97), p = 0.001; HR: 0.89 (95% CI 0.85–0.92), p < 0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between Cohorts B and C. In conclusion, the real-world survival of de novo mPCa remains poor, with a median OS and CSS improvement of only 4 months in the latest years.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Periostin (POSTN) is an extracellular matrix protein associated with tumor progression and shorter survival in prostate cancer (PCa). Here, we performed an integrative analysis of POSTN’s role in ...patients with PCa. Clinical and POSTN data from large-scale datasets were analyzed. POSTN cutoffs were identified with X-Tile, and STRING was used for protein-protein interaction analysis. In a cohort of 48 patients with metastatic castration-resistant prostate cancer (mCRPC), we used the AdnaTest platform to isolate circulating tumor cells and extract POSTN mRNA. Plasma samples were also tested for POSTN protein expression by dot blot assay. Data from large-scale datasets did not reveal any association between POSTN genetic alterations and outcome. In primary tumors, we found a significant correlation between POSTN mRNA overexpression, worse baseline prognostic features, and shorter disease-free survival. POSTN was overexpressed in mCRPC and correlated with aggressive features. In our cohort of mCRPC patients, we found a positive correlation between POSTN plasma levels and androgen-receptor variant 7 positivity and an association with shorter overall survival. Our integrative analysis shows that POSTN is associated with poor clinical features and worse outcome in patients with PCa. Further studies are warranted to uncover the function of POSTN in PCa progression and to validate the prognostic significance of POSTN in mCRPC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients ...most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed the prognostic power of systemic inflammation biomarkers and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET)-derived parameters and their potential interplay in this clinical setting. The following baseline laboratory parameters were collected in 59 mCRPC patients treated with Ra-223: neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelets-to-lymphocyte ratio (PLR), and systemic inflammation index (SII), while maximum Standardized Uptake Value, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were calculated in the 48 of them submitted to baseline FDG-PET. At the univariate analysis, NLR, dNLR, MTV, and TLG were able to predict the overall survival (OS). However, only NLR and MTV were independent predictors of OS at the multivariate analysis. Additionally, the occurrence of both increased NLR and MTV at baseline identified mCRPC patients at higher risk for lower long-term survival after treatment with Ra-223. In conclusion, the degree of systemic inflammation, the quantification of the metabolically active tumor burden and their combination might represent potentially valuable tools for identifying mCRPC patients who are most likely to benefit from Ra-223. However, further studies are needed to reproduce these findings in larger settings.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite major advances in the understanding of the formation and dynamics of nanoclusters in the past decades, theoretical bases for the control of their shape are still lacking. We investigate ...strategies for driving fluctuating few-particle clusters to an arbitrary target shape in minimum time with or without an external field. This question is recast into a first passage problem, solved numerically, and discussed within a high temperature expansion. Without field, large-enough low-energy target shapes exhibit an optimal temperature at which they are reached in minimum time. We then compute the optimal way to set an external field to minimize the time to reach the target, leading to a gain of time that grows when increasing cluster size or decreasing temperature. This gain can shift the optimal temperature or even create one. Our results could apply to clusters of atoms at equilibrium, and colloidal or nanoparticle clusters under thermo- or electrophoresis.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related death worldwide. Based on the patient's stage of disease, treatment options include surgery, radiotherapy, and ...chemotherapy. Although chemotherapy remains the main therapeutic approach for advanced NSCLC, targeted therapy represents a good chance of treatment for this subgroup of patients. Currently this approach is based on previous evaluation of clinically relevant mutations and the Sanger sequencing is the main approach to assign mutational status and to guide the appropriate treatment; however this tool is characterized by a low sensitivity. Recently, the advent of next-generation sequencing (NGS) has dramatically revolutionized the molecular knowledge of cancer by increasing the feasibility and possibility to sequence DNA ranging from large scale studies to targeted regions. This review reports an overview of different applications of the NGS as novel approach to study NSCLC, thereby providing information about mutational spectrum of this cancer in order to identify novel targetable mutations and to predict the emergence of drug resistance. All studies demonstrated several advantages of this approach over the traditional tools. In particular the NGS was also able to reveal mutations in low percentage, and to screen the mutational status of different critical samples such as biopsies, cytological samples and circulating plasma DNA, offering innovative diagnostic opportunities. Despite several problems have to be overcome toward the personalized therapy, the NGS represents a highly attractive system to identify mutations improving the outcome of patients with this deadly disease.
PURPOSEThe current study aimed to determine the utility of including the study of deep subfascial lymphatic vessels in a 2-compartment lymphoscintigraphy for the diagnosis of lymphedema in patients ...with limb swelling. Lymphoscintigraphy is a valuable imaging tool for the timely diagnosis of peripheral lymphedema. However, there is a lack of standardization in its application, especially regarding which type of lymphatic vessels to examine (superficial, deep, or both).
METHODSTwo hundred fifty-eight patients with lymphedema underwent segmental lymphoscintigraphy. The transport index (TI) was calculated to categorize the flow of the superficial and deep vessels as normal (<10) or pathological (≥10). The scores from 248 patients (48 unilateral arm, 86 unilateral leg, 114 bilateral leg) were tested with a 3-way analysis of variance to examine the relationship between affected limb, deep or superficial pathways, and primary or secondary lymphedema. The relationship between clinical presentation and TI was also investigated.
RESULTSIn general, primary and secondary lymphedema patients had similar patterns of lymphoscintigraphic lymphatic abnormalities. Patients with unilateral clinical presentation can have bilateral TI abnormalities. The vast majority of patients (88%–98%) had either the deep subfascial vessels alone, or both the superficial and deep vessels, with a pathological TI.
CONCLUSIONSA 2-compartment lymphoscintigraphy is able to accurately detect lymphatic flow abnormalities in patients with limb swelling. Given that the vast majority of patients had deep lymphatic vessels abnormalities, inclusion of these vessels in the lymphoscintigraphic diagnostic protocol is recommended.
Abstract
Objective
Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this ...study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials.
Methods
Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan–Meier curves, log-rank test and multivariable Cox’s models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose.
Results
Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium’s good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium’s favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged.
Conclusions
In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium’s favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium’s good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.
The PAMERIT study retrospectively confirmed first-line pazopanibas active, efficacious, safe and cost-effective in the real-worldmRCC patients, particularly in IMDC good prognosis patients.
Background
Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.
Methods
By a pre-specified analysis of the Meet-URO 15 ...multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs.
Results
The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables.
Conclusions
Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions.
•Etoposide is a chemotherapeutic agent that shows significant activity in preclinical models of prostate cancer and increased activity is observed in the most aggressive cells.•Overexpression of ...topoisomerase II alfa identifies tumors with neuroendocrine features associated with shorter patients’ survival and could be useful to predict response to etoposide.•Specific patients with castration-resistant prostate cancer could benefit from etoposide treatment, alone or in combination with other agents.
Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC.
Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal.
VP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients’ prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss.
Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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