Francesco Massari

Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma.

BACKGROUNDnSeveral tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a tumor flare (TF) but its clinical relevance is still questionable.nnnOBJECTIVEnThis analysis investigates the occurrence of tumor flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC.nnnDESIGN, SETTING, AND PARTICIPANTSnPatients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnOverall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 - GR1). Cox proportional hazards regression was used to assess the prognostic role.nnnRESULTS AND LIMITATIONSnSixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] -0.07 to 0.53) and 0.70cm/mo (IQR 0.21-1.46), respectively (p=0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08-1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001-1.225; p=0.048).nnnCONCLUSIONSnThis study reports clinical evidence that TKI discontinuation results in acceleration of tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients.nnnPATIENT SUMMARYnIn this report, we looked at the outcomes for patients affected by metastatic kidney tumors who discontinued treatment with antiangiogenic agents. We found that tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in tumor growth rate, which is related to patient survival.

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib

Background In this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC). Results Patients were stratified into high SII (≥ 730) and low SII (< 730) groups. SII was associated with objective response, p < 0.0001. The median PFS was 6.3 months (95% CI 5.5–8.9) in patients with SII ≥ 730 and 18.7 months (95% CI 14.7–22.8) in those with SII < 730, p < 0.0001. The median OS was 43.6 months (95% CI 35.3–52.1) in patients with SII < 730, and 13.5 months (95% CI 9.8–18.5) in those with SII ≥ 730, p < 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively). Materials and Methods We included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses. Conclusions The SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC.

Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients.

Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine

Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms ‘BRAF,’ ‘mutation,’ and ‘cancer/tumor.’ These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.

Targeting the Programmed Cell Death-1 Pathway in Genitourinary Tumors: Current Progress and Future Perspectives

BACKGROUNDnImmune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent.nnnMETHODnPD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles.nnnRESULTSnPD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques.nnnCONCLUSIONnRCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish.

Impact of visceral metastases on outcome to abiraterone after docetaxel in castration-resistant prostate cancer patients

BACKGROUNDnThe objective of this study was to analyze the impact of visceral metastases in castration-resistant prostate cancer (CRPC) treated with abiraterone.nnnMATERIALS & METHODSnAll CRPC patients received abiraterone 1000 mg daily plus prednisone 10 mg orally daily. Liver and lung metastases were considered as visceral metastases.nnnRESULTSnOf 265 CRPC patients, 49 had visceral metastases. Results on progression-free survival were not significantly different in patients with or without visceral metastases. Conversely, the median overall survival between the two groups was 12.4 and 18.5 months (p = 0.01), respectively, and median overall survival of patients with liver-only disease versus other sites was 10.5 versus 18.5 months (p = 0.006), respectively.nnnCONCLUSIONnVisceral disease appears to be an important predictor of clinical outcome in CRPC patients treated with abiraterone.

Mirna Expression in Bladder Cancer and Their Potential Role in Clinical Practice

BACKGROUNDnTo date more than 3000 miRNA sequences have been described in humans and registered at miRBase since their discovery. However, the functions of only a few of these miRNAs have been experimentally determined using deep sequencing technology. Aberrant miRNA expression has been associated with differentiation, invasion and metastasis in several cancers. In this context, recent reports have suggested that miRNAs play important roles in the regulation of target genes by binding to complementary regions of messenger transcripts to repress their translation or regulate degradation. In addition, the expression profiles of certain miRNAs can function biologically as oncogenes and tumor suppressor genes.nnnMETHODnIn this review, we summarize the relationship between miRNAs expression and Bladder Cancer (BC). A comprehensive review of the literature has shown a differential expression between malignant and normal tissues, and that miRNAs could be the driving molecules of the BC progression. Similarly, the expression levels of miRNAs in urine and blood samples of BC patients have been demonstrated to be different from healthy people, a finding that might have diagnostic value.nnnCONCLUSIONnIn conclusion, the understanding of miRNAs mechanisms and cell distribution provides new opportunities for diagnosis, prognostic, disease monitoring and personalized therapy of BC patients.

Urinary Biomarkers for Prostate Cancer

BACKGROUNDnUrine may represent a convenient source of biomarkers for the early detection of Prostate Cancer (PCa) since it contains secreted prostatic products and exfoliated tumor cells. Furthermore, urine is easy to collect with non-invasive procedures which are repeatable.nnnMETHODnSeveral urinary biomarkers for PCa have been proposed in the past but only one (PCA3) has been approved for clinical use and even this is not widely utilized in the routine practice. Most of these, particularly the proteins, were abandoned due to lack of confirmation. DNA markers have been proposed but they are less suitable compared to other malignancies, such as bladder cancer due to the limited amount of DNA somatic alterations in PCa compared to gene fusions and pathway activations.nnnCONCLUSIONnRNA biomarkers are still the most promising and particularly miRNA and AMACR mRNA but the main weaknesses that prevented the full clinical implementation are the absence of a validated of the cut-off levels and the identification of consistent reference standards.

Circulating Tumor Cells: A Reliable Biomarker for Prostate Cancer Treatment Assessment?

BACKGROUNDnProstate cancer is a common malignancy with highly molecular heterogeneity responsible for a wide spectrum of clinical behavior. To date, several treatment options are available, whose selection is currently based mainly on clinical criteria. Given the weakness of conventional imaging and PSA assay, the identification of a prognostic and predictive biomarker for choosing the appropriate treatment and monitoring its efficacy is a very topical issue in prostate cancer management. Circulating tumor cells (CTCs) have substantial promise for early tumor diagnosis, disease recurrence and metastatic spread monitoring as well as for biological tumor characterization, thus representing a reliable translational real-time biomarkers of prostate cancer.nnnCONCLUSIONnThis paper summarized the main data available about CTCs detection, their prognostic value, and their potential predictive role for metastatic prostate cancer patients management.

Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3

R. (2016). Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3. Future Oncology, 12(12), 1431–1433. https://doi.org/10.2217/fon-2016-0113 Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3 Daniele Minardi‡,1, Roberta Mazzucchelli‡,2, Marina Scarpelli2, Francesco Massari3, Chiara Ciccarese4, Antonio Lopez-Beltran5, Liang Cheng6 & Rodolfo Montironi*,2 *Author for correspondence: r.montironi@univpm.it ‡Authors contributed equally 1Dipartimento di Scienze Cliniche e Specialistiche, Sezione di Urologia, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy 2Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy 2Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy 3Division of Oncology, S Orsola-Malpighi Hospital, Bologna, Italy 4Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy 5Department of Surgery, Cordoba University Medical School, Cordoba, Spain 6Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 2Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy Experts’ experience