22 results on '"Ficial M"'
Search Results
2. PD-L1 status and clinical outcomes to cabozantinib, sunitinib and everolimus in patients with metastatic clear-cell RCC treated on CABOSUN and METEOR clinical trials
- Author
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Choueiri, T.K., primary, Flaifel, A., additional, Xie, W., additional, Braun, D., additional, Ficial, M., additional, Jennings, R., additional, Nassar, A., additional, Escudier, B., additional, George, D.J., additional, Motzer, R.J., additional, Morris, M.J., additional, Powles, T., additional, Wang, E., additional, Huang, Y., additional, Freeman, G., additional, and Signoretti, S., additional
- Published
- 2018
- Full Text
- View/download PDF
3. Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors
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Fiorini, C., Francesco Massari, Pedron, S., Sanavio, S., Ciccarese, C., Porcaro, A. B., Artibani, W., Bertoldo, F., Zampini, C., Sava, T., Ficial, M., Caliò, A., Chilosi, M., D Amuri, A., Sanguedolce, F., Tortora, G., Scarpa, A., Delahunt, B., Porta, C., Martignoni, G., and Brunelli, M.
- Subjects
immunofluorescence analysis ,p-mTOR ,immunohistochemical ,mTOR ,Original Article ,Western blot ,Western blot, clear cell renal cell carcinoma, immunofluorescence analysis, immunohistochemical, mTOR, methods, p-mTOR, p-p70S6k ,clear cell renal cell carcinoma ,methods ,p-p70S6k - Abstract
Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p-mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies.
- Published
- 2014
4. LBA34 - PD-L1 status and clinical outcomes to cabozantinib, sunitinib and everolimus in patients with metastatic clear-cell RCC treated on CABOSUN and METEOR clinical trials
- Author
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Choueiri, T.K., Flaifel, A., Xie, W., Braun, D., Ficial, M., Jennings, R., Nassar, A., Escudier, B., George, D.J., Motzer, R.J., Morris, M.J., Powles, T., Wang, E., Huang, Y., Freeman, G., and Signoretti, S.
- Published
- 2018
- Full Text
- View/download PDF
5. Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors
- Author
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Fiorini C, Massari F, Pedron S, Sanavio S, Ciccarese C, Ab, Porcaro, Artibani W, Bertoldo F, Zampini C, Sava T, Ficial M, Caliò A, Chilosi M, D'Amuri A, Sanguedolce F, Giampaolo Tortora, Scarpa A, Delahunt B, Porta C, and Martignoni G
6. 124P Acquired resistance to first-line chemo- and EGFRab-therapy in mCRC: Biopsy analysis of the iSCORE trial.
- Author
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Lane, R., Mencel, J., Turkes, F., Challoner, B.R., McCafferty, N., Ntellas, P., Barber, L.J., Rana, I., Chen, H-C., Begum, R., Ficial, M., Tran, A., Terlizzo, M., Rao, S., Cunningham, D., Chau, I., Starling, N., and Gerlinger, M.
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- *
BIOPSY - Published
- 2024
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7. Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.
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Wang Y, Buck A, Piel B, Zerefa L, Murugan N, Coherd CD, Miklosi AG, Johal H, Bastos RN, Huang K, Ficial M, Laimon YN, Signoretti S, Zhong Z, Hoang SM, Kastrunes GM, Grimaud M, Fayed A, Yuan HC, Nguyen QD, Thai T, Ivanova EV, Paweletz CP, Wu MR, Choueiri TK, Wee JO, Freeman GJ, Barbie DA, and Marasco WA
- Subjects
- Animals, Mice, Humans, Carbonic Anhydrase IX genetics, Antigens, Neoplasm, Antibodies, T-Lymphocytes metabolism, Carcinoma, Renal Cell metabolism, Kidney Neoplasms pathology, Receptors, Chimeric Antigen genetics, Carbonic Anhydrases metabolism, Carbonic Anhydrases therapeutic use
- Abstract
One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target., (© 2024. The Author(s).)
- Published
- 2024
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8. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma.
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Saliby RM, El Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane MH, Madsen KN, Ficial M, Hirsch L, Wei XX, Steinharter JA, Harshman LC, Vaishampayan UN, Severgnini M, McDermott DF, Lee GM, Xu W, Van Allen EM, McGregor BA, Signoretti S, Choueiri TK, McKay RR, and Braun DA
- Subjects
- Humans, Bevacizumab therapeutic use, Vascular Endothelial Growth Factor A, B7-H1 Antigen, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations., (©2023 American Association for Cancer Research.)
- Published
- 2023
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9. Test yourself question: a 19-year-old male presents with progressive distal lower limb pain.
- Author
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Rajakulasingam R, Ficial M, and Saifuddin A
- Published
- 2022
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10. Answer To Test Yourself Question: A 19-year-old male presents with progressive distal lower limb pain.
- Author
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Rajakulasingam RR, Ficial M, and Saifuddin A
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- Adult, Humans, Male, Young Adult, Leg, Pain etiology
- Published
- 2022
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11. A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes.
- Author
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Calagua C, Ficial M, Jansen CS, Hirz T, Del Balzo L, Wilkinson S, Lake R, Ku AT, Voznesensky O, Sykes DB, Saylor PJ, Ye H, Signoretti S, Kissick H, Sowalsky AG, Balk SP, and Einstein DJ
- Subjects
- B7-H1 Antigen genetics, Genes, Tumor Suppressor, Humans, Lymphocytes, Tumor-Infiltrating, Male, Phenotype, Tumor Microenvironment genetics, CD8-Positive T-Lymphocytes, Prostatic Neoplasms genetics
- Abstract
Purpose: A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear., Experimental Design: We selected PD-L1-positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci., Results: One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8
+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+ PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+ PD-1+ TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1 , were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present., Conclusions: A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2 , and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer., (©2021 American Association for Cancer Research.)- Published
- 2021
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12. Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma.
- Author
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Ficial M, Jegede OA, Sant'Angelo M, Hou Y, Flaifel A, Pignon JC, Braun DA, Wind-Rotolo M, Sticco-Ivins MA, Catalano PJ, Freeman GJ, Sharpe AH, Hodi FS, Motzer RJ, Wu CJ, Atkins MB, McDermott DF, Shukla SA, Choueiri TK, and Signoretti S
- Subjects
- Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell immunology, Carcinoma, Renal Cell metabolism, Everolimus administration & dosage, Female, Follow-Up Studies, Humans, Kidney Neoplasms drug therapy, Kidney Neoplasms immunology, Kidney Neoplasms metabolism, Lymphocytes, Tumor-Infiltrating, Male, Nivolumab administration & dosage, Prognosis, Retrospective Studies, Survival Rate, Transcriptome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Carcinoma, Renal Cell secondary, Endogenous Retroviruses metabolism, Kidney Neoplasms pathology, T-Lymphocytes immunology, Viral Envelope Proteins metabolism
- Abstract
Purpose: We sought to validate levels of CD8
+ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025)., Experimental Design: Tumor tissues (nivo: n = 116, evero: n = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months)., Results: In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, P = 0.01) and DRR (33.3% vs. 14.1%, P = 0.03) and longer median PFS (9.6 vs. 3.7 months, P = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways ( q < 0.1) and immune-related gene signature scores ( q < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. ERVE-4 expression was associated with increased DRR and longer PFS in nivo-treated patients., Conclusions: High levels of CD8+ TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE-4 expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings., (©2020 American Association for Cancer Research.)- Published
- 2021
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13. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.
- Author
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Bakouny Z, Braun DA, Shukla SA, Pan W, Gao X, Hou Y, Flaifel A, Tang S, Bosma-Moody A, He MX, Vokes N, Nyman J, Xie W, Nassar AH, Abou Alaiwi S, Flippot R, Bouchard G, Steinharter JA, Nuzzo PV, Ficial M, Sant'Angelo M, Forman J, Berchuck JE, Dudani S, Bi K, Park J, Camp S, Sticco-Ivins M, Hirsch L, Baca SC, Wind-Rotolo M, Ross-Macdonald P, Sun M, Lee GM, Chang SL, Wei XX, McGregor BA, Harshman LC, Genovese G, Ellis L, Pomerantz M, Hirsch MS, Freedman ML, Atkins MB, Wu CJ, Ho TH, Linehan WM, McDermott DF, Heng DYC, Viswanathan SR, Signoretti S, Van Allen EM, and Choueiri TK
- Subjects
- B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen genetics, B7-H1 Antigen immunology, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen genetics, CTLA-4 Antigen immunology, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell mortality, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 immunology, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Immune Checkpoint Proteins genetics, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics, Kidney Neoplasms mortality, Mutation, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc immunology, Retrospective Studies, Rhabdoid Tumor drug therapy, Rhabdoid Tumor genetics, Rhabdoid Tumor mortality, Signal Transduction, Survival Analysis, Transcription, Genetic, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins immunology, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase immunology, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Renal Cell immunology, Gene Expression Regulation, Neoplastic, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Proteins immunology, Kidney Neoplasms immunology, Rhabdoid Tumor immunology
- Abstract
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
- Published
- 2021
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14. Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.
- Author
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Tannir NM, Signoretti S, Choueiri TK, McDermott DF, Motzer RJ, Flaifel A, Pignon JC, Ficial M, Frontera OA, George S, Powles T, Donskov F, Harrison MR, Barthélémy P, Tykodi SS, Kocsis J, Ravaud A, Rodriguez-Cid JR, Pal SK, Murad AM, Ishii Y, Saggi SS, McHenry MB, and Rini BI
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Hippo Signaling Pathway, Humans, Immunotherapy, Ipilimumab adverse effects, Nivolumab adverse effects, Protein Serine-Threonine Kinases, Sunitinib therapeutic use, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy
- Abstract
Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC., Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics., Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged., Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5 ., (©2020 American Association for Cancer Research.)
- Published
- 2021
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15. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.
- Author
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Braun DA, Hou Y, Bakouny Z, Ficial M, Sant' Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, Steinharter J, Sun M, Wind-Rotolo M, Pignon JC, Cherniack AD, Lichtenstein L, Neuberg D, Catalano P, Freeman GJ, Sharpe AH, McDermott DF, Van Allen EM, Signoretti S, Wu CJ, Shukla SA, and Choueiri TK
- Subjects
- Adult, Aged, Aged, 80 and over, Antigen Presentation genetics, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell immunology, Carcinoma, Renal Cell pathology, Chromosome Deletion, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 9 genetics, Class I Phosphatidylinositol 3-Kinases genetics, DNA-Binding Proteins genetics, Female, Fluorescent Antibody Technique, Gene Deletion, Genomics, Histocompatibility Antigens Class II genetics, Histone Demethylases genetics, Histone-Lysine N-Methyltransferase genetics, Humans, Kidney Neoplasms genetics, Kidney Neoplasms immunology, Kidney Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Male, Middle Aged, Mutation, PTEN Phosphohydrolase genetics, Prognosis, Proteasome Endopeptidase Complex genetics, Sequence Analysis, RNA, TOR Serine-Threonine Kinases genetics, Transcription Factors genetics, Tuberous Sclerosis Complex 1 Protein genetics, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Von Hippel-Lindau Tumor Suppressor Protein genetics, Exome Sequencing, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Nivolumab therapeutic use
- Abstract
PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8
+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.- Published
- 2020
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16. PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN.
- Author
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Flaifel A, Xie W, Braun DA, Ficial M, Bakouny Z, Nassar AH, Jennings RB, Escudier B, George DJ, Motzer RJ, Morris MJ, Powles T, Wang E, Huang Y, Freeman GJ, Choueiri TK, and Signoretti S
- Subjects
- Adult, Anilides therapeutic use, B7-H1 Antigen analysis, Biomarkers, Tumor analysis, Biopsy, Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell pathology, Chemotherapy, Adjuvant methods, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Everolimus therapeutic use, Female, Humans, Kaplan-Meier Estimate, Kidney pathology, Kidney surgery, Kidney Neoplasms mortality, Kidney Neoplasms pathology, Multicenter Studies as Topic, Nephrectomy, Prognosis, Progression-Free Survival, Pyridines therapeutic use, Randomized Controlled Trials as Topic, Sunitinib therapeutic use, B7-H1 Antigen metabolism, Biomarkers, Tumor metabolism, Carcinoma, Renal Cell therapy, Kidney Neoplasms therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Purpose: Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents., Experimental Design: IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR ( n = 306) and CABOSUN ( n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated., Results: Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients ( P = 0.034) and for patients treated with cabozantinib only ( P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression., Conclusions: Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy., (©2019 American Association for Cancer Research.)
- Published
- 2019
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17. Liver Metastases From Renal Oncocytoma With Vascular Extension.
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Cacciamani G, Cima L, Ficial M, Novella G, Siracusano S, Tedeschi U, Balzarro M, Montin U, Cerruto MA, De Marco V, Porcaro AB, Hes O, DʼErrico A, Martignoni G, Ghimenton C, Zaza G, Artibani W, Brunelli M, and Eccher A
- Abstract
The 2016 World Health Organization Renal Tumor Classification defines renal oncocytoma (RO) as a benign epithelial tumor; however, malignant histopathologic features have been documented. Rare cases with metastases have been reported. We describe the case of a 62-year-old woman who was referred to the Urology Clinic for a routine work-up. Magnetic resonance imaging and computerized tomography showed a 7-cm mass in the middle and lower portions of the left kidney and 2 suspected liver metastases. The patient underwent surgery. Microscopically both renal and liver lesions presented solid, solid-nested, and microcystic architecture, composed predominantly of large eosinophilic cells without any worrisome pattern except the vascular extension. The cells were positive for S100A1, CD117, and PAX-8 and negative for CAIX, CK7, and AMACR. Fluorescence in situ hybridization showed a disomic profile for the chromosomes 1, 2, 6, 7, 10, 17. No mutation of coding sequence of the SDHB, SDHC, SDHD, VHL, and BHD genes and no loss of heterozygosity at 3p were found. The final diagnosis was "RO" according to the 2016 World Health Organization Renal Tumor Classification with "liver metastases." This report provides a wide clinical-pathologic, immunophenotypical and molecular documentation of a RO with liver metastases.
- Published
- 2019
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18. Keratin14 mRNA expression in human pneumocytes during quiescence, repair and disease.
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Confalonieri M, Buratti E, Grassi G, Bussani R, Chilosi M, Farra R, Abrami M, Stuani C, Salton F, Ficial M, Confalonieri P, Zandonà L, and Romano M
- Subjects
- A549 Cells, Adolescent, Aged, Aged, 80 and over, Alveolar Epithelial Cells cytology, Alveolar Epithelial Cells metabolism, Cell Cycle Checkpoints, Cell Proliferation, Cell Transdifferentiation, Cells, Cultured, Cyclin D1 metabolism, Cyclin E metabolism, E2F1 Transcription Factor antagonists & inhibitors, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Female, Humans, Keratin-14 antagonists & inhibitors, Keratin-14 metabolism, Lung Diseases, Interstitial metabolism, Male, Middle Aged, Oncogene Proteins metabolism, RNA Interference, RNA, Small Interfering metabolism, Transcriptome, Keratin-14 genetics, Lung Diseases, Interstitial pathology, RNA, Messenger metabolism
- Abstract
The lung alveoli slowly self-renew pneumocytes, but their facultative regeneration capacity is rapidly efficient after an injury, so fibrosis infrequently occurs. We recently observed Keratin 14 (KRT14) expression during diffuse alveolar damage (DAD), but not in controls. We wonder if KRT14 may be a marker of pneumocyte transition from quiescence to regeneration. Quantitative PCR and Western blot analyses highlighted the presence of KRT14 (mRNA and protein) only in human lung samples with DAD or interstitial lung disease (ILD). In the exponentially growing cell lines A549 and H441, the mRNA and protein levels of KRT14 peaked at day one after cell seeding and decreased at day two, opposite to what observed for the proliferation marker E2F1. The inverse relation of KRT14 versus E2F1 expression holds true also for other proliferative markers, such as cyclin E1 and cyclin D1. Of interest, we also found that E2F1 silencing caused cell cycle arrest and increased KRT14 expression, whilst E2F1 stimulation induced cell cycle progression and decreased KRT14. KRT14 also increased in proliferative pneumocytes (HPAEpiC) just before transdifferentiation. Overall, our results suggest that KRT14 is a viable biomarker of pneumocyte activation, and repair/regeneration. The involvement of KRT14 in regenerative process may suggest a novel pharmaceutical target to accelerate lung repair.
- Published
- 2017
- Full Text
- View/download PDF
19. Usefulness of breast cytology after lipofilling.
- Author
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Ficial M, Parisi A, Remo A, Vasori S, and Manfrin E
- Subjects
- Adult, Aged, Breast Neoplasms surgery, Female, Humans, Middle Aged, Adipose Tissue transplantation, Breast Neoplasms pathology, Mammaplasty adverse effects, Neoplasm Recurrence, Local diagnosis
- Published
- 2016
- Full Text
- View/download PDF
20. Everolimus-induced epithelial to mesenchymal transition (EMT) in bronchial/pulmonary cells: when the dosage does matter in transplantation.
- Author
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Tomei P, Masola V, Granata S, Bellin G, Carratù P, Ficial M, Ventura VA, Onisto M, Resta O, Gambaro G, Chilosi M, Lupo A, and Zaza G
- Subjects
- A549 Cells, Actins genetics, Actins metabolism, Adult, Aged, Alveolar Epithelial Cells metabolism, Alveolar Epithelial Cells pathology, Bronchi enzymology, Bronchi pathology, Dose-Response Relationship, Drug, Female, Fibronectins genetics, Fibronectins metabolism, Gene Expression Regulation, Humans, Male, Middle Aged, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Pulmonary Fibrosis enzymology, Pulmonary Fibrosis genetics, Pulmonary Fibrosis pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Risk Assessment, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism, Tacrolimus adverse effects, Vimentin genetics, Vimentin metabolism, Alveolar Epithelial Cells drug effects, Bronchi drug effects, Epithelial-Mesenchymal Transition drug effects, Everolimus adverse effects, Immunosuppressive Agents adverse effects, Organ Transplantation adverse effects, Protein Kinase Inhibitors adverse effects, Pulmonary Fibrosis chemically induced, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Background: Everolimus (EVE) is a mammalian target of rapamycin inhibitor (mTOR-I) widely used in transplantation that may determine some severe adverse events, including pulmonary fibrosis. The pathogenic mechanism of mTOR-I-associated pulmonary toxicity is still unclear, but epithelial to mesenchymal transition (EMT) of bronchial/pulmonary cells may play a role., Methods: Three cell lines-human type II pneumocyte-derived A549, normal bronchial epithelial, and bronchial epithelial homozygous for the delta F508 cystic fibrosis-causing mutation-were treated with EVE or tacrolimus at different concentrations. Real-time polymerase chain reaction and immunofluorescence were used to evaluate mRNA and protein levels of EMT markers (alpha-SMA, vimentin, fibronectin). Subsequently, in 13 EVE- and 13 tacrolimus-treated patients we compared the rate of lung fibrosis, estimated by an arbitrary pulmonary fibrosis index score (PFIS)., Results: Biomolecular experiments demonstrated that high doses of EVE (100 nM) up-regulated EMT markers in all cell lines at both gene- and protein level. High concentrations of EVE were also able to reduce the mRNA levels of epithelial markers (E-cadherin and ZO-1) and to induce the phosphorylation of AKT. In the in vivo part of the study, PFIS was significantly higher in the EVE-group than the tacrolimus-group (p = 0.03) and correlated with trough levels (R
2 = 0.35)., Conclusions: Our data reveal, for the first time, a dose-dependent EVE-induced EMT in airway cells. They suggest that clinicians should employ, wherever possible, low dosages of mTOR-Is in transplant recipients, assessing periodically their pulmonary function.- Published
- 2016
- Full Text
- View/download PDF
21. Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors.
- Author
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Fiorini C, Massari F, Pedron S, Sanavio S, Ciccarese C, Porcaro AB, Artibani W, Bertoldo F, Zampini C, Sava T, Ficial M, Caliò A, Chilosi M, D'Amuri A, Sanguedolce F, Tortora G, Scarpa A, Delahunt B, Porta C, Martignoni G, and Brunelli M
- Abstract
Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p-mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies.
- Published
- 2014
22. Keratin-14 expression in pneumocytes as a marker of lung regeneration/repair during diffuse alveolar damage.
- Author
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Ficial M, Antonaglia C, Chilosi M, Santagiuliana M, Tahseen AO, Confalonieri D, Zandonà L, Bussani R, and Confalonieri M
- Subjects
- Acute Lung Injury pathology, Acute Lung Injury physiopathology, Alveolar Epithelial Cells physiology, Animals, Biomarkers, Female, Humans, Male, Mice, Pulmonary Alveoli cytology, Pulmonary Alveoli physiopathology, Keratin-14 metabolism, Pulmonary Alveoli injuries, Regeneration, Respiratory Distress Syndrome pathology, Stem Cells physiology
- Published
- 2014
- Full Text
- View/download PDF
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