Apalutamide-induced lichenoid reaction in a patient with non-metastatic castrate-resistant prostate cancer

Introduction Apalutamide is an oral selective androgen receptor inhibitor, approved by the FDA for the treatment of patients with non-metastatic, castration-resistant prostate cancer (M0 CRPC) at high risk of developing metastases and for patients with metastatic castration-sensitive prostate (mHSPC) in association with androgen deprivation therapy (ADT). In the registration studies, skin reactions were reported among the most common side effects and as an adverse event of special interest. Case Report Apalutamide-induced rash includes a wide spectrum of different types of skin reactions, but few cases reports and case series have described this adverse event. Here, we report an M0 CRPC patient who experienced a rare skin adverse event, a lichenoid reaction. Management & Outcome After 4 months of therapy with apalutamide, the patient reported dorsal pricking and dry skin. Lichenoid reaction was confirmed histologically and its correlation to the drug was demonstrated after pursuing a multidisciplinary approach. Discussion To our knowledge, this is one of the first cases of Apalutamide-related lichenoid reaction and this clinical case showed the relevance of a multidisciplinary management when assessing drug-related adverse events. A broader knowledge of the spectrum of drug-related reactions would allow for a better diagnosis and therapy management by both physicians and patients

Characterization of Tumor and Immune Tumor Microenvironment of Primary Tumors and Metastatic Sites in Advanced Renal Cell Carcinoma Patients Based on Response to Nivolumab Immunotherapy: Preliminary Results from the Meet-URO 18 Study

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study)

: Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy

Analyses of tumor microenvironment in advanced renal cell carcinoma patients receiving immunotherapy (Meet-URO 18 study) - supplementary material

eTable 1. Correlation between IHC parameters.eTable 2. Correlation of the IHC parameters with overall survival.eTable 3. Correlation of the IHC parameters with objective response rate.eTable 4. Correlation of the IHC parameters with duration of response.</p

The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis

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 &lt; 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction &lt;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 &lt; 0.001 for both) and higher platelets (p = 0.004 and p &lt; 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 &lt; 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

DataSheet_1_The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis.docx

BackgroundTreatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.MethodsBy 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.ResultsThe analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p ConclusionsEarly neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions.</p

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study

76siWe aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.noneBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, AlessandroBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, Alessandr

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity