Clinical features and response to immune combinations in patients with renal cell carcinoma and sarcomatoid de-differentiation (ARON-1 study).

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First-line immunotherapy (IO)-based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real-world data confirming the adequate first-line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO-based combinations within the ARON-1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non-sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first-line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non-sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6-44.2) in sRCC and 35.3 months (95%CI 30.2-40.4) in non-sRCC patients (p = .013). The median progression-free survival (PFS) was longer in non-sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first-line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO-based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted.

Remarkable response to gemcitabine rechallenge in advanced urothelial carcinoma: a case report.

Therapeutic alternatives in advanced urothelial carcinoma are limited, especially in advanced lines, with only a few drugs having demonstrated relevant clinical benefit. This article discusses about a young patient with significant cardiovascular comorbidities, already treated with recommended first- and second-line drugs, and suffering from liver metastases. Despite the known poor prognosis of this disease and the few supporting data, given his peculiar clinical history, we opted to treat him with a third-line gemcitabine rechallenge with a notable response on his liver lesions. We present an intriguing case, both in terms of the therapeutic sequence and the disease course.

Skin metastasis of BRCA mutated prostate cancer: A case report and a brief review of literature.

RATIONALE: Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers. PATIENT CONCERNS: Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization. DIAGNOSES: A diagnosis of skin metastasis from prostate cancer was reported. OUTCOMES: The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression. LESSONS: A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis.

Sodium levels and immunotherapy efficacy in mRCC patients with bone metastases: sub analysis of Meet-Uro 15 study.

Background: Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy. Materials and methods: This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Among 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 vs. 12.0, p=0.04). Post-treatment sodium levels ≥140 mEq/L were associated with improved PFS (9.6 vs. 3.2 months) and OS (25.1 vs. 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels ≥140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 vs. 3.3 months and OS 42.2 vs. 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels. Conclusion: Elevated sodium levels (≥140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings.

Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1).

BACKGROUND: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. RESULTS: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). CONCLUSION: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

Interleukin-8 in Colorectal Cancer: A Systematic Review and Meta-Analysis of Its Potential Role as a Prognostic Biomarker.

Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in colorectal cancer (CRC) remains to be established. We: (i) conducted a systematic review of published literature on IL-8 expression in CRC; (ii) searched public transcriptomics databases; (iii) investigated IL-8 expression, by tumor and infiltrating cells, in a series of CRC samples; and (iv) carried out a meta-analysis of published literature correlating IL-8 expression and CRC prognosis. IL-8 possesses an important role as a mediator of the bidirectional crosstalk between tumor/stromal cells. Transcriptomic analysis indicated that specific IL-8 transcripts were significantly overexpressed in CRC compared to normal colon mucosa. Moreover, in our series we observed a statistically significant correlation between PTEN-loss and IL-8 expression by infiltrating mononuclear and tumor cells. In total, 12 papers met our meta-analysis inclusion criteria, demonstrating that high IL-8 levels significantly correlated with shorter overall survival and progression-free survival. Sensitivity analysis demonstrated a highly significant correlation with outcome for circulating, but not for tissue-detected, IL-8. IL-8 is overexpressed in CRC tissues and differentially produced by tumor or stromal components depending on CRC genetic background. Moreover, circulating IL-8 represents a strong prognostic factor in CRC, suggesting its use in the refining of prognostic CRC assessment and potentially the tailoring of therapeutic strategies in individual CRC patients.

High Levels of Circulating Monocytic Myeloid-Derived Suppressive-Like Cells Are Associated With the Primary Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: An Exploratory Analysis.

Background: Immunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes. Methods: This is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan-Meier method and the Cox proportional hazards model. Results: Twenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median. Conclusions: In this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.

Nivolumab in Combination with Stereotactic Body Radiotherapy in Pretreated Patients with Metastatic Renal Cell Carcinoma. Results of the Phase II NIVES Study.

BACKGROUND: Nivolumab showed an overall survival (OS) benefit in pretreated metastatic renal cell carcinoma (mRCC). The role of stereotactic body radiotherapy (SBRT) in mRCC remains to be defined. OBJECTIVE: Our aim was to evaluate the efficacy and safety of SBRT in combination with nivolumab in second- and third-line mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The NIVES study was a phase II, single-arm, multicenter trial in patients with mRCC with measurable metastatic sites who progressed after antiangiogenic therapy, of whom at least one was suitable for SBRT. INTERVENTION: The patients received SBRT to a lesion at a dose of 10 Gy in three fractions for 7 d from the first infusion of nivolumab. Nivolumab was given at an initial dose of 240 mg every 14 d for 6 mo and then 480 mg q4-weekly in responding patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We hypothesized that nivolumab plus SBRT improves the objective response rate (ORR) compared with nivolumab alone from 25% (derived from historical controls) to 40%. Secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR) of irradiated and nonirradiated metastases, and safety. RESULTS AND LIMITATIONS: Sixty-nine patients were enrolled from July 2017 to March 2019. The ORR was 17% and the DCR was 55%. The median PFS was 5.6 mo (95% confidence interval [CI], 2.9-7.1) and median OS 20 mo (95% CI, 17-not reached). After 1.5 yr of follow-up, 23 patients died. The median time to treatment response was 2.8 mo and median duration of response was 14 mo. No new safety concerns arose. CONCLUSIONS: We did not find sufficient evidence to suggest that nivolumab in combination with SBRT provides an added benefit in pretreated mRCC patients; it should however be evaluated in patients with oligometastatic or oligoprogressive disease. PATIENT SUMMARY: Nivolumab in combination with stereotactic body radiotherapy does not provide evidence of increased outcomes in metastatic renal cell carcinoma patients. However this approach was safe and showed a good response of the irradiated lesions.

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. MATERIALS AND METHODS: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. RESULTS: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. CONCLUSIONS: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection.

Organisational challenges, volumes of oncological activity and patients' perception during the severe acute respiratory syndrome coronavirus 2 epidemic.

BACKGROUND: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed at the University Hospital Trust of Verona, Italy. On March 13th, the Oncology Section was converted into a 22-inpatient bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities. METHODS: We tracked down (i) volumes of oncological activities (January 1st - March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection-related hospital admissions of "active"' oncological patients. RESULTS: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in January-March 2020 was 8%, 6% and 3%, respectively; based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARS-CoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications). CONCLUSIONS: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum.

Renal cell carcinoma in one year: Going inside the news of 2017 - A report of the main advances in RCC cancer research.

Very interesting issues regarding RCC treatment have been raised during 2017. We analysed the main news that may potentially modified clinical practice. Conflicting data came from trials testing targeted therapies in the adjuvant setting, supporting the necessity of further investigations. One of the key goals of RCC research is focused on the first-line therapy, with particular interest focus on immunotherapy combinations. Redefine the standard of care with the aim of improving patients' survival represents an imperative need. Enhancing immunotherapy antitumor activity by combining immune checkpoint inhibitors with anti-angiogenetic therapies is a noteworthy research field, with promising results. In addiction, we analysed in the metastatic setting data about the role of cytoreductive nephrectomy and the possibility of delay the start of first-line therapy after an active surveillance period. Based on recent developments, the paper outlines future prospective of RCC research.

Prognostic impact of proliferation for resected early stage 'pure' invasive lobular breast cancer: Cut-off analysis of Ki67 according to histology and clinical validation.

INTRODUCTION: The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC). METHODS: Clinical-pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well. RESULTS: Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 ≤ 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 ≤ 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap. CONCLUSIONS: Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology.

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of Ki67 assay according to histology: prognostic relevance for resected early stage 'pure' and 'mixed' lobular breast cancer.

BACKGROUND: The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. METHODS: Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between 'pure' or 'mixed' histology ILC and Ki67. RESULTS: At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8%, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21%); 10-years DFS and OS were 75.1, 66.5, and 30.2% (p = 0.01) and 84.3, 76.4 and 59% (p = 0.003), for patients with a Ki67 < 6%, between 6 and 21%, and >21%, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85%, OS 100%). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with 'pure' ILC performed worse than 'mixed' histology. CONCLUSIONS: Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with 'pure' ILC.

Prognostic model for advanced breast carcinoma with luminal subtype and impact of hormonal maintenance: Implications for post-progression and conditional survival.

BACKGROUND: The aim of this analysis was to develop and validate a prognostic model for advanced breast cancer (ABC) with luminal subtype based on the combination of clinical, pathological and therapeutic predictors to provide a practical tool to evaluate patients' prognosis. METHODS: Clinical and pathological data were retrospectively correlated to progression-free and overall survival (PFS/OS) using a Cox model. Significant treatment variables were adjusted with the propensity score analysis. A continuous score to identify risk classes was derived according to model ratios. The performance of the risk-class model was tested for post-progression survival (PPS) and conditional survival (CS) as well. RESULTS: Data from 335 patients (3 institutions) were gathered (median follow-up 58 months). At multivariate analysis Ki67, Performance Status (PS) and number of metastatic sites were significant predictors for PFS, whereas Ki67, PS, brain metastases, PFS after 1st-line therapy, number of chemotherapy lines, hormonal therapy and maintenance were significant predictors for OS. The hormonal maintenance resulted to be prognostic after adjustment with propensity score analysis. A two-class model significantly differentiated low-risk and high-risk patients for 2-year PFS (31.5% and 11.0%, p < 0.0001), and 3-years OS (57.1% and 4.8%, p < 0.0001). A three-class model separated low risk, intermediate-risk, and high-risk patients for 2-year PFS (40.8%, 24.4%, and 11.0%, p < 0.0001) and 3-year OS (68.1%, 24.8%, and 4.8%, p < 0.0001). Both models equally discriminate the luminal ABC prognosis in terms of PPS and CS. CONCLUSIONS: A risk stratification model including 'easy-to-obtain' clinical, pathological and therapeutic parameters accurately separates luminal ABC patients into different risk classes.