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Background: Understanding the risk relationship between statin use and immunerelated adverse events (irAEs) in patients undergoing immune checkpoint inhibitors (ICIs) therapy is crucial for optimizing oncological management. Objective: This study aimed to investigate whether the use of statins increases the risk of irAEs in patients receiving ICI therapy. Methods: This study primarily utilized data from FAERS database. Multivariable logistic regression was the principal method of analysis, and the Benjamini-Hochberg procedure was employed to adjust for multiple hypothesis testing. Results: In a group of 145,214 patients undergoing ICI therapy, 9,339 reported using statin medications. Multivariable analysis indicated an increased risk of irAEs among statin users (OR 1.199, 95% CI: 1.141-1.261; FDR p < 0.001) in comparison to those not using statins. Notably, increased risks were observed particularly in patients diagnosed with lung, pancreatic, and renal cancers. The link between statin usage and increased irAEs risk remained consistent across various ICIs treatments. Conclusions: Statin medication usage is linked to an elevated probability of experiencing irAEs in patients enrolled in ICI therapy. In cancer patients receiving immune checkpoint inhibitors, careful consideration of statin use is essential to avoid potentially increased irAEs risk. These findings provide critical guidance for clinicians in developing treatment strategies that balance therapeutic efficacy and safety in oncological management. [ABSTRACT FROM AUTHOR]

Simple Summary: Incidence of brain metastases from genito-urinary cancers has increased over the last years due to improved imaging techniques and better survival outcomes for patients even at an advanced metastatic stage thanks to therapeutic advances. However, no clear consensus exists on their management, and every case ought to be discussed in a multidisciplinary panel. We perform a single-centre retrospective study to report on incidence, patient demographics, clinicopathological characteristics, and treatment modalities. We also manage to identify predictive factors of outcome. Background: Incidence of brain metastases is precisely unknown and there is no clear consensus on their management. We aimed to determine the incidence of brain metastases among patients with genito-urinary primaries, present patients' characteristics and identify prognostic factors. Method: We identified 51 patients treated in Geneva University Hospitals between January 1992 and December 2019. We retrospectively correlated their overall survival with 23 variables. We repeated a multivariate analysis with significant variables. Results: Overall incidence of Brain Metastases (BMs) among Genito-Urinary (GU) patients is estimated to be 1.76% (range per primary GU tumour type: 0.00–6.65%). BMs originate from germ cell tumours in two cases (3.92%), from urothelial cell carcinoma in 15 cases (29.41%), from prostate cancer in 13 cases (25.49%), and from renal cell carcinoma in 21 cases (41.18%); there are no BMs from penile cancer in our cohort. The median age at BM diagnosis is 67 years old (range: 25–92). Most patients (54%) have a stage IV disease at initial diagnosis and 11 patients (22%) have BM at initial diagnosis. Only six patients (12%) are asymptomatic at BM diagnosis. The median Overall Survival (OS) from BM diagnosis is 3 months (range: 0–127). Five patients (10%) are long survivors (OS > 24 months). OS is significantly influenced by patient performance status and administration of systemic treatment. In the absence of meningeal carcinomatosis, OS is influenced by systemic treatment and stereotactic radiosurgery. We also apply the Graded Prognostic Assessment (GPA) score to our cohort and note significant differences between groups. Conclusion: Brain metastases from solid tumours is not a uniform disease, with a prognosis varying a lot among patients. The optimal management for patients with genito-urinary malignancies with brain metastases remain unclear and further research is needed. [ABSTRACT FROM AUTHOR]

Background: Lipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients. Methods: We conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan–Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response. Results: We constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes. Conclusions: Our findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations. [ABSTRACT FROM AUTHOR]

Background: Cancer stem-like cells (CSCs), a distinct subset recognized for their stem cell-like abilities, are intimately linked to the resistance to radiotherapy, metastatic behaviors, and self-renewal capacities in tumors. Despite their relevance, the definitive traits and importance of CSCs in the realm of oncology are still not fully comprehended, particularly in the context of clear cell renal cell carcinoma (ccRCC). A comprehensive understanding of these CSCs' properties in relation to stemness, and their impact on the efficacy of treatment and resistance to medication, is of paramount importance. Methods: In a meticulous research effort, we have identified new molecular categories designated as CRCS1 and CRCS2 through the application of an unsupervised clustering algorithm. The analysis of these subtypes included a comprehensive examination of the tumor immune environment, patterns of metabolic activity, progression of the disease, and its response to immunotherapy. In addition, we have delved into understanding these subtypes' distinctive clinical presentations, the landscape of their genomic alterations, and the likelihood of their response to various pharmacological interventions. Proceeding from these insights, prognostic models were developed that could potentially forecast the outcomes for patients with ccRCC, as well as inform strategies for the surveillance of recurrence after treatment and the handling of drug-resistant scenarios. Results: Compared with CRCS1, CRCS2 patients had a lower clinical stage/grading and a better prognosis. The CRCS2 subtype was in a hypoxic state and was characterized by suppression and exclusion of immune function, which was sensitive to gefitinib, erlotinib, and saracatinib. The constructed prognostic risk model performed well in both training and validation cohorts, helping to identify patients who may benefit from specific treatments or who are at risk of recurrence and drug resistance. A novel therapeutic target, SAA2, regulating neutrophil and fibroblast infiltration, and, thus promoting ccRCC progression, was identified. Conclusions: Our findings highlight the key role of CSCs in shaping the ccRCC tumor microenvironment, crucial for therapy research and clinical guidance. Recognizing tumor stemness helps to predict treatment efficacy, recurrence, and drug resistance, informing treatment strategies and enhancing ccRCC patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic body radiotherapy (SBRT) is a treatment technique that delivers higher doses of conformal radiation precisely to specific targets. SBRT is utilized for the treatment of the more common cancers such as lung, liver and prostate malignancies, both in the early stage and the oligometastatic setting. The aim of this review is to highlight the current role of SBRT for renal cell carcinoma (RCC), a disease which was previously thought to be radioresistant, particularly to conventionally fractionated radiotherapy. There is now an increasing body of literature encompassing published phase II trials, reviews and meta-analyses demonstrating the effectiveness of SBRT in both early-stage RCC (as an alternative to patients who are not surgical candidates) and within the context of metastasis-directed therapy (MDT) for patients with oligometastatic and oligoprogressive RCC. Ongoing randomized trials are also exploring the role of SBRT as a cytoreductive treatment in metastatic RCC. Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published. [ABSTRACT FROM AUTHOR]

Simple Summary: ICI-based combinations have led to a significant change in mRCC medical treatment. However, data from real-world (RW) cohorts are rare. In this multicenter study, we evaluated the safety and effectiveness of cabozantinib plus nivolumab in real-world cohorts from centers in Germany, Switzerland, and Austria. The median PFS in the overall cohort was 18.6 months. We also analyzed subgroups in relation to the IMDC, histology, and with regard to the presence of bone metastasis. In summary, our real-word data support the promising efficacy data of the pivotal trials, particularly in patients with non-ccRCC and those without bone metastases at the start of the treatment. Introduction: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. Methods: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan–Meier (KM) plots were utilized where appropriate. Results: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0–15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3–5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand–foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. Discussion/Conclusions: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study. [ABSTRACT FROM AUTHOR]

The gut microbiota plays an essential role in maintaining immune homeostasis and influencing the immune landscape within the tumor microenvironment. This review aims to elucidate the interactions between gut microbiota and tumor immune dynamics, with a focus on colorectal cancer (CRC). The review spans foundational concepts of immuno-microbial interplay, factors influencing microbiome composition, and evidence linking gut microbiota to cancer immunotherapy outcomes. Gut microbiota modulates anti-cancer immunity through several mechanisms, including enhancement of immune surveillance and modulation of inflammatory responses. Specific microbial species and their metabolic byproducts can significantly influence the efficacy of cancer immunotherapies. Furthermore, microbial diversity within the gut microbiota correlates with clinical outcomes in CRC, suggesting potential as a valuable biomarker for predicting response to immunotherapy. Conclusions: Understanding the relationship between gut microbiota and tumor immune responses offers potential for novel therapeutic strategies and biomarker development. The gut microbiota not only influences the natural history and treatment response of CRC but also serves as a critical modulator of immune homeostasis and anti-cancer activity. Further exploration into the microbiome's role could enhance the effectiveness of existing treatments and guide the development of new therapeutic modalities. [ABSTRACT FROM AUTHOR]

Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event. Case presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma. Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering theman adjuvant treatment, reducing the risk of hyperprogression. Fromthese cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic therapy for hepatocellular carcinoma has been advancing rapidly. With the advent of drugs with high response rates and combination immunotherapy, some patients have attained cancer-free status, while others achieved prolonged survival. Under these circumstances, systemic therapies are being developed not only to address advanced stages but also intermediate and early stages of hepatocellular carcinoma, and treatment concepts and strategies for hepatocellular carcinoma are undergoing substantial changes. Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are a type of immunotherapy used to treat a variety of cancers by helping a patient's own immune system to kill cancer cells. ICIs received their regulatory approval based on the results of large, randomized clinical trials. However, certain patient groups were excluded from these trials, so their outcomes are unknown. We performed a multicenter, retrospective study of real-world data in the United States in patients who had received at least one cycle of ICI treatment to evaluate the efficacy and safety of ICIs in patient groups underrepresented in clinical trials. Unique patient groups included age > 75 years, non-White race, positive smoking history, poor performance status, obesity, autoimmune diseases, chronic viral infections, multiple previous cancer therapies, or >three metastatic sites. Overall, ICIs were safe and efficacious in these patient groups. We noted that poor performance status and a history of multiple cancer therapies were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer immune-related adverse events. Regulatory approval of immune checkpoint inhibitors (ICIs) was based on results of large, randomized clinical trials, resulting in limited outcomes data in patient cohorts typically underrepresented in such trials. The objective of this study was to evaluate the efficacy and safety of ICIs in these unique patient cohorts. This is a multicenter, retrospective analysis of real-world data at six academic and community clinics in the United States from 1 January 2011 to 1 April 2018. Patients were included if they had received at least one cycle of ICI treatment. Unique patient cohorts included age > 75 years, non-White race, positive smoking history, ECOG performance status (PS) ≥ 2, BMI ≥ 30 kg/m2, autoimmune diseases (AIDs), chronic viral infections (CVI), extensive prior lines of therapy (LOTs), or >three metastatic sites. Immune-related adverse events (irAEs), overall survival (OS), and time to treatment failure were evaluated in the entire cohort and in NSCLC patients treated with PD-(L)1 monotherapy. Outcomes and their association with unique patient cohorts were compared on univariate analysis and multivariate analysis to those without a particular characteristic in the entire NSCLC PD-(L)1 monotherapy cohorts. In total, 1453 patients were included: 56.5%—smokers, 30.4%—non-White, 22.8%—elderly, 20.8%—ECOG PS ≥ 2, 15.7%—history of AIDs, and 4.7%—history of CVI. The common ICIs were nivolumab (37.1%) and pembrolizumab (22.2%). Black patients, compared to White patients, experienced fewer irAEs (OR 0.54, p < 0.001). An ECOG PS of ≥2 (HR = 2.01, p < 0.001) and an increased number of previous LOTs were associated with poor OS (the median OS of 26.2 vs. 16.2 vs. 9.6 months for one vs. two vs. three prior LOTs, p < 0.001). The above results were confirmed in anti-PD-(L)1 monotherapy non-small cell lung cancer patients (n = 384). Overall, ICIs were safe and efficacious in these typically underrepresented patient cohorts. We noted ECOG PS ≥ 2 and an increased prior LOTs were associated with poor ICI efficacy, and Black patients, compared to White patients, experienced fewer irAEs. [ABSTRACT FROM AUTHOR]

Simple Summary: Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with treatments that have limited efficacy and often have significant toxicities. We previously demonstrated the presence of Notch signaling in uLMS as well as decreased cell viability and Notch expression after exposure to the gamma secretase inhibitor MK-0752. The aim of this study was to assess the combination of MK-0752 and chemotherapeutics commonly used for the treatment of uLMS. Using two human uLMS cell lines, SK-UT-1B and SK-LMS-1, we demonstrated synergism between MK-0752 and docetaxel, doxorubicin, and gemcitabine using MTT assays. These synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. We found decreased invasion, an increase in the apoptotic sub-G1 cell cycle population, and differentially expressed genes and altered KEGG pathways after combination treatment. The combinations of MK-0752 and doxorubicin, MK-0752 and docetaxel, and MK-0752 with gemcitabine and docetaxel are potential novel therapeutic approaches for uLMS. Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. In SK-UT-1B, MK-0752 was synergistic with doxorubicin and gemcitabine plus docetaxel. In SK-LMS-1, MK-0752 was synergistic with all individual agents and with the combination of gemcitabine plus docetaxel. MK-0752, gemcitabine, and docetaxel decreased invasion in SK-UT-1B 2.1-fold* and in SK-LMS-1 1.7-fold*. In SK-LMS-1, invasion decreased 1.2-fold* after treatment with MK-0752 and docetaxel and 2.2-fold* after treatment with MK-0752 and doxorubicin. Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold*) and SK-LMS-1 (2.7-fold**), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold**). Both MK-0752 alone and in combination altered gene expression and KEGG pathways. In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (* p < 0.05, ** p < 0.01). [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the efficacy of complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) during the tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) era. Analyzing data from a multi-institutional database with 367 mRCC patients, the CM group exhibited significantly longer overall survival than the non-CM group in unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69). However, this superiority was not sustained in adjusted cohorts. The median disease-free survival (DFS) after CM was 24 months, with no significant differences noted based on the time of relapse. This study supports CM's potential in mRCC management during the TKI/ICI era, acknowledging limitations such as sample size and selection bias. Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered. [ABSTRACT FROM AUTHOR]

Introduction: There is debate on which are the best surrogate endpoint and metric to capture treatment effect on overall survival (OS) in RCTs testing immune-checkpoint inhibitors (ICIs). Methods: We systematically searched for RCTs testing ICIs in patients with advanced solid tumors. Inclusion criteria were: RCTs i) assessing PD-(L)1 and CTLA-4 inhibitors either as monotherapy or in combination with another ICI, and/or targeted therapy, and/or chemotherapy, in patients with advanced solid tumors; ii) randomizing at least 100 patients. We performed a meta-analysis of RCTs to compare the surrogacy value of PFS and modified-PFS (mPFS) for OS in RCTs testing ICIs, when the treatment effect is measured by the hazard ratio (HR) for OS, and by the HR and the ratio of restricted mean survival time (rRMST) for PFS and mPFS. Results: 61 RCTs (67 treatment comparisons and 36,034 patients) were included in the analysis. In comparisons testing ICI plus chemotherapy, HRPFS and HRmPFS both had a strong surrogacy value (R2 = 0.74 and R2 = 0.81, respectively). In comparisons testing ICI as monotherapy, HRPFS was the best surrogate, although having a moderate correlation (R2 = 0.58). In comparisons testing ICI plus other treatment(s), the associations were very weak for all the surrogate endpoints and treatment effect measures, with R2 ranging from 0.01 to 0.22. Conclusion: In RCTs testing ICIs, the value of potential surrogates for HROS was strongly affected by the type of treatment(s) tested. The evidence available supports HRPFS as the best surrogate, and disproves the use of alternative endpoints, such as the mPFS, or treatment effect measures, such as the RMST. [ABSTRACT FROM AUTHOR]

Simple Summary: Localized renal cell carcinoma (RCC) has an excellent prognosis. However, once metastatic, patient prognosis declines significantly. There is a rare patient subgroup with localized RCC stage T1 with distant metastasis (M1) and no lymph node involvement (N0). In this study, the survival of patients diagnosed with clear cell RCC (ccRCC) stage T1N0M1 were evaluated in comparison to ccRCC patients stage T1 without metastases (N0M0). As expected, stage T1N0M1 ccRCC patients showed a significantly worse outcome than stage T1N0M0 patients. To further characterize tumor characteristics of stage T1N0M1 ccRCC patients, CD8+ tumor infiltrating lymphocytes (TILs) were analyzed, as it is known that a number of CD8+ TILs is associated with a worse prognosis. It could be shown that tumor specimens from stage T1N0M1 ccRCC patients harbor a substantially higher number of CD8+ TILs than specimens from stage T1N0M0 ccRCC patients, thus resembling advanced stage ccRCC. Nevertheless, long-term survival of stage T1N0M1 ccRCC patients is possible. Metastatic renal cell carcinoma (RCC) is among the most lethal urological malignancies. However, small, localized RCCs (≤7 cm, stage T1) have an excellent prognosis. There is a rare patient subgroup diagnosed with synchronous distant metastasis (T1N0M1), of which very little is known in terms of survival outcomes and underlying disease biology. Herein, we examined the long-term survival of 27 patients with clear cell RCC (ccRCC) stage T1N0M1 in comparison to 18 patients without metastases (T1N0M0). Tumor tissue was stained by immunohistochemistry for CD8+ tumor infiltrating lymphocytes (TILs). As expected, patients with stage T1N0M1 showed a significantly worse median cancer specific survival (CSS; 2.8 years) than patients with stage T1N0M0 (17.7 years; HR 0.077; 95% CI, 0.022–0.262). However, eight patients (29.6%) with ccRCC stage T1N0M1 survived over five years, and three of those patients (11.1%) survived over a decade. Some of these patients benefitted from an intensified, multimodal treatment including metastasis-directed therapy. The number of CD8+ TILs was substantially higher in stage T1N0M1 ccRCCs than in stage T1N0M0 ccRCCs, suggesting a more aggressive tumor biology. In conclusion, long-term survival is possible in patients with ccRCC stage T1N0M1, with some patients benefitting from an intensified, multimodal treatment approach. [ABSTRACT FROM AUTHOR]

Introduction: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. Methods: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D = 1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. Results: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, p = 0.557) or OS (13.6 months, p = 0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD = 3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD = 1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3 = 2:15:10), general fatigue (21.8%) (grade 1:2:3 = 3:13:6), protein in urine (16.8%) (grade 1:2:3 = 0:4:13), and hypertension (13.9%) (grade 1:2:3 = 1:8:5). Conclusion: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have emerged as a revolutionary paradigm in oncology, offering a potent arsenal against various malignancies by harnessing the body's own immunological prowess. In a whirlwind of advancement, an abundance of new ICIs have come to light, rendering it a Herculean task for physicians to remain au courant with the rapidly evolving landscape. This comprehensive review meticulously explores the crescendo of clinical investigations and FDA approvals that have come to light during 2022 and 2023, showcasing the metamorphic impact of ICIs in cancer therapeutics. Delving into the pith of pivotal Phase 3 trials across diverse cancer types - including lung, renal, melanoma, and more - the review illuminates the significant strides made in enhancing patient outcomes, alongside the unveiling of novel ICIs that have garnered attention in the oncological community. The analysis extends to the notable presentations at the esteemed ESMO and ASCO conventions, providing a panoramic view of the contemporary advancements in ICI technology. Furthermore, the review underscores the imperative of continuous exploration in overcoming the extant challenges, such as the quest for reliable predictive biomarkers and the optimization of combinatorial strategies to surmount resistance and augment therapeutic efficacy. Through a holistic lens, this article elucidates the monumental impact of ICIs, marking a significant epoch in the odyssey towards rendering cancer a conquerable adversary. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the last 10 years, there has been a vast increase in the use of targeted and immunotherapy drugs in the management of advanced kidney cancer. As patients are living longer with cancer that has spread, the natural history has altered, with problems of poor tumour control in one or a few areas only. Local surgical removal of the tumour(s) frequently cannot be applied due to technical challenges or patient factors. Thermal ablation or stereotactic body radiotherapy (SBRT) may be utilised. Thermal ablation is a minimally invasive treatment where heat is generated and passed via a probe into the tumour to cause cancer cell death. SBRT is a non-invasive treatment where high radiobiological doses of radiation are precisely delivered in one, or a few, treatments to kill cancer cells. This systematic review aims to evaluate the existing evidence for these treatments to help improve personalised care for individual patients. Intensified systemic therapy in metastatic renal cell carcinoma (mRCC) has led to improved patient outcomes. Patients commonly require local control of one or a few metastases. The aim was to evaluate metastasis-directed ablative therapies in extracranial mRCC. Two databases and one registry were searched, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach, for all prospective and matched-pair case–control mRCC studies of radiofrequency ablation (RFA), cryotherapy, microwave ablation (MWA), and stereotactic body radiotherapy (SBRT). Eighteen studies were identified. Fourteen investigated SBRT in 424 patients. Four thermal ablation studies were identified: two cryotherapy (56 patients) and two RFA studies (90 patients). The median participant number was 30 (range 12–69). The combined median follow-up was 17.3 months (range 8–52). Four SBRT studies reported local control (LC) at 12 months, median 84.4% (range 82.5–93). Seven studies (six SBRT and one cryotherapy) reported an LC rate of median 87% (79–100%). Median overall survival (OS) was reported in eight studies (five SBRT, two cryotherapy, and one RFA) with a median of 22.7 months (range 6.7–not reached). Median progression-free survival was reported in seven studies (five SBRT, one cryotherapy, and one RFA); the median was 9.3 months (range 3.0–22.7 months). Grade ≥ 3 toxicity ranged from 1.7% to 10%. SBRT has excellent local control outcomes and acceptable toxicity. Only four eligible thermal ablative studies were identified and could not be compared with SBRT. Translationally rich definitive studies are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are the most mature treatment of immunotherapy and have changed the mode of cancer treatment. Recent studies showed that combining ICIs with targeted drugs is a potential strategy in some tumors, while in other tumors, this combination increases toxicity but does not improve efficacy. This review first comprehensively covers the current status of studies in the combination of ICIs and targeted drugs in the treatment of solid tumors, involving the underlying mechanisms, clinical effects, side effects, and potential predictive biomarkers, and provides a perspective for future directions and potential therapeutic strategies of immunotherapy in solid tumors. Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special drug target is required. Numerous studies have confirmed the synergistic effect of combining ICIs with targeted therapy. For example, triple therapy of PD-L1 inhibitor atezolizumab plus BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib has been approved as the first-line treatment in advanced melanoma patients with BRAFV600 mutations. However, not all combinations of ICIs and targeted therapy work. Combining ICIs with EGFR inhibitors in non-small-cell lung cancer (NSCLC) with EGFR mutations only triggered toxicities and did not improve efficacy. Therefore, the efficacies of combinations of ICIs and different targeted agents are distinct. This review firstly and comprehensively covered the current status of studies on the combination of ICIs mainly referring to PD-1 and PD-L1 inhibitors and targeted drugs, including angiogenesis inhibitors, EGFR/HER2 inhibitors, PARP inhibitors and MAPK/ERK signaling pathway inhibitors, in the treatment of solid tumors. We discussed the underlying mechanisms, clinical efficacies, side effects, and potential predictive biomarkers to give an integrated view of the combination strategy and provide perspectives for future directions in solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are being increasingly used after primary treatment of early-stage tumors to treat any residual disease and prevent recurrence. Herein, we provide a comprehensive review of pivotal clinical studies demonstrating efficacy and safety outcomes when ICIs are utilized after surgery in patients with melanoma, urothelial cancer, renal cell carcinoma, lung cancer, gastroesophageal cancer, and hepatobiliary malignancies. In addition, we highlight the potential role of these agents within the emerging field of transplant oncology. To guide the selection of eligible patients for ICIs, we outline approved and emerging biomarkers that may predict benefit from use of these agents and help monitor response, especially in the absence of visible disease on imaging. Furthermore, we provide real-world considerations with regards to tolerability and cost-effectiveness of these agents and necessary future directions that should be explored to increase the survival outcomes associated with the use of ICIs after surgery. The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk–benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: To summarize the main discoveries made over the past few years to treat metastatic clear cell renal cell carcinoma, including different generations of anti-VEGF TKIs and immune checkpoint inhibitors (ICI), and provide an overview of the future developments to come in this field. We discuss new therapeutic approaches, such as escalation/de-escalation str. Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial cancers, such as lung, breast, and colon cancers, have high mortality rates because of their ability to spread across multiple organs in the body. Besides the standard of care which includes chemotherapy and radiotherapy, approaches directed to use patient's own immune responses against the disease called immunotherapies have emerged as a powerful treatment option. In the past 10 years, immune checkpoint blockade, a form of immunotherapy which either stimulates or removes the breaks of the immune response against cancer, is having the largest impact in the clinic. However epithelial cancers are commonly either naturally resistant or develop resistance to these types of treatments. Hence, there is an urgent need to boost the effectiveness of immune checkpoint blockers. Small molecule inhibitors are chemical molecules which are specifically designed to target important cancer proteins and unlike chemotherapy, typically have manageable toxicity. These inhibitors have shown good efficacy in reducing tumour growth but more recently, they have been shown to enhance the performance of immune cells in eliminating cancers. In this review, we have focused on tactical usage of small molecule inhibitors to boost the efficacy of immune checkpoint blockers. We believe our review will pave the way for novel research combining the two therapeutic modalities. Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future. [ABSTRACT FROM AUTHOR]

Simple Summary: Immuno-Oncology (IO) based combinations are now the standard of care for frontline advanced clear cell renal cell carcinoma. Despite the unprecedented durable efficacy of such combinations, many patients do not respond to IO or will eventually develop resistance. This review summarizes the ongoing efforts in drug development in clear cell renal cell carcinoma focusing on novel targets. The dual immune checkpoint blockade targeting CTLA-4 and PD-1 (ipilimumab/nivolumab) or the IO combinations targeting PD-1 and anti-VEGF TKIs (pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib) have demonstrated an overall survival benefit in advanced clear cell renal cell carcinoma (ccRCC). Despite this significant improvement in clinical outcomes in the frontline setting from IO/IO or the IO/TKI combinations, there is a subset of patients of advanced ccRCC that do not respond to such combinations or will lose the initial efficacy and have disease progression. Therefore, a remarkable unmet need exists to develop new therapeutics to improve outcomes. With an enhanced understanding of ccRCC biology and its interaction with the tumor microenvironment, several new therapies are under development targeting ccRCC metabolism, cytokine-signaling, alternative immune checkpoint proteins, and novel biological pathways. In addition, microbiome products enhancing IO response, antibody–drug conjugates, and targeted radionuclides are also being investigated. This review summarizes selected emerging agents that are under development in ccRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the efficacy and safety of molecular-targeted therapies (MTTs) in 29 patients who discontinued the combination therapy of nivolumab plus ipilimumab (NIVO+IPI) for advanced or metastatic renal cell carcinoma as real-world outcomes. Patients receiving MTTs had a median follow-up of 8 months. The objective response rate was 44.8%, and the disease control rate was 72.4%. After NIVO+IPI, the median overall survival was 18 months, and progression-free survival (PFS) was 8 months. Patients with bone metastases had a significantly shorter median PFS when treated with MTTs after NIVO+IPI than those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI. This study aimed to evaluate the effectiveness and safety of molecular-targeted therapies (MTTs) after the discontinuation of nivolumab and ipilimumab (NIVO+IPI) combination therapy in patients who had been diagnosed with advanced/metastatic renal cell carcinoma as real-world outcomes. We enrolled patients treated with MTTs following initial therapy with NIVO+IPI at nine institutions in Japan. We evaluated the objective response rate (ORR) as the primary endpoint and disease control rate (DCR), best overall response, and oncological outcomes (overall survival (OS) and progression-free survival (PFS)) as the secondary endpoints. We also evaluated factors predictive of disease progression after the administration of MTTs. Patients were followed up for a median of 8 months. The ORR was 44.8%, and the DCR was 72.4%. The median OS and PFS of MTTs after NIVO+IPI were 18 months and 8 months, respectively. A total of 31% of patients experienced grade 3/4 MTT-related adverse events. The median PFS in patients with bone metastases was significantly shorter than that in those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI. [ABSTRACT FROM AUTHOR]

Background. Sex, age, and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic risk may influence the immune response. Nonetheless, the correlation between these factors and the survival benefits of immune-based combination therapies in patients with metastatic renal cell carcinoma (mRCC) is controversial and undefined. As a result, the purpose of this research is to evaluate the potential differences of immune-based combination therapies on survival benefits from mRCC subgroups. Methods. PubMed, Cochrane Library, Embase, and http://www.clinicaltrials.gov were searched from inception to March 17, 2022. Randomized clinical trials (RCTs) comparing overall survival (OS) or progression-free survival (PFS) in patients with mRCC treated by immune-based combinations vs. contemporary first-line therapies were included. Results. Five RCTs with a total of 4206 subjects were included. An OS and PFS benefit of immune-based combinations were found for patients of different sex, age, and IMDC intermediate/poor risk. No obvious difference in relative PFS benefit from immune-based combinations over the control group was found in patients of different genders (P = 0.71 , I2 = 0%), ages (P = 0.55 , I2 = 0%), or IMDC prognostic risks (P = 0.38 , I2 = 0%). However, the difference in OS benefit was significant regarding age (P = 0.009 , I2 = 85.5%) and IMDC prognostic risk (P = 0.004 , I2 = 82.2%). Conclusions. This meta-analysis found that immune-based combination therapies should not be restricted to certain patients with mRCC in gender categories. However, age and IMDC prognostic risk of mRCC patients are associated with different outcomes of OS and thus help identify those patients most probably to benefit from immune-based combination therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Ipilimumab and Nivolumab (IPI-NIVO) improved survival in a pivotal phase III trial conducted in patients with metastatic Renal Cell Carcinoma (mRCC) with intermediate or poor International Metastatic RCC Database Consortium (IMDC) score when compared to sunitinib. A compassionate use program of IPI-NIVO was launched in Italy from April through October 2019. The aim of our retrospective study was to assess the outcome of mRCC patients treated with IPI-NIVO within the Italian compassionate use program. Despite one third of patients not completing the induction phase of IPI-NIVO due to either toxicity or early progression, the 12-month survival rate of 66.8% confirms that IPI-NIVO combination is an effective first-line regimen for mRCC patients with IMDC intermediate-poor risk score. This is a retrospective analysis on the safety and activity of compassionate Ipilimumab and Nivolumab (IPI-NIVO) administered to patients with metastatic Renal Cell Carcinoma (mRCC) with intermediate or poor International Metastatic RCC Database Consortium (IMDC) score as a first-line regimen. IPI was infused at 1 mg/kg in combination with Nivolumab 3 mg/kg every three weeks for four doses, followed by maintenance Nivolumab (240 or 480 mg flat dose every two or four weeks, respectively) until disease progression or unacceptable toxicity. A total of 324 patients started IPI-NIVO at 86 Italian centers. Median age was 62 years, 68.2% IMDC intermediate risk. Primary tumor had been removed in 65.1% of patients. Two hundred and twenty patients (67.9%) completed the four IPI-NIVO doses. Investigator-assessed overall response rate was 37.6% (2.8% complete). Twelve-month survival rate was 66.8%, median progression-free survival was 8.3 months. Grade 3 or 4 treatment-related adverse events occurred in 67 patients (26.9%). IMDC intermediate risk, nephrectomy, BMI ≥ 25 kg/m2, and steroid use for toxicities correlated with improved survival, while age < 70 years did not. IPI-NIVO combination is a feasible and effective regimen for the first-line treatment of intermediate-poor IMDC risk mRCC patients in routine clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment landscape of metastatic renal cell carcinoma has changed dramatically over the course of the last decade. The use of doublet immunotherapy or targeted therapy/immunotherapy regimens has become the standard of care. Herein, we outline the important elements and considerations in the treatment of renal cell carcinoma and explore prospective treatment options within this setting. Over the last decade, the treatment paradigm of metastatic renal cell carcinoma has rapidly evolved, with notable changes in the front-line setting. Combination therapies involving the use of either doublet therapy with immune checkpoint inhibitors or combination VEGFR-directed therapies with immune checkpoint inhibitors have significantly improved clinical outcomes, including prolonged overall survival and durable response to treatment. We aim to highlight the Food and Drug Administration-approved front-line therapy options, the navigation of treatment selection, and the future directions of metastatic renal cell carcinoma therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: In their advanced stages, the mainstay of kidney cancer treatment is with medications such as targeted or immune therapies. Breakthroughs in scientific understanding of cancer drug development have led to substantial improvements in life expectancy. Although several combinations are available to choose from, it remains unclear which is best, and furthermore why cancers become resistant to treatment. This review article explores the scientific basis behind drug treatments in kidney cancers, with particular focus on blood vessel development and the immune system, and summarizes the available evidence supporting multi-drug treatments in this context. Angiogenesis inhibitors have been adopted into the standard armamentarium of therapies for advanced-stage renal cell carcinomas (RCC), but more recently, combination regimens with immune checkpoint inhibitors have demonstrated better outcomes. Despite this, the majority of affected patients still eventually experience progressive disease due to therapeutic resistance mechanisms, and there remains a need to develop novel therapeutic strategies. This article will review the synergistic mechanisms behind angiogenesis and immunomodulation in the tumor microenvironment and discuss the pre-clinical and clinical evidence for both clear-cell and non-clear-cell RCC, exploring opportunities for future growth in this exciting area of drug development. [ABSTRACT FROM AUTHOR]

Background: Immune-Oncology (IO) improves Overall Survival (OS) in metastatic Renal Cell Carcinoma (mRCC). The prognostic impact of previous Cytoreductive Nephrectomy (CN) and radical nephrectomy (RN), with curative intent, in patients treated with IO is not well defined. The aim of our paper is to evaluate the impact of previous nephrectomy on outcome of mRCC patients treated with IO. Methods: 287 eligible patients were retrospectively collected from 16 Italian referral centers adhering to the MeetUro association. Patients treated with IO as second and third line were included, whereas patients treated with IO as first line were excluded. Kaplan–Meier method and log-rank test were performed to compare Progression Free Survival (PFS) and OS between groups. In our analysis, both CN and RN were included. The association between nephrectomy and other variables was analyzed in univariate and multivariate setting using the Cox proportional hazard model. Results: 246/287 (85.7%) patients had nephrectomy before IO treatment. Median PFS in patients who underwent nephrectomy (246/287) was 4.8 months (95%CI 3.9–5.7) vs 3.7 months (95%CI 1.9–5.5) in patients who did not it (HR log rank 0.78; 95%CI 0.53 to 1.15; p = 0.186). Median OS in patients who had previous nephrectomy (246/287) was 20.9 months (95%CI 17.6–24.1) vs 13 months (95%CI 7.7–18.2) in patients who did not it (HR log rank 0.504; 95%CI 0.337 to 0.755; p = 0.001). In the multivariate model, nephrectomy showed a significant association with OS (HR log rank 0.638; 95%CI 0.416 to 0.980), whereas gland metastases were still associated with better outcome in terms of both OS (HR log rank 0.487; 95%CI 0.279 to 0.852) and PFS (HR log rank 0.646; 95%CI 0.435 to 0.958). Conclusions: IO treatment, in patients who had previously undergone nephrectomy, was associated with a better outcome in terms of OS. Further prospective trials would assess this issue in order to guide clinicians in real word practice. [ABSTRACT FROM AUTHOR]

Summary: CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02837991 NCT02837991; July 20, 2016. [ABSTRACT FROM AUTHOR]

In the treatment of cancer, chemotherapy plays an important role though the efficacy of anticancer drug administered orally is limited, due to their poor solubility in physiological medium, inability to cross biological membrane, high Para-glycoprotein (P-gp) mediated drug efflux, and pre-systemic metabolism. These all factors cumulatively reduce drug exposure at the target site leading to multidrug resistance (MDR). Lipid based carriers systems has been explored to overcome solubility and permeability related issues of anti-cancer drugs. The lipid based formulations have also been reported to circumvent the effect of P-gp and CYP3A4. Further long chain triglycerides (LCT) has shown their ability to access Lymphatic route over Medium Chain Triglycerides, as the former has been extensively used for targeting anti-cancer drugs at proliferating cells through lymphatic route. Therefore this review tries to reflect the usefulness of lipid based drug carriers systems (viz. liposome, solid lipid nanoparticle, nano-lipid carriers, self-emulsifying, lipidic pro-drugs) in targeting lymphatic system and overcoming issues related to solubility and permeability of anti-cancer drugs. Moreover, we have also tried to reflect how critically lipid based carriers are important in maximizing therapeutic safety and efficacy of anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to assess the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and anti-tumor efficacy of CKD-581, a novel pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma (MM) refractory to standard therapy. Methods In this phase I study, CKD-581 was intravenously administered on days 1, 8, and 15 of a 28-day cycle. A standard 3 + 3 cohort design was used to determine the MTD. Acetylated histones H3 and H4 in peripheral blood mononuclear cells were measured for pharmacodynamic assessment in a subpopulation of patients. Results Thirty-nine patients were treated with CKD-581 at 9 dose levels from 10 mg/m2 to 210 mg/m2. The DLTs were grade 3 neutropenia that delayed the treatment for >2 weeks (one patient at a dose of 50 mg/m2) and grade 4 thrombocytopenia (two patients at a dose of 210 mg/m2). The MTD of CKD-581 was 160 mg/m2. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (n = 5, 12.8%) and neutropenia (n = 2, 5.1%). The peak concentration and area under the curve values for CKD-581 increased in proportion to the dose, indicating linear pharmacokinetics. A partial response was observed in 2 patients (5.6%), and stable disease was observed in 16 (44.4%) patients. In the pharmacodynamic evaluation, acetylation of H3 and H4 was observed at all doses of ≥50 mg/m2. Conclusion CKD-581 was well tolerated by the patients with lymphoma or MM refractory to standard therapy. It exhibited dose-proportional pharmacokinetics and modest anti-tumor efficacy. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last 15 years, a deep improvement in the knowledge regarding the biological mechanisms responsible for neoplastic cell development and progression has led to a dramatic change in the treatment landscape of metastatic clear cell renal carcinoma. Nowadays, it is known that neo-angiogenesis is a key player in tumor growth and metastatic spread. In particular, the crucial role of the mutation of the von Hippel–Lindau (VHL) tumor suppressor gene, leading to angiogenesis through the transcription of multiple pro-angiogenic factors, is clearly recognized. On the basis of this biological evidence, three classes of targeted therapies with antiangiogenetic activity have received approval for the treatment of advanced disease: tyrosine kinase inhibitors (TKIs); a monoclonal antibody that interferes with vascular endothelial growth factor (VEGF); and two mammalian target of rapamycin (mTOR) inhibitors. These drugs showed impressive results in terms of progression-free survival and objective response rate. In addition, a "second therapeutic revolution" has recently started, due to the latest information on the immunogenic characteristics of renal cell carcinoma and the interplay between angiogenesis and immune surveillance systems. Consequently, immune checkpoint inhibitors, alone or in combination with TKIs, have been approved. In this review, we analyze the pharmacological characteristics and activity of antiangiogenic drugs approved for the treatment of metastatic clear cell renal carcinoma. Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic cholecystectomy (LC) is safe in acute cholecystitis, but the exact timing remains ill-defined. This study evaluated the effect of timing of LC in patients with acute cholecystitis.Methods: Prospective data from the hospital registry were reviewed. All patients admitted with acute cholecystitis from June 1994 to January 2004 were included in the cohort.Results: Laparoscopic cholecystectomy was attempted in 1,967 patients during the study period; 80% were women, mean patient age was 44 years (range, 20-73 years). Of the 1,967 LC procedures, 1,675 were successful, and 292 were converted to an open procedure (14%). Mean operating time for LC was 1 h 44 min (SD +/- 50 min), versus 3 h 5 min (SD +/- 79 min) when converted to an open procedure. Average postoperative length of stay was 1.89 days (+/- 2.47 days) for the laparoscopic group and 4.3 days (+/- 2.2 days) for the conversion group. No clinically relevant differences regarding conversion rates, operative times, or postoperative length of stay were found between patients who were operated on within 48 h compared to those patients who were operated on post-admission days 3-7.Conclusions: The timing of laparoscopic cholecystectomy in patients with acute cholecystitis has no clinically relevant effect on conversion rates, operative times, or length of stay. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinomas (ccRCC) have several distinct immunological features, including a high degree of immune infiltration and relatively low mutational burdens, the resistance to cytotoxic chemotherapy, and relative sensitivity to anti-angiogenic therapy and immunotherapies. Immune checkpoint inhibitor (ICI) therapy has become standard care in the treatment of ccRCC, but a better understanding of the molecular and cellular characteristics of ccRCC is needed to truly optimize the use of ICI therapy. With a focus on cancer immunology, we summarize the clinical trials of ICIs in ccRCC, the molecular and cellular correlates of these clinical trials, and the single-cell RNA sequencing studies to provide a comprehensive overview of the immune landscape within the ccRCC tumor microenvironment, in particular in the context of ICI therapy. We will discuss potential molecular and cellular biomarkers that can be used to predict therapeutic responses in ccRCC patients. Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an "atypical" cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These "atypical" features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) have become a first-choice therapy option in the treatment of clear cell renal cell carcinoma (ccRCC). A predictive biomarker is urgently needed since not all patients respond and adverse events occur. Therefore, an ex vivo tissue slice culture (TSC) model was tested to investigate the effects of nivolumab on tumor infiltrating immune cells (TIIC). A decrease in programmed death receptor 1 expression, as well as effects on density and proliferation of TIIC, were observed. Thus, the TSC model could serve as a test platform for response prediction to ICIs. Background: In the treatment of clear cell renal cell carcinoma (ccRCC), nivolumab is an established component of the first-line therapy with a favorable impact on progression free survival and overall survival. However, treatment-related adverse effects occur and, to date, there is no approved predictive biomarker for patient stratification. Thus, the aim of this study was to establish an ex vivo tissue slice culture model of ccRCC and to elucidate the impact of nivolumab on tumor infiltrating immune cells. Methods: Fresh tumor tissue of ccRCC was treated with the immune checkpoint inhibitor nivolumab using ex vivo tissue slice culture (TSC). After cultivation, tissue slices were formalin-fixed, immunohistochemically stained and analyzed via digital image analysis. Results: The TSC model was shown to be suitable for ex vivo pharmacological experiments on intratumoral immune cells in ccRCC. PD1 expression on tumor infiltrating immune cells was dose-dependently reduced after nivolumab treatment (p < 0.01), whereas density and proliferation of tumor infiltrating T-cells and cytotoxic T-cells were inter-individually altered with a remarkable variability. Tumor cell proliferation was not affected by nivolumab. Conclusions: This study could demonstrate nivolumab-dependent effects on PD1 expression and tumor infiltrating T-cells in TSC of ccRCC. This is in line with results from other scientific studies about changes in immune cell proliferation in peripheral blood in response to nivolumab. Thus, TSC of ccRCC could be a further step to personalized medicine in terms of testing the response of individual patients to nivolumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-clear cell renal cell carcinomas (ncRCC) make up a heterogeneous group subclassified into different subtypes that differ in genetic and biochemical characteristics from each other and from ccRCC. ncRCC are a rare finding in clinical practice, and no standard-of-care has yet been established. Treatment choices are in fact based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. The aim of this review is to supplyt precise recommendations for each histological type focusing on pathogenetic mechanisms of nc-RCC, summarizing the therapeutic strategies adopted over the last few decades, and exploring the emerging role of immunotherapy and new targeted drugs as future potential treatment options. Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment scenario of metastatic renal cell carcinoma has drastically changed in recent years, with the advent of immunotherapy. Since 2015 immune-checkpoint inhibitors, either alone or in combination with other compounds, are constantly enriching the treatment scenario, with a drastic change of patients' outcomes. The benefit from immunotherapy is difficult to capture with the currently available assessment radiological criteria. Often, with rhe use of immunotherapy, we can observe atypical patterns of response, such as hyperprogression or pseudoprogression. Pseudoprogression consists of an initial increase in tumor burden followed by a response to therapy, while hyperprogression is defined as a tumor growth rate that was at least 2-fold greater in patients with disease progression during immunotherapy. We performed a retrospective monocentric study to explore the impact of tumor growth rate change after immunotherapy administration as second or later line of treatment in patients with metastatic renal cell carcinoma. Treatment response is usually assessed by the response evaluation criteria in solid tumors (RECIST). These criteria may not be adequate to evaluate the response to immunotherapy, considering the peculiar patterns of response reported with this therapy. With the advent of immunotherapy these criteria have been modified to include the evaluation of the peculiar responses seen with this type of therapy (iRECIST criteria), including pseudoprogressions and hyperprogressions. Tumor growth rate (TGR) is a dynamic evaluation that takes into account the kinetics of response to treatment and may help catch the real efficacy of an immunotherapy approach. We performed a retrospective monocentric study to explore the impact of TGR change after nivolumab administration as the second or later line of treatment in patients with metastatic renal cell carcinoma (RCC). We evaluated 27 patients, divided into three categories: Disease control (DC) if there was no PD; lower velocity PD (LvPD) if disease progressed but the TGR at second assessment (TGR2) was lower than the TGR at first assessment (TGR1); higher velocity PD (HvPD) if TGR2 was higher than TGR1. The median OS for the DC group was 11.0 months (95% CI 5.0–17.0) (reference) vs. (not reached) NR (95% CI NR-NR) for LvPD (HR 0.27; 95% CI 0.06–1.30; p 0.102) vs. NR (95% CI NR–NR) for HvPD (HR 0.23; 95% CI 0.06–0.88; p 0.032). There was no difference between LvPD and DC (HR 1.21; 95% CI 0.20–7.28; p 0.838). In patients with metastatic RCC, the second or later line of nivolumab treatment may lead to a deceleration in TGR resulting in an improved survival outcome similar to that observed in patients experiencing tumor regression. In this subgroup, especially in the presence of a clinical benefit, continuing the treatment beyond progression can be recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinicians often erroneously discount prognostic information as unlikely to change patient management. This is fueled by the mistaken belief that only "predictive" subgroups or biomarkers can modify the differences in clinical benefit between treatment choices. We use the treatment of metastatic clear cell carcinoma as an example to illustrate how clinical decisions can be informed by prognostic variables. Diametrically opposite decisions can be made depending on individual patient prognosis and on the clinical outcome of interest that clinicians choose to focus on. We also demonstrate why such patient-specific treatment decisions inevitably should be guided by each patient's goals and values, which can be explicitly represented by utility functions. We argue that well-informed patient-specific decision-making may be carried out as three consecutive tasks: (1) estimating key parameters of a statistical model, (2) using prognostic information to convert these parameters into clinically interpretable values, and (3) specifying joint utility functions to quantify risk–benefit trade-offs between clinical outcomes. Using the management of metastatic clear cell renal cell carcinoma as our motivating example, we explain the role of prognostic covariates that characterize between-patient heterogeneity in clinical outcomes. We show that explicitly specifying the joint utility of clinical outcomes provides a coherent basis for patient-specific decision-making. [ABSTRACT FROM AUTHOR]

Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is a leading cause of cancer death worldwide. In the majority of patients, cancers are diagnosed at advanced stages of disease and are resistant to current treatments. Therefore, more effective and less toxic therapeutic agents are urgently needed. Monoclonal antibody (mAb)-based technology is an important tool in the discovery of novel therapeutic targets and development of novel therapeutic agents including antibody-based drugs. In this article, we review the therapeutic potential of monoclonal antibody-based agents when used as single agents or in combination with other treatments in pancreatic cancer, factors contributing to the poor response to therapy and emerging opportunities for more effective treatment with antibody-based agents. Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitor (ICI) therapy has proven effective for many cancer patients, but predicting which patients with renal cell carcinoma (RCC) will respond has been challenging. We analyzed clinical characteristics and molecular parameters of a cohort of patients with RCC treated with anti-programmed death 1 (PD-1)/PD-L1 therapy to determine factors that correlate with patient outcome. We found that the composition of circulating immune cells in the blood, development of immune-related toxicities, and gene expression patterns within the tumor correlate with patient response. In addition, we see that high expression of PD-L1 and lower numbers of unique T cell clones in RCC tumors are associated with improved survival. In summary, our findings corroborate previously published work and introduce new potential factors impacting response to ICI therapy that deserve further investigation. Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05–5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis for gastric cancer remains poor, with a median overall survival of approximately 1 year. Ramucirumab and pembrolizumab have each demonstrated antitumor activity and a favorable safety profile as treatments for patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer in the second and third-line setting respectively. However, both agents failed to demonstrate survival benefit over chemotherapy in the first-line setting. Twenty-eight treatment-naïve patients with advanced/metastatic G/GEJ adenocarcinoma were treated with ramucirumab plus pembrolizumab in this phase 1a/b trial. Our results showed that this combination was well tolerated with no unexpected toxicities, and promising durable survival results, particularly among patients with PD-ligand 1 positive tumors. The results of our study therefore support modulating the tumor microenvironment with dual inhibition of VEGFR2 and PD-1 pathways in the first-line patients with advanced G/GEJ cancer. Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and -negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastasis (BM) is generally one of poor prognostic factors in patients with advanced renal cell carcinoma. However, because of longer control of extra-cranial disease by the recent introduction of molecular target therapy and immune checkpoint inhibitor, the incidence of BM has been recently increasing and to progress the treatment of BM is one of urgent medical unmet needs. Although the pivotal clinical trials usually excluded patients with BM, BM subgroup data from the prospective and retrospective series have been gradually accumulated. To select the appropriate strategy, individual patient and tumor characteristics (e.g., Karnofsky Performance Status (KPS), systemic cancer burden, the number/size/location of BM) are important information. Among the local treatments, the technology of stereotactic radiosurgery (SRT) has been especially advanced and its adaptation has been expanded. The combination of SRT with molecular target therapy and/or immune checkpoint inhibitor would be promising to further enhance the efficacy without increased toxicity. In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients' survival. The pivotal clinical trials of those agents usually excluded patients with brain metastasis. The incidence of brain metastasis has been increasing in the actual clinical setting because of longer control of extra-cranial disease. Brain metastasis subgroup data from the prospective and retrospective series have been gradually accumulated about the risk classification of brain metastasis and the efficacy and safety of those new agents for brain metastasis. While the local treatment against brain metastasis includes neurosurgery, stereotactic radiosurgery, and conventional whole brain radiation therapy, the technology of stereotactic radiosurgery has been especially advanced, and the combination with systemic therapy such as molecular target therapy and immune checkpoint inhibitor is considered promising. This review summarizes recent progression of multimodality treatment of brain metastasis of renal cell carcinoma from literature data and explores the future direction of the treatment. [ABSTRACT FROM AUTHOR]

According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to further improve chemotherapy through controlled delivery of chemotherapeutics, while local radiotherapy dose can be enhanced by targeting the GNPs to the tumor. There have been over 20 nanotechnology-based therapeutic products approved for clinical use in the past two decades. Hence, the goal of this review is to understand what we have achieved so far and what else we can do to accelerate clinical use of GNP-based therapeutic platforms to minimize normal tissue toxicity while increasing the efficacy of the treatment. Nanomedicine will revolutionize future cancer treatment options and our ultimate goal should be to develop treatments that have minimum side effects, for improving the quality of life of all cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy-based treatment options have become standard of care in metastatic renal cell carcinoma. Despite significant improvement in overall survival with these therapies, the tumors of many patients will eventually progress. This review highlights the ongoing efforts to develop biomarkers to help predict which patients are most likely to benefit from treatment with immunotherapy. Immunotherapy-based combinations, driven by PD-1, PD-L1, and CTLA-4 inhibitors, has altered the treatment landscape for metastatic renal cell carcinoma (RCC). Despite significant improvements in clinical outcomes, many patients do not experience deep or lasting benefits. Recent efforts to determine which patients are most likely to benefit from immunotherapy and immunotherapy-based combinations have shown promise but have not yet affected clinical practice. PD-L1 expression via immunohistochemistry (IHC) has shown promise in a few clinical trials, although variations in the IHC assays as well as the use of different values for positivity presents unique challenges for this potential biomarker. Several other candidate biomarkers were investigated including tumor mutational burden, gene expression signatures, single gene mutations, human endogenous retroviruses, the gastrointestinal microbiome, and peripheral blood laboratory markers. While individually these biomarkers have yet to explain the heterogeneity of treatment response to immunotherapy, using aggregate information from these biomarkers may inform clinically useful predictive biomarkers. [ABSTRACT FROM AUTHOR]