Impact of clinicopathological features on immune-based combinations for advanced urothelial carcinoma: a meta-analysis.

Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74-0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72-0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.

Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand?

Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.

Current and Future Role of Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: Which Way to Go Forward.

Immunotherapy has revolutionized previous triple-negative breast cancer (TNBC) treatment algorithms, prompting researchers and clinicians to consider the expansion of the role of immunotherapy in other settings, including the earlier stage of the disease (e.g., as neoadjuvant and adjuvant therapy). The role of chemoimmunotherapy have been assessed in some recently presented and published clinical trials, including the KEYNOTE-522, the IMpassion031, and the GeparNUEVO. In the current Editorial, we will provide a critical snapshot of these studies, exploring strengths and limitations of neoadjuvant chemotherapy in early TNBC.

Second-Line Chemotherapy in Elderly Patients with Advanced Biliary Tract Cancer: A Multicenter Real-World Study.

Objectives: The ABC-06 and the NIFTY trials recently established the role of second-line chemotherapy (2L) in patients with advanced biliary tract cancer (BTC). Our real-world study aimed to explore 2L in BTC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. The Kaplan−Meier methods were used to estimate survival, and the log-rank test was used to make comparisons. Results: A total of 190 BTC patients treated with 2L were identified and included in the analysis. Among them, 52 (27.3%) were aged ≥ 70 years (range 70−87 years). No statistically significant differences in both median overall survival (mOS) and median progression-free survival (mPFS) were recorded between the elderly and younger patients. Absolute lymphocyte count < 1000/mmc (p < 0.001) and albumin level < 3 g/dL (p < 0.001) were independently associated with worse prognoses. Conclusions: The results of this real-world study suggest that for patients aged ≥ 70 years, 2L could be equally effective for younger patients with survival outcomes aligned to those from the ABC-06 and NIFTY trials. The delivery of 2L should be carefully evaluated and monitored in this patient subset.

Metaplastic breast cancer: an old histotype but a current therapeutic problem.

Metaplastic breast cancer (MPBC) is a rare and aggressive tumor type in great need of satisfactory therapies. Although most cases of MPBC are 'triple negative', they are nonetheless related to worse outcomes compared with other triple-negative invasive tumors. MPBC presents high levels of genetic and molecular heterogeneity, suggesting that novel targeted therapies can be exploited. Overexpression of PD-L1 and high levels of tumor-infiltrating lymphocytes have also been observed in these tumors, suggesting a role for immunotherapy. We present an updated literature revision on clinical, histopathological and molecular features of MPBC and their significance to prognosis and therapy options. We discuss emerging efforts to improve and personalize prognostic and therapeutic approaches, exploiting the molecular signature of MPBC with targeted therapies and immunotherapies.

Eribulin in Male Patients With Breast Cancer: The First Report of Clinical Outcomes.

BACKGROUND: Evidence on the management and treatment of male breast cancer is scant. We report the analysis of a multicenter Italian series of patients with male breast cancer treated with eribulin. To our knowledge, this is the first report on the use or eribulin in this setting. PATIENTS AND METHODS: Patients were retrospectively identified in 19 reference centers. All patients received eribulin treatment, according to the standard practice of each center. Data on the identified patients were collected using a standardized form and were then centrally reviewed by two experienced oncologists. RESULTS: A total of 23 patients (median age, 64 years; range, 42-80) were considered. The median age at the time of diagnosis of breast cancer was 57 years (range, 42-74). HER2 status was negative in 14 patients (61%), and 2 patients (9%) had triple-negative disease. The most common metastatic sites were the lung (n = 14; 61%) and bone (n = 13; 56%). Eribulin was administered for a median of 6 cycles (range, 3-15). All patients reported at least stable disease; two complete responses (9%) were documented. Eribulin was well-tolerated, with only four patients (17%) reporting grade 3 adverse events and two (9%) with treatment interruptions because of toxicity. Eight subjects (35%) did not report any adverse event during treatment. For patients with a reported fatal event, the median overall survival from the diagnosis of metastatic disease was 65 months (range, 22-228). CONCLUSION: Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer. IMPLICATIONS FOR PRACTICE: Evidence on the management and treatment of male breast cancer is eagerly awaited. Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer.

The calm before the storm: a report from the International Liver Cancer Association Congress 2015--part 1.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.

The calm before the storm: a report from the International Liver Cancer Association Congress 2015 - part 2.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.

Sorafenib: 10 years after the first pivotal trial.

Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.

The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer.

PURPOSE: Colon carcinoma is a malignant tumor showing a marked preference to metastasize to distant organs. The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. However, whether circulating cytokines are linked to the circulation of tumor cells, as individual cells or clusters, remain unclear. In this study, we investigated the circulating levels of TGF-beta, CXCL1, VEGF and PAI-1 as potential bioindicators of the presence of CTCs in patients with metastatic colon cancer. METHODS: Circulating tumor cells (CTCs) were isolated from peripheral blood by immunomagnetic separation and phenotypically characterized in a cohort of 103 patients with metastatic colon cancer. TGF-beta, CXCL1, VEGF and PAI-1 concentrations were determined by immunoassay in plasma samples from the same patients. RESULTS: We detected two different populations of CTCs, single cells or clusters in patients with metastatic colon cancer. Importantly, we found that the presence of clustered CTCs is significantly associated with elevated circulating levels of TGF-beta and CXCL1 and with reduced overall survival. Finally, we observed that circulating levels of cytokines are differently associated with the two populations of CTCs. CONCLUSIONS: Taken together, these findings show that detection of clustered CTCs represents a negative prognostic factor in patients with metastatic colon cancer. The presence of clustered CTCs is associated with elevated circulating levels of cytokines such as TGF-beta and CXCL1. This suggests an additional role for circulating cytokines as predictive tool for cancer prognosis and diagnosis of minimal residual disease as well as assessment of tumor sensitivity to anticancer therapy.

EASL HCC summit: liver cancer management.

EASL HCC Summit, Geneva, Switzerland, 13-16 February 2014. The European Association for the Study of the Liver (EASL) organized the 2014 EASL HCC Summit in Geneva, Switzerland. We discuss here the most interesting and provocative contents from the clinical program of the summit. The objective of this segment was to provide an in-depth review on the different management issues related to early detection, diagnosis and treatment of hepatocellular carcinoma, and, in addition, to highlight the ways of dealing with such an important and rapidly involving field.

Unresectable lung malignancy: combination therapy with segmental pulmonary arterial chemoembolization with drug-eluting microspheres and radiofrequency ablation in 17 patients.

PURPOSE: To evaluate the feasibility, safety, and effectiveness of combining segmental pulmonary arterial chemoembolization (SPACE) and percutaneous radiofrequency (RF) ablation in patients with unresectable lung neoplasms or patients with resectable neoplasms who refused surgery and to compare the local tumor progression (LTP) rate with that in previous studies of RF ablation alone. MATERIALS AND METHODS: After institutional review board approval and informed consent, 17 patients with primary and metastatic lung cancer were enrolled in this prospective study. Between January 2008 and February 2011, 20 nodules (median diameter, 3.0 cm; range, 2.0-5.0 cm) were treated during 19 sessions. Antineoplastic agents loaded on 50-100-µm microspheres were selectively infused into specific pulmonary arteries. Percutaneous computed tomography (CT)-guided RF ablation of lung nodules was performed 48 hours after SPACE. Follow-up consisted of enhanced CT 48 hours after combination treatment was completed, after 30 days, and every 3 months thereafter. Fluorine 18 fluorodeoxyglucose positron emission tomography was performed 3 months after combination therapy and then every 6 months. The t test was used to compare groups. RESULTS: Technical success was achieved in 100% of cases. Ventilation-lung single photon emission computed tomography showed a wide area without ventilation in the lung parenchyma treated with SPACE. The LTP rate was 21% (three of 14 nodules) in 3-5-cm-diameter tumors and 0% (zero of six nodules) in tumors of 3 cm or smaller in diameter. Complete response was achieved in 65% (11 of 17) of patients at minimum follow-up of 6 months. Overall, treatment was well tolerated. Major complications were pneumothorax in five of 19 sessions (26%) and one bronchopleural fistula (one of 19, 5%). No treatment-related changes in general lung function were noted. CONCLUSION: Combination therapy with RF ablation after SPACE to treat unresectable lung tumors is technically feasible, safe, and effective and may represent an advantage over RF ablation alone.

The Mediterranean Lifestyle to Contrast Low-Grade Inflammation Behavior in Cancer.

A healthy diet and an active lifestyle are both effective ways to prevent, manage, and treat many diseases, including cancer. A healthy, well-balanced diet not only ensures that the body gets the right amount of nutrients to meet its needs, but it also lets the body get substances that protect against and/or prevent certain diseases. It is now clear that obesity is linked to long-term diseases such as heart disease, diabetes, and cancer. The main reasons for people being overweight or obese are having bad eating habits and not moving around enough. Maintaining weight in the normal range may be one of the best things to avoid cancer. It has been scientifically proven that those who perform regular physical activity are less likely to develop cancer than those who lead a sedentary lifestyle. Moving regularly not only helps to maintain a normal body weight, avoiding the effects that favor tumor growth in overweight subjects, but also makes the immune system more resistant by counteracting the growth of tumor cells. Physical activity also helps prevent cardiovascular and metabolic diseases. In this review, it is highlighted that the association between the Mediterranean diet and physical activity triggers biological mechanisms capable of counteracting the low-grade chronic inflammation found in patients with cancer. This assumes that healthy lifestyles associated with cancer therapies can improve the expectations and quality of life of cancer patients.

Safety evaluation of Datopotamab deruxtecan for triple-negative breast cancer: a meta-analysis.

BACKGROUND: TROP-2 is emerging as a valid and fruitful strategy in triple-negative breast cancer (TNBC) patients, and several agents are currently under evaluation, including Datopotamab deruxtecan (Dato-DXd). RESEARCH DESIGN AND METHODS: Herein, we performed a meta-analysis aimed to evaluate any grade adverse events, grade 3-4 adverse events, dose reduction, and serious adverse events in TNBC patients treated with Dato-DXd in clinical trials. RESULTS: The pooled results suggests that Dato-DXd is associated with a favorable safety profile: while any grade treatment-related toxicities were common, grade 3-4 events were not particularly frequent and mainly represented by stomatitis (13.88%; 95% CI, 10.68 - 17.09). CONCLUSIONS: These findings may help to comprehensively define the safety profile of Dato-DXd and to assist in the design of future clinical trials in this setting.

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.

Role of Etiology in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Counterfactual Event-Based Mediation Analysis.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan−Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20−23) in the group with other etiologies and 15 months (14−16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32−5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15−4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82−2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8−10) in patients with other etiologies and 6 months (5−7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.

Which role for predictors of response to immune checkpoint inhibitors in hepatocellular carcinoma?

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a frequently diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Recent years have seen the emergence of novel systemic treatments for HCC patients, including immune checkpoint inhibitors (ICIs). Nonetheless, several questions regarding HCC immunotherapy remain unanswered, especially in terms of biochemical predictors of response. AREAS COVERED: In the current paper, we will discuss available evidence regarding predictive biomarkers of response to HCC immunotherapy. A literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION: The identification of predictive biomarkers represents an unmet need in HCC patients receiving ICIs. The HCC medical community is called to further efforts aimed to elucidate the effective role of PD-L1 expression, TMB, MSI, gut microbiota, and other emerging biomarkers.

The Impact of Concomitant Proton Pump Inhibitors on Immunotherapy Efficacy among Patients with Urothelial Carcinoma: A Meta-Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy. METHODS: We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC. RESULTS: Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31-1.84) and 1.43 (95% CI, 1.23-1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs. CONCLUSIONS: The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.

Lenvatinib plus pembrolizumab: the next frontier for the treatment of hepatocellular carcinoma?

INTRODUCTION: While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results. AREAS COVERED: This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed. EXPERT OPINION: The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.

Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects.

INTRODUCTION: Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED: The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION: Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.