Autotaxin-Lysophosphatidate Axis: Promoter of Cancer Development and Possible Therapeutic Implications.

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.

Anaplastic Classic Kaposi Sarcoma: PD-L1 Expression and Response to Immunotherapy: A Case Report and Review of the Literature.

Anaplastic classic Kaposi sarcoma (CKS) is an extremely rare pathologic variant of CKS characterized by high aggressiveness and poor prognosis. We report the clinical course of this malignant histologic form in an otherwise healthy 67-year-old male from Apulia in Southern Italy. The anaplastic progression arose during a long history of CKS and developed after multiple local and systemic treatments. The extremely aggressive and chemorefractory nature of the disease dictated amputation of a lower limb and, later, surgery for metastatic pulmonary involvement. At subsequent relapse, therapy with the anti-PD-1 inhibitor pembrolizumab was started. The immunotherapy was selected based on the PD-L1 expression in the tumor and tumor microenvironment. Remarkably, PD-1 blockade induced a complete and durable response in the patient, with a disease-free survival that has exceeded 18 months, and follow-up is still ongoing.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

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.

Challenges and Future Trends of Hepatocellular Carcinoma Immunotherapy.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [...].

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.

Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications.

Gastric cancer (GC) represents the fifth most frequently diagnosed cancer worldwide, with a poor prognosis in patients with advanced disease despite many improvements in systemic treatments in the last decade. In fact, GC has shown resistance to several treatment options, and thus, notable efforts have been focused on the research and identification of novel therapeutic targets in this setting. The tumor microenvironment (TME) has emerged as a potential therapeutic target in several malignancies including GC, due to its pivotal role in cancer progression and drug resistance. Therefore, several agents and therapeutic strategies targeting the TME are currently under assessment in both preclinical and clinical studies. The present study provides an overview of available evidence of the inflammatory TME in GC, highlighting different types of tumor-associated cells and implications for future therapeutic strategies.

Dual HER2 Blockade: An Emerging Option in Metastatic Biliary Tract Cancer?

Biliary tract cancer (BTC) includes a heterogeneous group of aggressive and rare hepatobiliary malignancies, including gallbladder cancer, ampullary carcinomas, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma, further subclassified into distal (dCCA) and perihilar cholangiocarcinoma (pCCA) [...].

Immunotherapy in Biliary Tract Cancer: Worthy of a Second Look.

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several malignancies, the role of immunotherapy in biliary tract cancer (BTC) is currently under investigation and ICIs are still looking for their niche in this setting. In this Editorial, we discuss recently published data regarding ICIs in BTC, with a particular focus in terms of selection of patients and biomarker-driven trials.

Targeting BRAF-Mutant Biliary Tract Cancer: Recent Advances and Future Challenges.

BACKGROUND: Biliary tract cancers (BTCs) represent a heterogeneous group of aggressive solid tumors with limited therapeutic options, and include gallbladder cancer (GBC), ampulla of Vater cancer (AVC), intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). METHODS & RESULTS: In the current review, we will discuss recent results of clinical trials testing targeted therapies in BRAF-mutant BTCs, with a particular focus on the recently published Phase II ROAR trial and ongoing active and recruiting clinical trials. CONCLUSIONS: Although the extended use of molecular profiling has paved the way toward a new era in BTC management, targeted therapies are limited to iCCA so far, and the prognosis of patients with metastatic disease has substantially not changed in the last decade. In this discouraging scenario, BRAF inhibition is currently emerging as a novel treatment option in patients harboring BRAF mutations.

Third- and later-line treatment in advanced or metastatic gastric cancer: a systematic review and meta-analysis.

Aim: We performed a systematic review and meta-analysis to investigate the efficacy and safety of third-line (TLT) and salvage treatment (ST) in advanced or metastatic gastric cancer. Materials & methods: Eligible studies included randomized clinical trials assessing TLT and ST versus placebo or best supportive care. Outcomes of interest included: overall survival, objective response rate and disease control rate in TLT; progression-free survival in ST; grade 3-4 adverse events in ST. Results: The use of TLT and ST was superior to placebo or best supportive care in terms of prolonging overall survival and progression-free survival. Hematological toxicities were more frequent in ST. Conclusion: TLT and ST are considerable and tolerable treatment options for patients with advanced or metastatic gastric cancer. Given the substantial heterogeneities affecting the efficacy analyses, these results have to be interpreted cautiously.

Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma: a retrospective single-center experience.

Background & aims: Very few data are available in literature about the role of radiofrequency ablation (RFA) in intrahepatic cholangiocarcinoma (ICC) and previous studies are mainly case reports and case series on a very small number of patients and nodules. In this study, we aimed to evaluate effectiveness and safety of RFA for the treatment of unresectable ICC.Methods: This is a retrospective observational cohort study comprising all consecutive patients treated with RFA for unresectable ICC at Policlinico Sant'Orsola Malpighi Hospital, Bologna, Italy. Primary endpoint was Local Tumor Progression-Free Survival (LTPFS) while Overall Survival (OS) was also assessed as secondary endpoint.Results: From January 2014 to June 2019, 29 patients with 117 nodules underwent RFA. Technique effectiveness 1 month after RFA was 92.3%; median LTPFS was 9.27 months. Univariate analysis and multivariate analysis showed that LTPFS was significantly related to tumor size ≥20 mm. At a median follow up of 39.9 months, median OS from the date of RFA was 27.5 months, with an OS of 89%, 45% and 11% at 1, 2 and 4 years, respectively. Number of overall lesions and the sum of their diameter at the moment of the first RFA significantly affected OS in multivariate analysis. Minor and major complication rates were 14% and 7%, respectively.Conclusion: Tumor size ≥20 mm was associated with lower LTPFS, representing a potential useful threshold value. A careful evaluation of tumor burden appears as a crucial element in choosing the best therapeutic strategy in unresectable ICC.