Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or ...sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas.
This was an observational, retrospective, international study that included patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models.
A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months.
Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
Cancer still remains a leading cause of death despite improvements in diagnosis, drug discovery and therapy approach. Therefore, there is a strong need to improve methodologies as well as to increase ...the number of approaches available. Natural compounds of different origins (i.e., from fungi, plants, microbes, etc.) represent an interesting approach for fighting cancer. In particular, synergistic strategies may represent an intriguing approach, combining natural compounds with classic chemotherapeutic drugs to increase therapeutic efficacy and lower the required drug concentrations. In this review, we focus primarily on those natural compounds utilized in synergistic approached to treating cancer, with particular attention to those compounds that have gained the most research interest.
Asbestos is considered the main cause of diseases in workers exposed to this mineral in the workplace as well as an environmental pollutant. The association between asbestos and the onset of ...different diseases has been reported, but asbestos exposure specific biomarkers are not known. MicroRNAs (miRNAs) are small, single-strand, non-coding RNAs, with potential value as diagnostic, prognostic, and predictive markers in liquid biopsies. Sera collected from workers ex-exposed to asbestos (WEA) fibers were compared with sera from healthy subjects (HS) of similar age, as liquid biopsies. The expression of the circulating miRNA 197-3p was investigated employing two different highly analytical PCR methods, i.e. RT-qPCR and ddPCR. MiR-197-3p levels were tested in sera from WEA compared to HS. MiR-197-3p tested dysregulated in sera from WEA (n = 75) compared to HS (n = 62). Indeed, miR-197-3p was found to be 2.6 times down-regulated in WEA vs. HS (p = 0.0001***). In addition, an inverse correlation was detected between miR-197-3p expression level and cumulative asbestos exposure, being this miRNA down-regulated 2.1 times in WEA, with high cumulative asbestos exposure, compared to WEA with low exposure (p = 0.0303*). Circulating miR-197-3p, found to be down regulated in sera from WEA, is proposed as a new potential biomarker of asbestos exposure.
Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.
A series of 123 formalin-fixed, ...paraffin-embedded tissue samples with clinical annotations were retrospectively tested with a commercial library kit (Ion AmpliSeq Cancer Hotspot Panel v.2, Life Technologies, Grand Island, NY) to investigate 50 genes plus other two, BRCA1-associated protein-1 (BAP-1) and neurofibromatosis-2 (NF2), frequently altered in MPM. DNA was obtained from tissues after manual microdissection and enriched for at least 50% cancer cells. Variations affecting protein stability or previously correlated to cancer, more frequently identified (≥25 patients with at least 10% of allelic frequency), were subsequently evaluated by Sanger sequencing. Immunohistochemistry staining for BAP1 and NF2 proteins was also performed.
The commonest genetic variations were clustered in two main pathways: the p53/DNA repair (TP53, SMACB1, and BAP1) and phosphatidylinositol 3-kinase–AKT pathways (PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, and NF2). PIK3CA:c.1173A>G mutation, STK11:rs2075606 (T>C), or TP53:rs1042522 (Pro/Pro) was significantly associated with time to progressive disease (TTPD; all p values < 0.01). Furthermore, the accumulation of genetic alterations correlated with shorter TTPD and reduced overall survival (TTPD p value = 0.02, overall survival p value = 0.04). BAP1 genetic variations identified were mainly located in exons 13 and 17, and BAP1 nonsynonymous variations were significantly correlated with BAP1 protein nuclear localization.
Next-generation sequencing was applied to a relatively large retrospective series of MPM using formalin-fixed, paraffin-embedded archival material. Our results indicate a complex mutational landscape with a higher number of genetic variations in the p53/DNA repair and phosphatidylinositol 3-kinase pathways, some of them with prognostic value.
Summary Background Previous studies have suggested that trabectedin (ecteinascidin-743) could have antitumour activity in soft-tissue sarcoma. We aimed to study the usefulness of trabectedin in the ...treatment of patients with myxoid liposarcomas, a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins. Methods 51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4, 2001, and Sept 18, 2006 at five institutions in a compassionate-use programme were analysed retrospectively. Centralised radiological and pathological reviews were done for most patients. Trabectedin was given either as a 24-h continuous infusion or as a 3-h infusion, every 21 days, at 1·1–1·5 mg2 . 558 courses of trabectedin were given in total, with a median of ten courses for each patient (range 1–23). The primary endpoints were response rate and progression-free survival, and the secondary endpoint was overall survival. Findings According to Response Evaluation Criteria in Solid Tumors (RECIST), after a median follow-up of 14·0 months (IQR 8·7–20·0), two patients had complete responses (CR) and 24 patients had partial responses (PR); the overall response was 51% (95% CI 36–65). Five patients had early progressive disease. In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had centralised radiological review, tissue-density changes, consisting of a decrease in tumour density on CT scan or a decrease in contrast enhancement on MRI (or both), preceded tumour shrinkage. Median progression-free survival was 14·0 months (13·1–21·0), and progression-free survival at 6 months was 88% (79–95). Interpretation Trabectedin was associated with antitumour activity in this series of patients with myxoid liposarcoma. The noted patterns of tumour response were such that tissue density changes occurred before tumour shrinkage in several patients. In some patients, tissue-density changes only were seen. Long-lasting tumour control was noted in responsive patients. The compassionate-use programme is still ongoing. This analysis has resulted in the initiation of two prospective studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic settings. Furthermore, the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied.
Background
Bile duct injury is a rare but serious complication of laparoscopic cholecystectomy and the primary cause is misinterpretation of biliary anatomy. This may occur more frequently with a ...single-incision approach due to difficulties in exposing and visualizing the triangle of Calot. Intraoperative cholangiography was proposed to overcome this problem, but due to multiple issues, it is not used routinely. Indocyanine green (ICG) near-infrared (NIR) fluorescent cholangiography is non invasive and provides real-time biliary images during surgery, which may improve the safety of single-incision cholecystectomy. This study aims to evaluate the efficacy and safety of this technique during single-site robotic cholecystectomy (SSRC).
Methods
Patients presenting with symptomatic biliary gallstones without suspicion of common bile duct stones underwent SSRC with ICG-NIR fluorescent cholangiography using the da Vinci Fluorescence Imaging Vision System. During patient preparation, 2.5 mg of ICG was injected intravenously. During surgery, the biliary anatomy was imaged in real time, which guided dissection of Calot’s triangle. Perioperative outcomes included biliary tree visualizations, operative time, conversion and complications rates, and length of hospital stay.
Results
There were 45 cases between July 2011 and January 2012. All procedures were completed successfully; there were no conversions and at least one structure was visualized in each patient. The rates of visualization were 93 % for the cystic duct, 88 % for the common hepatic duct, and 91 % for the common bile duct prior to Calot’s dissection; after Calot’s dissection, the rates were 97 % for all three ducts. Mean hospital stay was 1.1 days and there were no bile duct injuries or any other major complications.
Conclusion
Real-time high-resolution fluorescent imaging to identify the biliary tree anatomy during SSRC using the da Vinci Fluorescence Imaging Vision System was safe and effective.
Background
First described in 1977, myxofibrosarcoma is one of the most common sarcoma subtypes of the elderly. Until some years ago, myxofibrosarcoma was diagnosed as “myxoid malignant fibrous ...histiocytoma.” The aim of this retrospective case series analysis was to investigate prognostic factors and the clinical outcome of a cohort of patients with myxofibrosarcoma treated at a single institution.
Methods
We reviewed 158 patients with localized myxofibrosarcoma who underwent surgery at the Istituto Nazionale Tumori of Milan, Italy, over 15 years. Local recurrence, distant metastases, and survival were analyzed.
Results
One hundred twenty patients had primary tumors, while 38 patients had locally recurrent tumors. Five-year overall survival was 77%. Tumor size, grade, and margins were statistically significant predictors of survival. Five-year local recurrence and distant metastases rate were 18% and 15%, respectively. Surgical margins were the only statistically significant prognosticator of local relapses. Patients treated with radiotherapy had the same prognosis as nontreated patients, but likely they had worse local presentations. The histological grade correlated with distant recurrences but not with local relapses. The value of adjuvant chemotherapy could not be determined.
Conclusions
Patients with myxofibrosarcoma have a better disease-specific survival than other sarcoma subtypes, but also a higher local relapse rate. This is likely related to the peculiar local growth pattern of these tumors. Adequate surgery should be pursued, while the role of adjuvant therapies need to be investigated.
Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and relatively chemoresistant and radioresistant malignancy with limited therapeutic options. Our objective was to investigate the ...prevalence of programmed death ligand 1 (PD-L1) and the characteristics of the immune environment in this disease.
A total of 99 archival tumors from advanced-stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories, and 87 of them were profiled for immune gene expression by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and phosphoinisitide-3-kinase pathways.
PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells or the infiltrating immune cells. Gene expression analysis suggested that MPM is an inflamed tumor type and can be classified into three different subgroups on the basis of the different expression profiles of immune-related genes, of which two groups showed varying degrees of expression of immune-related genes. Overall, these molecular findings suggest that these subgroups of MPM associated with PD-L1 positivity and expression of immune-related genes accounting for 60% of MPMs represent a candidate subtype that may respond to cancer immunotherapy.
These data suggest that 60% of patients with MPM characterized by either PD-L1 expression or an inflamed status are attractive candidates for cancer immunotherapeutic options.
Inflammatory mediators present in the tumor milieu may promote cancer progression and are considered promising targets of novel biological therapies. We previously reported that the marine antitumor ...agent trabectedin, approved in Europe in 2007 for soft tissue sarcomas and in 2009 for ovarian cancer, was able to downmodulate the production of selected cytokines/chemokines in immune cells. Patients with myxoid liposarcoma (MLS), a subtype characterized by the expression of the oncogenic transcript FUS-CHOP, are highly responsive to trabectedin. The drug had marked antiproliferative effects on MLS cell lines at low nanomolar concentrations. We tested the hypothesis that trabectedin could also affect the inflammatory mediators produced by cancer cells. Here, we show that MLS express several cytokines, chemokines, and growth factors (CCL2, CCL3, CCL5, CXCL8, CXCL12, MIF, VEGF, SPARC) and the inflammatory and matrix-binder protein pentraxin 3 (PTX3), which build up a prominent inflammatory environment. In vitro treatment with noncytotoxic concentrations of trabectedin selectively inhibited the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by MLS primary tumor cultures and/or cell lines. A xenograft mouse model of human MLS showed marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after trabectedin treatment. Similar findings were observed in a patient tumor sample excised after several cycles of therapy, indicating that the results observed in vitro might have in vivo relevance. In conclusion, trabectedin has dual effects in liposarcoma: in addition to direct growth inhibition, it affects the tumor microenvironment by reducing the production of key inflammatory mediators.
The epigenetic role of microRNAs is established at both physiological and pathological levels. Dysregulated miRNAs and their targets appear to be a promising approach for innovative anticancer ...therapies. In our previous study, circulating miR-197-3p tested dysregulated in workers ex-exposed to asbestos (WEA). Herein, an epigenetic investigation on this circulating miRNA was carried out in sera from malignant pleural mesothelioma (MPM) patients. MiR-197-3p was quantified in MPM (n = 75) sera and comparatively analyzed to WEA (n = 75) and healthy subject (n = 75) sera, using ddPCR and RT-qPCR techniques. Clinicopathological characteristics, occupational, non-occupational information and overall survival (OS) were evaluated in correlation studies. MiR-197-3p levels, analyzed by ddPCR, were significantly higher in MPM than in WEA cohort, with a mean copies/µl of 981.7 and 525.01, respectively. Consistently, RT-qPCR showed higher miR-197-3p levels in sera from MPM with a mean copies/µl of 603.7, compared to WEA with 336.1 copies/µl. OS data were significantly associated with histologic subtype and pleurectomy. Circulating miR-197-3p is proposed as a new potential biomarker for an early diagnosis of the MPM onset. Indeed, miR-197-3p epigenetic investigations along with chest X-ray, computed tomography scan and spirometry could provide relevant information useful to reach an early and effective diagnosis for MPM.
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