Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy.

KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.

The SBRT method is a promising treatment for LAPC. Local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity. Resectability can also be achieved.

This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.

The relationship between peroxisome proliferator-activated receptor γ (PPARG) expression and epigenetic changes occurring in colorectal-cancer pathogenesis is largely unknown. We investigated whether PPARG is epigenetically regulated in colorectal cancer (CRC) progression. PPARG expression was assessed in CRC tissues and paired normal mucosa by western blot and immunohistochemistry and related to patients' clinicopathological parameters and survival. PPARG promoter methylation was analyzed by methylation-specific-PCR and bisulphite sequencing. PPARG expression and promoter methylation were similarly examined also in CRC derived cell lines. Chromatin immunoprecipitation in basal conditions and after epigenetic treatment was performed along with knocking-down experiments of putative regulatory factors. Gene expression was monitored by immunoblotting and functional assays of cell proliferation and invasiveness. Methylation on a specific region of the promoter is strongly correlated with PPARG lack of expression in 30% of primary CRCs and with patients' poor prognosis. Remarkably, the same methylation pattern is found in PPARG-negative CRC cell lines. Epigenetic treatment with 5′-aza-2′-deoxycytidine can revert this condition and, in combination with trichostatin A, dramatically re-activates gene transcription and receptor activity. Transcriptional silencing is due to the recruitment of MeCP2, HDAC1 and EZH2 that impart repressive chromatin signatures determining an increased cell proliferative and invasive potential, features that can experimentally be reverted. Our findings provide a novel mechanistic insight into epigenetic silencing of PPARG in CRC that may be relevant as a prognostic marker of tumor progression.

We examined the peroxisome proliferator-activated receptor ␥ (PPARG) locus in an attempt to identify expressed sequence tags and/or conserved non-coding sequences in the intron sequences containing open reading frames and potentially able to encode new proteins. We identified a new PPARG transcript, defined ␥ORF4, which harbors a readthrough in intron 4. The expected translated protein lacks the ligand-binding domain encoded by exons 5 and 6. We identified the transcript in human tumor cell lines and tissues, synthesized the cDNA, and cloned it in expression vectors. Using transient transfections, we found that ␥ORF4 cDNA is translated into a predominantly nuclear protein that does not transactivate a reporter gene. Moreover, the isoform is dominant negative versus PPAR␥. Interestingly, ␥ORF4 was expressed in vivo in a series of sporadic colorectal cancers. In some cases, it was expressed, albeit at lower levels, also in the mucosa adjacent to the tumors, suggesting that it may be related to tumorigenesis. A tumorigenic effect of ␥ORF4 is in line with our finding that ␥ORF4 has not only lost the capacity to restrain cell growth but has acquired the potential to stimulate it. In conclusion, this study demonstrates that ␥ORF4 is expressed in vivo, that it has lost some PPAR␥ properties, and that it affects PPAR␥ functioning. The ability to counteract PPAR␥ suggests that ␥ORF4 plays a role in the pathogenesis of colorectal cancers.

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