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Purpose: Careful patient selection plays a crucial role in avoiding overtreatment and further increases survival rates in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal metastases (PM). Methods: The clinical and molecular factors influencing survival in patients who had undergone CRS with HIPEC between January 2015 and December 2018 were analyzed. Results: Sixty-six patients underwent CRS with HIPEC during the study period. The median overall survival (OS) was 36 months, with a 3-year OS of 43%. Multivariate analysis revealed increased PCI (HR: 1.21; 95% CI: 1.02–1.41; p = 0.020), right-sided primary tumor (HR: 3.01; 95% CI: 1.27–7.13; p = 0.017), and BRAF V600E mutation (HR: 4.55; 95% CI: 1.21–17.21; p = 0.025) as independent predictors for worse OS. Conclusion: In addition to confirming the prognostic role of PCI, our study extends the role of BRAF mutation and right primary tumor location as markers for worse prognosis.

• Standard chemotherapy plus surgery yields to unsatisfying results in BRAF-mutated colorectal liver metastases (CLM). Combination of targeted agents (encorafenib, a BRAF inhibitor, and cetuximab, an anti-EGFR) is the new standard of care for BRAF V600E-mutated mCRC refractory to a first-line standard chemotherapy. Up to now no evidence is available concerning the activity of this novel treatment as conversion therapy in CLM setting. • Our case provides evidence, for the first time to our knowledge, of the activity of encorafenib plus cetuximab as conversion regimen for BRAF V600E-mutated CLM. Additional observations in this case report concern mechanisms underlying rapid occurrence of acquired resistance and the role of CEA serum levels as biomarker to monitor treatment activity and occurrence of resistance, allowing to optimize the timing of surgery. • Further evidence on the role of doublet targeted regimen (encorafenib plus cetuximab) as conversion treatment in the setting of BRAF-mutant CLM is warranted.

Hepatic resection is the gold standard treatment for patients affected by liver-limited colorectal metastases. Reports addressing the impact of multidisciplinary team (MDT) evaluation on survival are controversial. The aim of this study was to evaluate the benefit of MDT management in these patients in our Institution experience. The objective of the analysis was to compare survivals of patients managed within our MDT (MDT cohort) to those of patients referred to surgery from other hospitals without MDT discussion (non-MDT cohort). Of the 523 patients, 229 were included in the MDT cohort and 294 in the non-MDT cohort. No difference between the two groups was found in terms of median overall survival (52.5 vs 53.6 months; HR 1.13; 95% CI, 0.88–1.45; p = 0.344). In the MDT cohort there was a higher number of metastases (4.5 vs 2.7; p < 0.0001). The median duration of chemotherapy was lower in MDT patients (8 vs 10 cycles; p < 0.001). Post-operative morbidity was lower in the MDT cohort (6.2 vs 21.5%; p < 0.001). One hundred and ninety-seven patients in each group were matched by propensity score and no significant difference was observed between the two groups in terms of OS and DFS. Our study does not demonstrate a survival benefit from MDT management, but it allows surgery to patients with a more advanced disease. MDT assessment reduces the median duration of chemotherapy and post-operative morbidities.

Molecular assessment of colorectal cancer (CRC) is receiving growing attention, beyond RAS and BRAF, because of its influence on prognosis and prediction in cancer treatment. PTEN (phosphatase and tensin homologue), a tumor suppressor, regulating cell division and apoptosis, has been explored, and significant evidence suggests a role in cetuximab and panitumumab resistance linked to the epidermal growth factor receptor (EGFR) signal transduction pathway. Factors influencing PTEN activity should be analyzed to develop strategies to maximize the tumor suppressor role and to improve tumor response to cancer treatment. Therefore, an in-depth knowledge of the PI3K-Akt pathway—one of the major cancer survival pathways—and the role of PTEN—a major brake of this pathway—is essential in the era of precision medicine. The purpose of this literature review is to summarize the role of PTEN as a predictive factor and possible therapeutic target in CRC, focusing on ongoing studies and the possible implications in clinical practice.

Background: Breast lymphoma (BL) is a rare entity. Although mimicking clinical presentation and radiological features of epithelial breast malignancies, prognosis and treatment management are different. Here we report our single institution experience in such population.Methods: The database of our pathology institute was retrospectively searched for breast neoplasms coded as lymphoma from January 2000 to January 2017. The assessed data were: gender, age at diagnosis, laterality, stage (primary or secondary), histopathological diagnosis and grading (high vs. low) treatment, recurrence and survival status. Progression-free survival (PFS), overall survival (OS) and 5-year recurrence rate were estimated. An exploratory analysis comparing survival (PFS, OS and 5-year recurrence rate) between high- and low-grade histotypes and primary and secondary stages was performed.Results: Fifteen patients were included in the analysis. All patients were affected by B-cell type lymphomas; the most frequent subtype was diffuse large B-cell lymphoma (DLBCL). Patients affected by high-grade lymphomas were treated with polychemotherapy followed in about half of cases by consolidative ipsilateral breast radiotherapy. Patients affected by low-grade lymphomas were treated with local treatment only (surgical resection +/- radiotherapy). No patient received radical surgery or axillary dissection. At a median follow up of 9 years, four patients had relapsed (all affected by high-grade lymphomas) with central nervous system (CNS) involved in half cases. Both median PFS and OS were not reached, but a slight trend toward a better survival was noticed in favor of primary breast lymphoma (PBL), while a clearer survival benefit was observed in the low-grade cohort. The estimated 5-year survival rate was 77% within the whole population, 78% vs. 66% for primary vs. secondary and 100% vs. 66% for low-grade vs. high-grade BL.Conclusions: Our data concerning clinical and pathological features are consis

Background: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. Methods: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m -2 per day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. Conclusions: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Background: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. Methods: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m -2 per day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. Conclusions: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

INTRODUCTION: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance. MATERIAL AND METHODS: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor. RESULTS: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line. CONCLUSION: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce

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