Circulating tumour cells in colorectal cancer

Abstract Background The detection of circulating tumour cells (CTC) in blood sample in patients with early or advanced colorectal cancer has a potential prognostic value. Methods The challenge of CTC detection is related to the requirement of high sensitivity combined with high specificity method. CTCs detection can be distinguished between indirect and direct methods. The former ones are based on the recognition of tissue-, organ- or tumour-specific markers by immuno-histochemistry (indirect immuno-mediated methods) or (real-time) RT-PCR (indirect molecular methods), whilst the latter are related to CTCs selection based on the physical properties of density and sizes. Ongoing and future isolation by size of epithelial tumour cells (ISET) developments concerning automated image analysis on the filter and transmission of high definition images through the web for 'on line' cytopathological consultations are aimed to speed up the work of cytopathologists on CTC/ circulating tumour microemboli (CTM) detection. Conclusions CTC detection in colorectal cancer (CRC) correlates with pathological stage and clinical outcome in particular in those patients with advanced disease. CRC CTC level before and after CT are an independent prognostic factor for progression-free and overall survival. The positive prognostic value of complete clearance CTC after surgery may be useful to select patients for adjuvant chemotherapy

Phase I/II trial of gemcitabine plus cisplatin and etoposide in patients with small-cell lung cancer

Objective: The objectives of this phase 1/11 study were to define the maximum tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and gemcitabine (PEG) in the treatment of previously untreated patients with small-cell lung cancer (SCLC). Patients and Methods: Chemonaive patients received fixed doses of gemcitabine (1000 mg/m(2) on days I and 8) and cisplatin (70 mg/m(2) on day 2) and escalating doses of etoposide (starting dose of 50 mg/m(2) on days 3,4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors were used. Results: From September 1998 to April 2000, 56 patients with limited- or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two different etoposide doses were tested in eight patients. At the second level (75 mg/m(2)), two out of two patients experienced dose-limiting toxicities (neutropenia and thrombocytopenia) and no further dose-escalation was attempted, thus an etoposide dose of 50 mg/m 2 was defined as the MTD. In the subsequent phase 11 evaluation, 48 additional patients were enrolled, for a total of 54 patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred in 66.7 and 53.7%,, of patients, respectively. Non-hematologic toxicity was mild, with grade 3 diarrhea and fatigue as the main side effects. Two patients died of neutropenic sepsis (one at 75 mg/m(2) and the other at So I n g/In 2 etoposide). Ten complete and 29 partial responses were reported, for an overall response rate of 72.2% (95% confidence interval, 56.6-85.0%). The median duration of response and median survival were 8.0 and 10 months, respectively, with a 1-year survival probability of 37.5%. Conclusions: he combination of PEG is feasible and well tolerated as front-line chemotherapy in SCLC. A randomized comparison of this triplet is underway. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Familial adenomatosis polyposis–related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis

[Introduction] Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine).[Patients and methods] We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves.[Results] We identified 37 patients (median age 29 years, range 7–44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3–12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years.[Conclusions] This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT

Personalization of regorafenib treatment in metastatic gastrointestinal stromal tumours in real-life clinical practice

Background: Regorafenib (REG) has now been approved as the standard third-line therapy in metastatic gastrointestinal stromal tumour (GIST) patients at the recommended dose and schedule of 160 mg once daily for the first 3 weeks of each 4-week cycle. However, it has a relevant toxicity profile that mainly occurs within the first cycles of therapy, and dose and schedule adjustments are often required to reduce the frequency or severity of adverse events and to avoid early treatment discontinuation. To date, large amounts of data on the use of REG in metastatic GIST patients in daily clinical practice are not available, and we lack information about how this treatment personalization really affects the quality of life (QoL) of patients. The aim of the present retrospective study is to build a comprehensive picture of all alternative REG strategies adopted in daily clinical practice for use in metastatic GIST patients. Methods: Metastatic GIST patients treated with dose adjustment or alternative schedules of REG at seven reference Italian centres were retrospectively included. Results: For a total of 62 metastatic GIST patients, we confirmed that REG treatment adjustment is common in clinical practice and that it is very heterogeneous, with approximately 20 different strategies being adopted. Independent of which strategy is chosen, treatment personalization has led to a clinical benefit defined as complete or partial resolution of side effects in almost all patients, affecting the duration of REG treatment. Conclusions: The personalization of REG, even if it is heterogeneous, seems to be crucial to maximize the overall treatment duration

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. © 2014 American Association for Cancer Research

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study

Background: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. Patients and methods: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. Results: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. Conclusion: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib

Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations : Results from a Multi-institutional European Retrospective Study

Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort. Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location. Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.Peer reviewe

Bone sarcomas: ESMO–EURACAN–GENTURIS–ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up

Production costs have been covered by ESMO from central funds

AlmaLaurea\u2019s Role in Helping Graduates in the Italian Job Market

The chapter provides information concerning the context in which AlmaLaurea operates and the main foundations on which its activities are based: an annual \u201cgraduate profile\u201d survey on the internal efficiency of the higher education system; an annual \u201cgraduates\u2019 employment conditions\u201d survey on the system\u2019s external efficiency; an on-line databank of graduate r\ue9sum\ue9s. Some examples of findings drawn from the two most recent annual surveys are provided. A more in-depth presentation is devoted to describing Italian graduates\u2019 experience of traineeships during their studies. The final section of the chapter briefly discusses other AlmaLaurea activities that contribute to helping youths\u2019 decision-making processes as regards higher education and the job market and its international initiatives. AlmaLaurea is a consortium among 65 Italian universities, accounting for 80% of the nation\u2019s graduates. It pursues a variety of goals pertaining to the provision of information to member universities and the creation of networks linking the latter, graduates, and the business world