Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer.

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Inflammatory indices as prognostic markers in metastatic colorectal cancer patients treated with chemotherapy plus Bevacizumab.

Background: Validated predictors of sensitivity or resistance to Bevacizumab (Bev) are not available, and Inflammatory Indexes (IIs) has been reported to be useful prognostic factors in various malignant solid tumours, including metastatic colorectal cancer (mCRC). Objectives: To explore the prognostic value of IIs in mCRC patients treated with first-line chemotherapy plus Bev. Design: One hundred and eighty-two patients diagnosed with mCRC and treated with first line chemotherapy plus Bev were considered for this prospective non-pharmacological study. Neutrophil, lymphocyte, platelet, aspartate transaminase (AST) and lactate dehydrogenase (LDH) tests were carried out at baseline and before each treatment cycle, according to clinical practice. Methods: Pre-treatment Systemic Immune-inflammation Index (SII), Colon Inflammatory Index (CII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) were evaluated to assess a correlation with progression-free survival (PFS) and overall survival (OS). Results: In the overall population, PFS and OS were lower in patients with high SII (HR 1.64, p = 0.006 and HR 1.75, p = 0.004, respectively) and high ALRI (HR 2.13, p = 0.001 and HR 1.76, p = 0.02, respectively), but no difference was detected according to CII value. The multivariate analysis confirmed both SII and ALRI as independent prognostic factors for PFS (HR 1.64 and 2.82, respectively) and OS (HR 1.65 and 2.12, respectively). Conclusion: Our results demonstrate and confirm that IIs, and in particular SII and ALRI, are easy to measure prognostic markers for patient candidates to first line chemotherapy plus Bev for mCRC.

Inflammatory Indexes can predict the efficacy of bevacizumab in metastatic colorectal cancer Bevacizumab (Bev) is a humanized monoclonal antibody with antiangiogenic activity, used in combination with chemotherapy as a standard first line treatment for many metastatic colorectal cancer patients. Validated predictors of sensitivity or resistance to Bevacizumab are not available, although several studies have investigated this issue in recent years. In this study, we investigated whether some selected baseline inflammatory indexes levels, namely Systemic Immune-inflammation Index (SII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) could predict the survival in patients with metastatic colorectal cancer treated with Bevacizumab plus chemotherapy. We enrolled 182 patients diagnosed with mCRC and treated with first line chemotherapy plus Bev. For each patient we tested blood neutrophils, lymphocytes, platelets, aspartate transaminase (AST) and lactate dehydrogenase (LDH) before each treatment cycle, according to clinical practice. We calculated the SII value as platelet count × neutrophil count/lymphocyte count, and ALRI as AST/lymphocyte count. We found that patients with high SII and high ALRI values had lower survival as compared to those with low values. These parameters represent reproducible, inexpensive and easy to measure biomarkers to be used in both clinical practice and clinical trials, for patient selection.

Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.

Impact of Signet-Ring Cell Histology in the Management of Patients with Non-Metastatic Gastric Cancer: Results from a Retrospective Multicenter Analysis Comparing FLOT Perioperative Chemotherapy vs. Surgery Followed by Adjuvant Chemotherapy.

BACKGROUND: FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. METHODS: We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. RESULTS: Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56-6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55-6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50-7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18-12-68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. CONCLUSIONS: Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients.

Second-line therapy in pancreatic ductal adenocarcinoma (PDAC) patients with germline BRCA1-2 pathogenic variants (gBRCA1-2pv).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking. METHODS: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFS2) and overall survival (mOS2), was performed. A secondary analysis addressed the impact of timing of platinum introduction on the outcome of patients receiving at least a first-line combination chemotherapy (1LT). RESULTS: Eighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFS2 and a doubled response rate, in the platinum-based 2LT subgroup as compared to the platinum-free (8.8 versus 3.7 months, p = 0.013). Seventy-seven patients were included in the secondary analysis. Median PFS1 of 3- and 4-drug platinum-based 1LT significantly outperformed both platinum-free combinations and platinum-based doublets (11.4 versus 6.4 versus 7.9 months, p = 0.01). Albeit still immature, data on mOS paralleled those on mPFS. CONCLUSIONS: This study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage.

Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS). METHODS: Patients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients' individual data were collected from patients' records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan-Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests. RESULTS: A total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors. CONCLUSIONS: In our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might "fill the gap" in response rates that was seen in our study.

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients.

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer.

OPINION STATEMENT: Advanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An "immunoscore," based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial.

BACKGROUND: The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. METHODS: This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. FINDINGS: A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. INTERPRETATION: NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. CLINICALTRIALS. GOV IDENTIFIER: NCT02043730.

An observational retrospective analysis of the main metastatic site and corresponding locoregional treatment as a prognostic factor in metastatic gastric cancer.

Despite novel drugs, the prognosis for patients with metastatic gastric cancer remains poor. In rare instances, locoregional therapies are used in addition to standard chemotherapy in patients with oligometastatic involvement. This type of approach has not been supported by solid published evidence. The aim of the present retrospective study was to assess the prognostic impact of factors such as metastatic site, tumour histology and locoregional treatment in patients with metastatic gastric cancer. A total of 184 patients with metastatic gastric or gastroesophageal junction adenocarcinoma who received at least one line of palliative therapy with doublet or triplet chemotherapy were enrolled in the current analysis. Median overall survival (OS) was 8.32 months (95% CI, 7.02-9.41) and median progression-free survival (PFS) was 4.16 months (95% CI, 3.24-5.08). Lung metastases vs. other sites of metastatic involvement [hazard ratio (HR), 0.27; P=0.0133] and intestinal histology (HR, 0.48; P=0.08) were significantly associated with an improved OS. Improved PFS was also observed (HR, 0.49; P=0.10 and HR, 0.72; P=0.08 for lung metastases and intestinal histology, respectively). Second line chemotherapy and locoregional treatment of metastases (surgery or radiotherapy) were associated with improved OS (HR, 0.52; P<0.0001 and HR, 0.35; P<0.0001, respectively). Multivariate analysis confirmed an independent prognostic role for OS only for locoregional treatment, second line treatment and intestinal histology. The present results suggested that the presence of lung metastases alone was not a relevant prognostic factor and was influenced by the availability of further lines of treatment or by locoregional treatments. Locoregional treatments in patients with oligometastatic disease should be offered as they allow prolonged survival in patients with otherwise relatively short life expectancy.

Systemic immune-inflammation index: a prognostic tiebreaker among all in advanced pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) detains a dismal prognosis and has a limited number of prognostic factors. Inflammation has been demonstrated to play a key role both in PDAC initiation and progression and several inflammation-based prognostic scores have been investigated in a wide range of malignancies. We compared the most analyzed inflammation-based prognostic scores in order to establish their potential impact on prediction of the outcome in advanced PDAC patients. METHODS: A total of 234 advanced PDAC patients undergoing first-line chemotherapy in our institute were retrospectively analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using Kaplan-Meier method and survival differences were evaluated using the log-rank test. Level of statistical significance P was set at 0.05. Only those variables that proved to be associated with statistically significant differences in outcome were compared in multivariate analysis using multiple Cox regression, as to identify their independent role and their relative power against each other. RESULTS: In the whole cohort, median overall survival (OS) was 8.7 months (95% CI: 7.8-9.4 months), median progression-free survival (PFS) was 3.8 months (95% CI: 3.1-4.2 months). At univariate analysis high systemic immune-inflammation index (SII) was related to shorter OS [hazard ratio (HR) =2.04, 95% CI: 1.59-4.19, P=0.0001] and PFS (HR =1.52, 95% CI: 1.11-2.20, P=0.01). This was maintained at multivariate analysis both for OS (HR =2.11, 95% CI: 1.29-3.46, P=0.003) and PFS (HR =1.64, 95% CI: 1.14-2.37, P=0.008), whereas other inflammation-based scores lost their independent role. Elevated SII (≥1,200) was associated with low albumin levels (P=0.03) and with elevated lactate dehydrogenase (LDH) (P=0.01). CONCLUSIONS: Elevated SII represents an independent negative prognostic factor above all others for both OS and PFS in advanced PDAC patients treated with first-line chemotherapy, thus confirming a pivotal role of systemic inflammation on PDAC progression and on patient outcome.

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing.

Colorectal cancer is characterized by high incidence worldwide. Despite increased awareness and early diagnosis thanks to screening programmes, mortality remains high, particularly for patients with metastatic involvement. Immune checkpoint inhibitors or poly (ADP-ribose) polymerase (PARP)-inhibitors have met with disappointing results when used in this setting, opposed to other malignancies. New drugs with different mechanisms of action are needed in this disease. Drug repurposing might offer new therapeutic options, as patients with metastatic colorectal cancer often share risk factors for other chronic diseases and thus frequently are on incidental therapy with these drugs. The aim of this review is to summarise the published results of the activity of drugs used to treat chronic medications in patients affected by colorectal cancer. We focused on antihypertensive drugs, Non-Steroid Anti-inflammatory Drugs (NSAIDs), metformin, antidepressants, statins and antibacterial antibiotics. Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect. It is hoped that further prospective trials that take into account the role of these drugs as anticancer medications are conducted.

Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up of Exocrine Pancreatic Ductal Adenocarcinoma: Evidence Evaluation and Recommendations by the Italian Association of Medical Oncology (AIOM).

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations.

Acute Peripheral Motor Neuropathy Induced by Oxaliplatin-Correlated Hypokalaemia.

Neurotoxicity is one of the most common side effects of oxaliplatin-based therapy. Most patients who receive at least 3-4 months of treatment suffer from peripheral sensory neurotoxicity (PSN), characterised by the loss or impairment of tactile and proprioceptive sensory function. Motor impairment, such as muscle weakness or palsy, has been rarely described, and the physiopathology of PSN, as well as the motor symptoms due to oxaliplatin-based treatment, are not adequately understood. Here we report the case of a patient who experienced severe acute peripheral motor neuropathy as a side effect of oxaliplatin-based treatment. We also review other cases of PSN published in the literature and suggest a novel hypothesis on the physiopathology of this particular event. Take-away lessons: Not all of the neurological symptoms observed during oxaliplatin-based treatment can be traced back directly to the oxaliplatin itself, and other factors, such as electrolyte imbalances, may contribute to the symptoms. Patients with gastro-intestinal malignancies are the patients most affected by neurotoxicity due to the side effects of chemotherapy and the disease itself.

Expression Profiling of Circulating Tumor Cells in Pancreatic Ductal Adenocarcinoma Patients: Biomarkers Predicting Overall Survival.

The interest in liquid biopsy is growing because it could represent a non-invasive prognostic or predictive tool for clinical outcome in patients with pancreatic ductal adenocarcinoma (PDAC), an aggressive and lethal disease. In this pilot study, circulating tumor cells (CTCs), CD16 positive atypical CTCs, and CTC clusters were captured and characterized in the blood of patients with PDAC before and after palliative first line chemotherapy by ScreenCell device, immunohistochemistry, and confocal microscopy analysis. Gene profiles were performed by digital droplet PCR in isolated CTCs, five primary PDAC tissues, and three different batches of RNA from normal human pancreatic tissue. Welsh's t-test, Kaplan-Meier survival, and Univariate Cox regression analyses have been performed. Statistical analysis revealed that the presence of high CTC number in blood is a prognostic factor for poor overall survival and progression free survival in advanced PDAC patients, before and after first line chemotherapy. Furthermore, untreated PDAC patients with CTCs, characterized by high ALCAM, POU5F1B, and SMO mRNAs expression, have shorter progression free survival and overall survival compared with patients expressing the same biomarkers at low levels. Finally, high SHH mRNA levels are negatively associated to progression free survival, whereas high vimentin mRNA levels are correlated with the most favorable prognosis. By hierarchical clustering and correlation index analysis, two cluster gene signatures were identified in CTCs: the first, with high expression of VEGFA, NOTCH1, EPCAM, IHH, is the signature of PDAC patients before chemotherapy, whereas the second, with an enrichment in the expression of CD44, ALCAM, and POU5F1B stemness and pluripotency genes, is reported after palliative chemotherapy. Overall our data support the clinic value of the identification of CTC's specific biomarkers to improve the prognosis and the therapy in advanced PDAC patients.

Clinical impact of different exosomes' protein expression in pancreatic ductal carcinoma patients treated with standard first line palliative chemotherapy.

INTRODUCTION: Pancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy. PATIENTS AND METHODS: Patients were submitted to blood sample collection before chemotherapy (T0) and after 3 months (T3). We quantified by an ELISA-based technique specific proteins of cancer-derived exosomes (CD44,CD44v6,EpCAM,CD9,CD81,Tspan8,Integrin α6,Integrin ß4,CD24,CXCR4). We correlated the baseline levels of these factors and changes between T3 and T0 and survival outcomes. Survival analyses were performed by Kaplan-Meier method. Correlation was assessed by log-rank test and level of statistical significance was set at 0.05. Multivariate analysis was performed by logistic regression analysis. RESULTS: Nineteen patients were enrolled. EpCAM T0 levels and increased EpCAM levels from T0 to T3 were those mostly associated with differences in survival. Patients having higher EpCAM had median progression free survival (PFS) of 3.18vs7.31 months (HR:2.82,95%CI:1.03-7.73,p = 0.01). Overall survival (OS) was shorter for patients having higher EpCAM (5.83vs16.45 months,HR:6.16,95%CI:1.93-19.58,p = 0.0001) and also response rates (RR) were worse (20%vs87%,p = 0.015). EpCAM increase during treatment was associated with better median PFS (2.88vs7.31 months,HR:0.24,95%CI:0.04-1.22,p = 0.003). OS was also better (8.75vs11.04 months, HR:0.77,95%CI:0.21-2.73,p = 0.66) and RR were 60%vs20% (p = 0.28). Among clinical factors that might determine changes on PFS and OS, only ECOG PS was associated to significantly worse PFS and OS (p = 0.0137and<0.001 respectively).Multivariate analysis confirmed EpCAM T0 levels and EpCAM T0/T3 changes as independent prognostic factors for PFS. CONCLUSIONS: Pancreatic cancer patients exosomes express EpCAM, whose levels change during treatment. This represents a useful prognostic factor and also suggests that future treatment modalities who target EpCAM should be tested in pancreatic cancer patients selected by exosome EpCAM expression.

Medical treatment for cholangiocarcinoma.

Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.

Optimal management of resected gastric cancer.

Although advances in medical treatment for gastric cancer (GC) have been made, surgery remains the mainstay of cure for patients with localized disease. Improvement in surgical modalities leads to increased chance of cure for resected patients, but a non-negligible number of patients eventually relapse. On this basis, it has been hypothesized that the addition of complementary systemic or local treatments (such as chemotherapy and radiotherapy) could help in improving patients' survival by reducing the risk of recurrence. Several studies have tried to identify the best approach in localized GC: some of them have assessed the role of perioperative chemotherapy [CT] with different drug combinations, while others have focused on the benefit obtained by addition of radiotherapy, whose role is still under investigation. In particular, the role of chemoradiotherapy, both in adjuvant and neoadjuvant settings, is still uncertain. In the last few years, several clinicopathological and molecular factors have been investigated and identified as potential prognostic markers in GC. Many of these factors could have influenced the outcome of patients receiving combined treatments in the abovementioned studies. Patients have not been generally distinguished by the site of disease (esophageal, gastric and junctional cancers) and surgical approach, making data difficult to be interpreted. The purpose of this review was to shed light on these highly controversial topics.

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study.

BACKGROUND: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer. OBJECTIVE: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting". PATIENTS AND METHODS: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0-1.27, p = 0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63-2.39, p = 0.03) were independent poor prognostic factors. CONCLUSIONS: These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.