Caloric Restriction Mimetics, Autophagy, and Anticancer Immunosurveillance. “The bacterial metabolite prodigiosin inhibits autophagy and suppresses antitumor immunity. Results from a fluorescent biosensor-based screening of bacterial metabolites”

Nutrition plays a crucial role in the development and progression of different types of cancer. Dietary components, as well as gut microbiota-derived factors, can exert metabolic and immunomodulatory functions on the host, both locally and systemically. Recent studies highlighted the role of specific gut microbes as predictors of response to immunotherapy. Autophagy has a key function in the elicitation of an immune in response to anticancer therapy. Here, we conducted an automatized fluorescent biosensor-based screening to identify autophagy modulators from a chemical library of host- and bacteria-derived metabolites and found prodigiosin, a red pigment produced by Serratia marcescens, as a potent inducer of LC3 dots in GFP-LC3 biosensor cells. Further autophagic flux analysis in RFP-GFP-LC3 tandem reporter cells and a GFP-Q74 Huntington’s disease model revealed that prodigiosin acts as an inhibitor of autophagic flux. Consistent with the described immunosuppressive role of prodigiosin, our in vivo experiment in BALB/c mice transplanted with syngeneic colon cancers suggest that prodigiosin impairs the activity of anti-PD1 immunotherapy

Antitumoral Efficacy of Two Turmeric Extracts According to Different Extraction Methods in Hepatocellular Carcinoma Cell Lines

Curcuminoids, bioactive molecules contained in turmeric, have been reported to exert anticancer effects in several human cancers, including hepatocellular carcinoma (HCC). However, the extraction method can significantly affect the structural characteristics of curcuminoids and their biological properties. On this basis, in the present study we investigated the content of curcuminoids and the anticancer activity of two turmeric powders extracted according two different methodologies: solvent extraction with ethyl acetate vs an ancient Indian extraction method of boiling of rhizomes in water followed by dehydration at the sun. Results obtained showed that extraction with ethyl acetate resulted in a significant recovery of curcuminoids and anticancer activity both in terms of cell cytotoxicity and migration/invasiveness inhibition in HCC cell lines, compared to common Indian practice. Overall these findings suggest that turmeric powders could have different efficacy, depending on the extraction method. This aspect should be taken into account when choosing the best product to be employed in the prevention and treatment of human diseases, including cancer

Adjuvant treatment in biliary tract cancer

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Despite radical surgery, the five-year overall survival (OS) does not exceed 40% in the best series. Adjuvant treatments are widely used even though they have mainly been investigated in small retrospective series until recently. Available data suggest that chemotherapy with 5-fluorouracil (and relative prodrugs) or gemcitabine can reduce the risk of relapse and potentially improve patients\u2019 long-term outcome. The role of adjuvant radiotherapy seems to be confined to patients with positive surgical margins. In addition, patients with highrisk factors for relapse (nodal involvement and non-radical resection) benefit most from chemotherapy. Recent results from large randomized trials have clarified the benefit of adjuvant treatments and probably defined a new standard of care

Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as monotherapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial.

The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure

Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma: a retrospective single-center experience

Background & aims: Very few data are available in literature about the role of radiofrequency ablation (RFA) in intrahepatic cholangiocarcinoma (ICC) and previous studies are mainly case reports and case series on a very small number of patients and nodules. In this study, we aimed to evaluate effectiveness and safety of RFA for the treatment of unresectable ICC. Methods: This is a retrospective observational cohort study comprising all consecutive patients treated with RFA for unresectable ICC at Policlinico Sant'Orsola Malpighi Hospital, Bologna, Italy. Primary endpoint was Local Tumor Progression-Free Survival (LTPFS) while Overall Survival (OS) was also assessed as secondary endpoint. Results: From January 2014 to June 2019, 29 patients with 117 nodules underwent RFA. Technique effectiveness 1 month after RFA was 92.3%; median LTPFS was 9.27 months. Univariate analysis and multivariate analysis showed that LTPFS was significantly related to tumor size ≥20 mm. At a median follow up of 39.9 months, median OS from the date of RFA was 27.5 months, with an OS of 89%, 45% and 11% at 1, 2 and 4 years, respectively. Number of overall lesions and the sum of their diameter at the moment of the first RFA significantly affected OS in multivariate analysis. Minor and major complication rates were 14% and 7%, respectively. Conclusion: Tumor size ≥20 mm was associated with lower LTPFS, representing a potential useful threshold value. A careful evaluation of tumor burden appears as a crucial element in choosing the best therapeutic strategy in unresectable ICC

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: A proof of concept

There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients na\uefve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8-9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733-11.267]in MC-patients and 5.1 months [95% CI: 4.098-6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5-6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370-0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations

Clinical Features of the Intrahepatic and Extrahepatic Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a very heterogeneous cancer in many aspects including epidemiology, risk factors, clinical presentation and genetics. Medical literature reflects this feature especially in terms of differences of clinical presentation among the intrahepatic/extrahepatic subtypes and according to related risk factors and geographic areas. Consequently these tumors are often challenging to diagnose and treat and the prognosis is poor.This manuscript deals with the clinical presentation and epidemiology of cholangiocarcinoma

Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study

: Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case-control studies or large independent cohorts

Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumour Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes

The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC