Search

Background: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making., Materials and Methods: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development., Results: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006)., Conclusions: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Seawater warming and marine heatwaves (MHWs) have a major role on the fragmentation and loss of coastal marine habitats. Understanding the resilience and potential for adaptation of marine habitat forming species to ocean warming becomes pivotal for predicting future changes, improving present conservation and restoration strategies. In this study, a thermo-tolerance experiment was conducted to investigate the physiological effects of short vs long MHWs occurring at different timing on recruits of Gongolaria barbata, a canopy-forming species widespread in the Mediterranean Sea. The recruits were collected from a population of the Marine Protected Area of Porto Cesareo (Apulia, Ionian Sea). Recruits length, PSII maximal photochemical efficiency (F v /F m ), photosynthetic pigments content, concentrations of antioxidant compounds and total antioxidant activity (DPPH) were the response variables measured during the experiment. Univariate asymmetrical analyses highlighted that all physiological variables were significantly affected by both the duration and the timing of the thermal stress with the only exception of recruits length. The higher F v /F m ratio, chlorophylls and carotenoids content, and antioxidant compounds concentration in recruits exposed to long-term stress likely indicate an acclimation of thalli to the new environmental conditions and hence, an increased tolerance of G. barbata to thermal stress. Results also suggest that the mechanisms of adaptation activated in response to thermal stress did not affect the natural growth rate of recruits. Overall, this study supports the hypothesis that canopy-forming species can adapt to future climate conditions demonstrating a physiological acclimation to cope with MHWs, providing strong evidence that adaptation of marine species to thermal stress is more frequent than expected, this contributing to design tailored conservation and restoration strategies for marine coastal habitat., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Pseudomyxoma peritonei (PMP) is a rare, slow growing tumor, traditionally considered chemoresistant. The only curative approach is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). At disease relapse, or in patients with inoperable disease at diagnosis, no standard treatment has been defined, though nonrandomized series showed promising results with fluoropyrimidine-based regimens., Patients and Methods: We conducted a prospective study in patients with relapsed or unresectable PMP and confirmed disease progression at baseline. Patients received MMC (7 mg/m 2 every 6 weeks, up to a maximum of 4 cycles) plus metronomic capecitabine (625 mg/sqm/day b.i.d.) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), overall response rate according to RECIST v1.1 criteria, serum markers response and safety., Results: Fifteen patients were included. At a median follow-up of 26.1 months (IQR, 17.7-49.6), median PFS was 17.9 months (95% CI, 11.0-NE), with 1-year PFS and OS rates of 73% and 87%. Safety profile was manageable, with only 13% G3/G4 treatment-related adverse events., Conclusion: Metronomic capecitabine, bevacizumab, and MMC are an active regimen in advanced and progressive PMP and favorably compares with historical series., Competing Interests: Disclosure F.P. received honoraria from Amgen, Bayer, Servier, Merck-Serono, MSD, BMS, Takeda, Astellas, Pierre-Fabre and received research grants for academic studies from Bristol-Myers Squibb, AstraZeneca, Agenus, Incyte, Amgen., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Marine litter pollution threatens marine ecosystems and biodiversity conservation, particularly on seafloors where all anthropogenic waste naturally sinks. In this study, we provide new information on the composition, density and origin of seafloor macrolitter as well as on plastic ingestion in deep-sea fish from bottom-trawling by-catch in the southern Tyrrhenian Sea. Plastic constituted the highest fraction of litter in terms of density (64 %) and weight (32 %) and was also retrieved in the gastrointestinal traits of Chlorophthalmus agassizi, Coelorhynchus coelorhynchus and Hoplosthethus mediterraneus. FT-IR spectroscopy analysis on the seafloor macrolitter and the ingested plastics revealed the presence of artificial polymers including PE, PET/polyester, PA widely used for food packaging, plastic bags and several common products, especially Single Use Plastic (SUP). These results underline how poor waste management schemes or their incorrect application strongly contribute to marine litter accumulation on seafloors and plastic ingestion in deep-sea fish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study aimed to assess the combined effects of ocean acidification (OA) and pollution to the polychaete Syllis prolifera inhabiting the CO 2 vent system of the Castello Aragonese (Ischia Island, Italy). We investigated the basal activities of antioxidant enzymes in organisms from the acidified site and from an ambient-pH control site in two different periods of the year. Results showed a limited influence of acidified conditions on the functionality of the antioxidant system. We then investigated the responsiveness of individuals living inside the CO 2 vent compared to those from the control to face exposure to acetone and copper. Results highlighted a higher susceptibility of organisms from the vent to acetone and a different response of antioxidant enzymes in individuals from the two sites. Conversely, a higher tolerance to copper was observed in polychaetes from the acidified-site with respect to controls, but any significant oxidative stress was induced at sublethal concentrations., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off)., Patients and Methods: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons., Results: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16)., Conclusions: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy., Competing Interests: Disclosure All authors have declared no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In coastal marine ecosystems coralline algae often create biogenic reefs. These calcareous algal reefs affect their associated invertebrate communities via diurnal oscillations in photosynthesis, respiration and calcification processes. Little is known about how these biogenic reefs function and how they will be affected by climate change. We investigated the winter response of a Mediterranean intertidal biogenic reef, Ellissolandia elongata exposed in the laboratory to reduced pH conditions (i.e. ambient pH - 0.3, RCP 8.5) together with an extreme heatwave event (+1.4 °C for 15 days). Response variables considered both the algal physiology (calcification and photosynthetic rates) and community structure of the associated invertebrates (at taxonomic and functional level). The combination of a reduced pH with a heatwave event caused Ellisolandia elongata to significantly increase photosynthetic activity. The high variability of calcification that occurred during simulated night time conditions, indicates that there is not a simple, linear relationship between these two and may indicate that it will be resilient to future conditions of climate change. In contrast, the associated fauna were particularly negatively affected by the heatwave event, which impoverished the communities as opportunistic taxa became dominant. Local increases in oxygen and pH driven by the algae can buffer the microhabitat in the algal fronds, thus favouring the survival of small invertebrates., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Coralline algae are calcareous algae able to build biogenic structures, thus playing a key-role as marine biodiversity promoters and calcium carbonate producers. The aim was to estimate the growth of Ellisolandia elongata under thermal stress. E. elongata were cultured for 2, 4 and 6 months under "natural" temperature (Tc) and increased temperature (Ti = Tc + 3 °C). In order to determine a possible culturing effect, growth in the field was also measured. For the first time, Alizarin Red S dye was used in high energy shallow water environments. Thallus linear extension was higher in the cultured specimens (Tc and Ti) compared to the field specimens. The carbonate mass in the field was higher than in Ti and Tc after 2, 4 months but decreased after 6 months. Partly unknown in situ environmental factors could have affected growth and calcification rates in the field while thermal adaptation could explain growth rates in the culturing experiment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: A subset of patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors show loss of function of succinate dehydrogenase, mostly due to germ-line mutations of succinate dehydrogenase subunits, with a predominance of succinate dehydrogenase subunit A. The clinical outcome of these patients seems favorable, as reported in small series in which patients were individually described. This work evaluates a retrospective survival analysis of a series of patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors., Methods: Sixty-nine patients with metastatic gastrointestinal stromal tumors were included in the study (11 KIT/PDGFRA wild-type, of whom 6 were succinate dehydrogenase deficient, 5 were non-succinate dehydrogenase deficient, and 58 were KIT/PDGFRA mutant). All six succinate dehydrogenase-deficient patients harbored SDHA mutations. Kaplan-Meier curves and log-rank tests were used to compare the survival of patients with succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors with that of KIT/PDGFRA wild-type patients without succinate dehydrogenase deficiency and patients with KIT/PDGFRA-mutant gastrointestinal stromal tumors., Results: Follow-up ranged from 8.5 to 200.7 months. The difference between succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors and KIT/PDGFRA-mutant or KIT/PDGFRA wild-type non-succinate dehydrogenase deficient gastrointestinal stromal tumors was significant considering different analyses (P = 0.007 and P = 0.033, respectively, from diagnosis of gastrointestinal stromal tumor for the whole study population; P = 0.005 and P = 0.018, respectively, from diagnosis of metastatic disease for the whole study population; P = 0.007 for only patients who were metastatic at diagnosis)., Conclusion: Patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors harboring succinate dehydrogenase subunit A mutations present an impressively long survival. These patients should be identified in clinical practice to better tailor treatments and follow-up over time.

Nicotinamide adenine dinucleotide (NAD) is a metabolite essential for cell survival and generated de novo from tryptophan or recycled from nicotinamide (NAM) through the nicotinamide phosphoribosyltransferase (NAMPT)-dependent salvage pathway. Alternatively, nicotinic acid (NA) is metabolized to NAD through the nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1)-dependent salvage pathway. Tumor cells are more reliant on the NAMPT salvage pathway making this enzyme an attractive therapeutic target. Moreover, the therapeutic index of NAMPT inhibitors may be increased by in NAPRT-deficient tumors by NA supplementation as normal tissues may regenerate NAD through NAPRT1. To confirm the latter, we tested novel NAMPT inhibitors, GNE-617 and GNE-618, in cell culture- and patient-derived tumor models. While NA did not protect NAPRT1-deficient tumor cell lines from NAMPT inhibition in vitro, it rescued efficacy of GNE-617 and GNE-618 in cell culture- and patient-derived tumor xenografts in vivo. NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumors to levels that sustained growth in vivo. Furthermore, NAM co-administration with GNE-617 led to increased tumor NAD levels and rescued in vivo efficacy as well. Importantly, tumor xenografts remained NAPRT1-deficient in the presence of NA, indicating that the NAPRT1-dependent pathway is not reactivated. Protection of NAPRT1-deficient tumors in vivo may be due to increased circulating levels of metabolites generated by mouse liver, in response to NA or through competitive reactivation of NAMPT by NAM. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as a rescue strategy.

The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and -3A5. Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Subclavian steal syndrome typically presents as angina in patients with internal mammary artery grafts. Atypical clinical presentations have been rarely described. We report an unusual case of subclavian steal syndrome presenting as pulmonary oedema with acute left ventricular diastolic dysfunction and preserved ejection fraction in a patient with internal mammary artery graft and severe stenosis of the proximal left subclavian artery. After successful angioplasty and stenting of subclavian artery, the patient remained asymptomatic for six months, but then experienced acute diastolic dysfunction and recurrent pulmonary oedema associated with critical subclavian in-stent restenosis with stent deformation. This report points out that, in patients with internal mammary-to-LAD grafts, subclavian steal syndrome may present as acute left ventricular diastolic dysfunction and pulmonary oedema even in the presence of normal ejection fraction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The problem of the surveillance for colorectal cancer after radical surgery is a widely debated argument. Like for other solid tumors, the issue is divided in 2 main routes: the early diagnosis of recurrence and the early diagnosis of a second primary cancer. Genetic and molecular features have been recognized as useful tools to measure these risks, however, the instruments are still insufficient to design a personalized strategy for the patient. In an era of "tailored therapies" in oncology, even the follow-up of the surgically treated patient for colorectal cancer should enter "a tailor's shop in which several competent tailors" should be available to manage a complex problem., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Resistance to tyrosine-kinase inhibitors remains an open issue in the treatment of patients with gastrointestinal stromal tumors. The complex biology of disease in the multi-resistant setting has led a progressively growing urgency and interest in development combined or integrated therapies. This mini-review outlines the rationale for developing new combined therapeutic approaches, and describes the state of the art of the various potential strategies and the promising research perspectives., (2009 Elsevier Ltd. All rights reserved.)

Nowadays molecular biology represents one of the most interesting topics in medical oncology, because it provides a global and detailed view on the molecular changes involved in tumour progression, leading to a better understanding of the carcinogenesis process, to discovering new prognostic markers and novel therapeutic targets. The gene expression profiling analysis with microarray technology has shown a great potential in cancer research and in medical oncology, mapping simultaneously the expression of thousands of genes in a single tumour sample and giving a measurement of articulated genes expression patterns. Colorectal cancer represents a wide and exciting area of research for molecular biology, due to the growing need of a molecular classification as well as prognostic and predictive molecular factors that may guide oncologists in patient's clinical management. The aim of this review is to analyze the state of art of gene expression profile in colorectal cancer using microarrays technologies and to explore some perspectives in this research field.

The epidermal growth factor receptor (EGFr) is one of the most studied molecules as a target for cancer therapy. Over these last few years, several studies attempting to identify predictive biomarkers of treatment response, such as the receptor status or other molecules related to the downstream signalling pathway, have been conducted. However, from a clinical point of view, the information obtained from ex vivo analyses still has various limitations that may be overcome by the combination with molecular imaging technologies which may provide a noninvasive, global, in vivo evaluation of the molecular tumour background. The aim of this review is to report the preclinical results of all positron emission tomography (PET) tracers synthesized until now for in vivo detection of EGFr in cancer. Two classes of PET compounds have been developed: labelled small molecules such as tyrosine kinase inhibitors and labelled monoclonal antibodies. The in vitro and in vivo results of these PET tracers are very different depending on the chemical properties, positron emission radionuclide, or animal models. As a consequence, various critical questions are still open, and the implications of a translation in the clinical setting for EGFr imaging in cancer patients is discussed.

In the last ten years, the development of several novel targeted drugs and the refinement of state of the art technologies such as the genomics and proteomics and their introduction to clinical practice have revolutionized the management of patients affected by cancer. However, everyday practice points out several clinical questions: the difficulty of response assessment to new drugs especially using standard RECIST criteria that do not provide information on biological, vascular or metabolic variations; the inadequate selection of patients who are likely to benefit from a targeted therapy excluding those with breast cancer and gastrointestinal stromal tumours; the need to know the global biological background of diseases especially in metastatic setting using repeatable non-invasive procedures. Molecular imaging could provide information on in vivo distribution of biological markers in response to targeted therapy and could improve the selection of patients before therapies. The aim of this review is to analyze the current role of conventional and innovative positron emission tomography (PET) radiotracers in clinical practice and to explore the promising perspectives of molecular imaging in cancer research.