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Roughly 20% of the neurons in the mouse cortex are inhibitory interneurons (INs). Of these, the three major subtypes are parvalbumin (PV), somatostatin (SST), and vasoactive intestinal polypeptide (VIP) expressing neurons. We used monosynaptic rabies tracing to compare the presynaptic input landscape onto these three IN subtypes in the mouse primary auditory cortex (A1). We compared both local patterns of monosynaptic inputs as well as long-range input patterns. The local monosynaptic input landscape to SST neurons was more widespread as compared to PV and VIP neurons. The brain-wide input landscape was rich and heterogeneous with40 brain regions connecting to all the three INs subtypes from both hemispheres. The general pattern of the long-range input landscape was similar among the groups of INs. Nevertheless, a few differences could be identified. At low resolution, the proportion of local versus long-range inputs was smaller for PV neurons. At mesoscale resolution, we found fewer inputs from temporal association area to VIP INs, and more inputs to SST neurons from basal forebrain and lateral amygdala. Our work can be used as a resource for a quantitative comparison of the location and level of inputs impinging onto discrete populations of neurons in mouse A1.

Nutrition and metabolism are altered in patients with gastroenteropancreatic neuroendocrine tumors, which is related to excessive production of gastrointestinal hormones, peptides, and amines that can cause maldigestion, diarrhea, steatorrhea, and altered gastrointestinal motility. Patients with carcinoid syndrome are at risk of malnutrition due to tryptophan depletion, reduced intake of food, and loss of appetite because of diarrhea and/or flushing. To date, there is limited information on the nutritional issues faced by patients with neuroendocrine tumors, and on what specific recommendations should be made to patients concerning nutrition at various stages of the disease process. Dietary planning should therefore be an integral part of multidisciplinary management for patients with neuroendocrine tumors. Herein, we review current guidance for nutrition in patients with neuroendocrine tumors, focusing on intake of amines and foods to avoid, as well as concurrent medications. We also propose a new and practical food pyramid based on the principles of Mediterranean diet 4.0 that can be easily adapted according to the unmet needs of patients with neuroendocrine tumors at all stages of disease. The overarching goal of the present review is to create greater awareness of nutritional care and considerations that should be given to patients with neuroendocrine tumors.

Background The COVID-19 pandemic has dramatically affected healthcare professionals’ lives. We investigated the potential mental health risk faced by healthcare professionals working in neonatal units in a multicentre cross-sectional observational study. Methods We included all healthcare personnel of seven level-3 and six level-2 neonatal units in Tuscany, Italy. We measured the level of physical exposure to COVID-19 risk, self-reported pandemic-related stress, and mental health load outcomes (anxiety, depression, burnout, psychosomatic symptoms, and post-traumatic symptoms) using validated, self-administered, online questionnaires during the second pandemic wave in Italy (October 2020 to March 2021). Results We analyzed 314 complete answers. Scores above the clinical cutoff were reported by 91% of participants for symptoms of anxiety, 29% for post-traumatic symptoms, 13% for burnout, and 3% for symptoms of depression. Moreover, 50% of the participants reported at least one psychosomatic symptom. Pandemic-related stress was significantly associated with all the measured mental health load outcomes, with an Odds Ratio of 3.31 (95% confidence interval: 1.87, 5.88) for clinically relevant anxiety, 2.46 (1.73, 3.49) for post-traumatic symptoms, 1.80 (1.17, 2.79) for emotional exhaustion, and 2.75 (1.05, 7.19) for depression. Female health care professionals displayed a greater risk of anxiety, and male health care professionals and nurses, of depressive symptoms. Conclusions Despite the low direct clinical impact of COVID-19 in newborns, neonatal professionals, due to both living in a situation of uncertainty and personal exposure to contacts with parents and other relatives of the newborns, and having to carry out activities once routine and now fraught with uncertainty, displayed clear signs of mental health load outcomes. They must be considered a specific population at risk for psychological consequences during the pandemic.

Single-agent gemcitabine is a moderately effective compound in metastatic breast cancer (mBC) treatment. Carboplatin is frequently used in addition to gemcitabine to improve tumor responses, but with an unclear effect on survival outcomes. In this study we evaluated the antitumor efficacy and safety profiles of gemcitabine and carboplatin-gemcitabine in mBC patients.We retrospectively collected data on patients treated between April 2012 and February 2018 with gemcitabine 800 mg/mOf 163 consecutive patients who met the inclusion criteria, 75 received gemcitabine and 88 carboplatin-gemcitabine. Patients in the combination cohort had received a lower number of previous chemotherapy lines (2 vs. 3), and were less likely to have received carboplatin (9 patients [10%] vs. 34 patients [45%]; P .0001). We found no PFS differences in carboplatin-gemcitabine and gemcitabine cohorts (4.24 vs. 4.61 months; adjusted hazard ratio, 0.98; P = .92), whereas the combination was associated with a trend toward higher ORR (18 patients [20.4%] vs. 8 patients [10.6%]; P = .089) and with significantly higher incidence of Grade 3/4 neutropenia (30 patients [34%] vs. 5 patients [6.6%]; P .0001).Using carboplatin in addition to gemcitabine is associated with more hematologic AEs but not with better PFS. Although single-agent gemcitabine remains a treatment option for heavily pretreated mBC patients, finding biomarkers of response to platinum salts might help to identify patients more likely to benefit from carboplatin-gemcitabine.

HER2-positive breast cancer (HER2 + BC) represents 15–20% of all BCs. In the last two decades, the introduction of monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) directed against HER2 impressively improved patient prognosis in all disease stages. Yet, not all patients with limited-stage disease are cured, and HER2+ metastatic BC (mBC) remains an almost invariably deadly disease. Primary or acquired resistance to anti-HER2 therapies is responsible for most treatment failures. In recent years, several resistance mechanisms have been identified, such as impaired drug binding to HER2, constitutive activation of signaling pathways parallel or downstream of HER2, metabolic reprogramming or reduced immune system activation. However, only a few of them have been validated in clinical series; moreover, in the era of standard-of-care dual HER2 blockade, these mechanisms should be re-assessed and, in case, confirmed with anti-HER2 combinations. Defining the best strategies to delay or revert resistance to anti-HER2 treatments will be crucial to improve their clinical efficacy.

Platinum salts are active against metastatic triple negative breast cancer (mTNBC), and biomarkers to predict their effectiveness are urgently needed. In recent years, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have emerged as prognostic biomarkers in many malignancies, but their predictive role in platinum-treated mTNBC patients remains unexplored. We performed a retrospective, single centre study to evaluate the association between baseline NLR or PLR and progression free survival (PFS) of mTNBC patients treated with platinum-based chemotherapy. As a control population, we analysed data from patients with hormone receptor-positive HER2-negative (HR+ HER2−) metastatic breast cancer. Among 57 mTNBC patients treated with the carboplatin-paclitaxel or carboplatin-gemcitabine combination, high NLR and PLR were associated with significantly lower PFS at both univariate and multivariable analysis. Conversely, we did not find a significant association between NLR or PLR and the PFS of 148 patients in the control population. Our findings suggest that the NLR and PLR are predictive of benefit from platinum-containing chemotherapy specifically in mTNBC patients. If validated in larger prospective studies, these easy-to-measure parameters could be combined with emerging predictive biomarkers, such as BRCA 1/2 mutations, to improve the selection of mTNBC patients more likely to benefit from platinum-based chemotherapy.

Background Chemotherapy is standard care in resected gastric cancer (GC). Despite the evidence that combination chemotherapy (CT) increases overall survival (OS) as compared to single agent therapy in metastatic disease, no study proved this benefit in the adjuvant setting. We performed a systematic review and meta-analysis based on trial data on the role of combination over single agent CT as adjuvant treatment of GC. Methods MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared combination vs. single agent CT in patients treated with radical surgery for non-metastatic GC. Data extraction was conducted according to the PRISMA statement. Statistical analyses were conducted to calculate the summary hazard ratio (HR) for OS and disease free survival (DFS) and 95% Confidence Intervals (CIs) by using random-effects or fixed effects models based on the heterogeneity of included studies. A subgroup analysis was performed in patients treated with D2 lymphadenectomy. Results A total of 3572 patients were available for this analysis, 1857 received D2 lymphadenectomy, and fluoropyrimidine was given in 97% of patients of the control arm. In the overall population, the combined therapy decrease the risk of death by 13% (HR=0.87; 95%CI, 0.79–0.95; p =0.004) with fixed effect and by 19% (HR=0.81; 95%CI, 0.68–0.97; p =0.02) with random effect; significant heterogeneity was found. When analysis was limited to studies that required D2 lymphadenectomy a significant reduction of the risk of death was found in favor of combination CT (HR=0.86; 95%CI, 0.76–0.98; p =0.02). In the 3487 patients valuable for DFS, combination CT decreased the risk of relapse by 23% (HR=0.77; 95%CI, 0.70–0.84; p p =0.12) with random effect; significant heterogeneity was found. Conclusions This analysis reported that adjuvant combination CT decreases the risk of death over single agent therapy in patients with non-metastatic GC.

Summary Background The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated. Methods MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results Seven eligible RCTs were identified. In the overall RAS wild-type population ( N =2719), anti-EGFR MoAbs significantly improved OS (HR=0.81; 95%CI, 0.71–0.92; p =0.002), PFS (HR=0.77; 95%CI, 0.60–0.98; p =0.03) and objective response rate (ORR) (RR=1.33; 95%CI, 1.09–1.62; p =0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS ( p p p =0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR=0.80; 95%CI, 0.69–0.92; p =0.003), but not PFS (HR=0.94; 95%CI, 0.74–1.19; p =0.59) or ORR (RR=1.10; 95%CI, 0.97–1.25; p =0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based). Conclusions The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.

The purpose of this paper is the analysis of the Plotinian and Iamblichean reading of the Aristotelian theory of abstraction, and its relationship with the status of mathematical entities, as they were conceived within a Platonic model, according to which mathematical objects are ontological autonomous and separate.

Aims Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

A still relevant number of patients with RAS-BRAF wild-type colorectal cancer (CRC) do not respond to treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, suggesting that additional biomarkers to guide patient selection are urgently needed. Circulating tumor cells (CTCs) may represent such a biomarker. In this prospective study, 38 patients with advanced RAS-BRAF-wild-type CRC received third-line therapy with cetuximab-irinotecan or panitumumab. Peripheral blood samples for CTC status determination were collected at baseline, during treatment at early (2-4 weeks) and at later (8-10 weeks) times. CTC enrichment was done with the AdnaTest ColonCancerSelect kit, whereas CTC detection was done with the AdnaTest ColonCancerDetect kit. CTC status positivity was defined according to the kit manufacturer's thresholds. Fifty percent of patients were defined as CTC positive at baseline and the overall RECIST response rate was 26%. CTC baseline status was not associated with treatment response, whereas early CTC status and CTC status changes during treatment were significantly associated with tumor response. Kaplan-Meier analysis showed a significantly shorter progression-free survival (median, 2.0 versus 4.0 months, p = 0.004) and overall survival (4.7 versus11.4, p = 0.039) in patients with early CTC + status compared with CTC - ones. In multivariable analysis including classical prognostic factors, the CTC status changes profile during treatment was an independent predictor of both progression-free survival (p

Taxanes are a mainstay in the treatment of metastatic breast cancer (mBC). Combination chemotherapy, including platinum–taxens doublets, can improve tumor responses and progression-free survival (PFS), but is associated with more toxicities and an uncertain benefit in terms of overall survival (OS). We performed a retrospective study on 274 consecutive patients with mBC treated at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, during the decade 2007–2016 with the combination of carboplatin AUC 2 plus paclitaxel 80 mg/m2, both given on days 1 and 8 in every 21-day cycle. 264 patients were evaluable for treatment safety and activity. The objective response rate (ORR) was 44.7%. Median PFS and OS were 8.6 and 23.7 months, respectively. Triple-negative breast cancer (TNBC) patients had significantly lower PFS and OS times compared to other biology groups. At multivariable analysis, previous exposure to taxanes, HR-positive HER2-negative biology, a higher number of metastatic sites, and de novo metastatic disease at diagnosis were associated with reduced PFS, while receiving maintenance therapy correlated with improved PFS. Overall, the treatment was quite well tolerated, with 10.2% of patients discontinuing one or both drugs because of adverse events (AEs). G3–G4 neutropenia occurred in 16.8% of patients, while the incidence of febrile neutropenia was 2.3%. Weekly carboplatin–paclitaxel regimen is active and well tolerated in mBC treatment. Prospective studies should be conducted to compare its efficacy and tolerability with standard single-agent paclitaxel or docetaxel treatment schedules, as well as with more recent combination regimens.

Aim Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs).

Background No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. Patients and methods Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. Results Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade ≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P = 0.004). TP53 status had no influence on the primary end point. Conclusions Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.

Background: Evidence for TP53 mutations as biomarker in colorectal cancer (CRC) is conflicting. Methods: We assessed TP53 mutations in 51 patients with advanced CRC enrolled into a phase II, randomised trial of first-line tegafur-uracil (UFT)/leucovorin (LV) plus irinotecan (n = 23) versus UFT/LV plus oxaliplatin (n = 28). Results: Non-functional TP53 mutations were found in 35% of patients. The response rate was not significantly different according to TP53 status. Progression-free and overall survival were longer in patients with TP53 mutations compared to those with wild-type TP53 (9 vs. 6.5 months, p = 0.0504, and 39.2 vs. 19.6 months, p = 0.0055, respectively). On multivariable analysis, TP53 mutation was independently associated with a decreased risk of death (hazard ratio 0.329, 95% CI 0.159-0.679; p = 0.0026). Treatment arm did not interact with TP53 in influencing outcomes. Conclusion:TP53 was not predictive of benefit from first-line irinotecan- or oxaliplatin-based chemotherapy. TP53 mutations may possibly be associated with a more indolent course of CRC after the diagnosis of metastatic disease.

Few data are available outlining outcomes of panitumumab in advanced colorectal cancer patients benefiting from prior cetuximab-based regimens.Thirty patients with KRAS wild type metastatic colorectal cancer with clinical benefit from prior cetuximab-based regimens between May 2004 and October 2011 were reviewed at nine Italian Institutions. Inclusion key criteria included interruption of cetuximab for reasons other than progressive disease. Patients were classified according to prior regimens (0 or ≥1), prior response or stabilization, surgery of metastases, and Köhne prognostic score. At the time of subsequent progression, patients were treated with single agent panitumumab until progressive disease, unacceptable toxicity, or consent withdrawal.Panitumumab obtained 67% disease control rate and 30% objective response rate, with median PFS of 4.2 and median OS of 9.6 mo. Patients with BRAF/NRAS/PI3KCA and KRAS (by mutant enriched technique) wild-type tumors had the best chance of response to panitumumab.Single agent panitumumab provided significant clinical benefit in heavily pretreated patients without acquired resistance to prior cetuximab-based regimens.

Mesenchymal-epithelial transition (MET) is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF). Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC), by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies.

The Treatise On Numbers develops a typical Plotinian inquiry about oneness and intelligible plurality, in which the analysis is based on the problem of the infinite inside the intelligible realm, as it seems to be presented in the socalled generation of numbers in Plato's Parmenides, where numbers are linked to Being, identified by Plotinus with the hypostasis of Intellect, and produce a process of unlimited division. In order to avoid this interpretation, Plotinus finds in other Plato's dialogues the proof that number is an eidetic nature, encompassing all the intelligible entities, so that the infinite has to be interpreted as what is produced by calculus. Other arguments are rather depending on the model of the Old Academy, concerning the relationship between forms and numbers: Plotinus wonders if numbers come ontologically before forms and indeed he states right this position. Other aspects of Plotinus' investigation, which can be traced back to the Old Academy, are the distinction between two kinds of numbers and the doctrine of the unified number. This model of number, quite ambiguous, may be identified with the indefinite dyad, even though the former has to be conceived, differently from that of Old Academy, within a mono-polar framework, according to which the sole principle is the One.

1. Il confronto che Plotino realizza con il pensiero stoico e gnostico a partire dal terreno dell’astrologia puo essere considerato paradigmatico all’interno della appropriazione ermeneutica che conduce il filosofo a rileggere e contaminare le proprie fonti muovendo dalla pretesa di una difesa della “dottrina platonica”. La questione, tecnica, degli influssi celesti e degli oroscopi viene inserita in una polemica contro le nozioni stoiche di πρόνοια e eἱμαρμένη che Plotino non rifiuta, ma sal...

Background There is lack of evidence about systemic treatment of pseudomyxoma peritonei (PMP) relapsing after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. There is also lack of biomarkers able to predict outcomes beyond known clinical and pathological prognostic features. Methods Fifteen patients with relapsed PMP and progressive disease within the last 6 months were included and received metronomic capecitabine (625 mg/mq/day b.i.d.) and bevacizumab (7.5 mg/Kg three-weekly) until progressive disease/unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Ion Torrent® next generation sequencing technology (Hot-spot Cancer Panel) was used to characterize molecular features. Results At a median follow up of 12 months, median PFS was 8.2 months and 1-year overall survival was 91 %. Partial responses were observed in 20 % of cases, but a significant reduction of tumor markers in up to 79 %. Treatment was very well tolerated without no new safety signals. All tumor samples except one had KRAS mutations. Patients with GNAS mutations had a significantly shorter median PFS as compared to GNAS wild-type ones (5.3 months vs. not reached; p

La raccolta di saggi qui presentata segue la linea dei ‘manuali’ previsti dall’Oxford Handbook, con il suo corredo bibliografico aggiornato (anche se, forse, eccessivamente ‘anglo-centrato’) in relazione alle tematiche individuate come ‘centrali’ nell’onto-epistemologia platonica e con l’obiettivo, dichiarato fin dalla Prefazione, di offrire al lettore gli strumenti necessari per un futuro approfondimento della filosofia e della tradizione platonica. Non, quindi, un volume per ‘specialisti’, ...

This paper describes our experience with magnetic resonance imaging (MRI) in the assessment of fetal anatomical structures and major fetal pathologies. The retrospective study included 128 pregnant women between the 22nd and 38th week of gestation. We used the following imaging protocol: T2-weighted single-shot fast spin-echo sequences for all foetuses and, in selected cases, gradient echo with steady-state free precession (SSFP), T1-weighted spoiled gradient echo [fast low-angle shot (FLASH)] with and without fat saturation, and T2 thick-slab sequences with multiplanar technique. In 32 cases, we performed diffusion-weighted sequences with apparent diffusion coefficient (ACD) maps on the brain, the kidneys and the lungs. We achieved diagnostic-quality images in 125 of 128 patients; MR image quality was unsatisfactory in three cases only. In 16 cases with previous negative ultrasound (US) findings, MRI confirmed the US diagnosis. MRI confirmed the positive US diagnosis in 67 of 109 cases (61.5%); in 11 cases it changed the US diagnosis, and in 31/109 the examination was negative. In addition, MRI identified other anomalies not recognised during US examination. With its ultrafast sequences, fetal MRI provides good detail of normal fetal anatomy and allows characterisation of suspected anomalies.

In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p

Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17–48). Bevacizumab induced significantly better pathological response rates (TRG1–3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

Chemotherapy is standard care in resected gastric cancer (GC). Despite the evidence that combination chemotherapy (CT) increases overall survival (OS) as compared to single agent therapy in metastatic disease, no study proved this benefit in the adjuvant setting. We performed a systematic review and meta-analysis based on trial data on the role of combination over single agent CT as adjuvant treatment of GC.MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared combination vs. single agent CT in patients treated with radical surgery for non-metastatic GC. Data extraction was conducted according to the PRISMA statement. Statistical analyses were conducted to calculate the summary hazard ratio (HR) for OS and disease free survival (DFS) and 95% Confidence Intervals (CIs) by using random-effects or fixed effects models based on the heterogeneity of included studies. A subgroup analysis was performed in patients treated with D2 lymphadenectomy.A total of 3572 patients were available for this analysis, 1857 received D2 lymphadenectomy, and fluoropyrimidine was given in 97% of patients of the control arm. In the overall population, the combined therapy decrease the risk of death by 13% (HR=0.87; 95%CI, 0.79-0.95; p=0.004) with fixed effect and by 19% (HR=0.81; 95%CI, 0.68-0.97; p=0.02) with random effect; significant heterogeneity was found. When analysis was limited to studies that required D2 lymphadenectomy a significant reduction of the risk of death was found in favor of combination CT (HR=0.86; 95%CI, 0.76-0.98; p=0.02). In the 3487 patients valuable for DFS, combination CT decreased the risk of relapse by 23% (HR=0.77; 95%CI, 0.70-0.84; p0.001) with fixed effect and by 27% (HR=0.73; 95%CI, 0.49-1.09; p=0.12) with random effect; significant heterogeneity was found.This analysis reported that adjuvant combination CT decreases the risk of death over single agent therapy in patients with non-metastatic GC.