Late toxicities burden in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib.

PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described. METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62). CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

How to incorporate left atrial strain in the diagnostic algorithm of left ventricular diastolic dysfunction.

The combination of early trans-mitral inflow and mitral annular tissue Doppler velocities (E/e' ratio) is widely applied to noninvasively estimate left ventricular (LV) filling pressures. However, when E/e' is between 8 and 14 its accuracy decreases substantially. Left atrial (LA) deformation analysis by speckle tracking echocardiography was recently proposed as an alternative approach to estimate LV filling pressures, but its role when E/e' is between 8 and 14 has been under-investigated. We aimed to assess whether LA strain could help to identify elevated filling pressures in patients with E/e' between 8 and 14. Among consecutive non-selected patients who underwent a comprehensive echocardiographic evaluation, we enrolled those with E/e' ratio > 8 and ≤ 14. Exclusion criteria were: organic mitral valve disease or mitral surgery; presence of mitral regurgitation greater than moderate in severity; diseases associated with pre-capillary pulmonary hypertension; and undetectable systolic pulmonary artery pressure (PAP-S). Peak LA longitudinal (PALS) and contraction strain (PACS) values was obtained by averaging all segments, and by separately averaging segments measured in the 4-chamber and 2-chamber views. Seventy-six patients had E/e' > 8 and ≤ 14 and formed the study cohort. Mean age 69 ± 12 years, LV ejection fraction (LVEF) 54.5 ± 11.2%, mean E/e' 11.2 ± 1.9, PAP-S 33 ± 7 mmHg, PALS 31.6 ± 11.7%. PALS was significantly associated to PAP-S after adjustment for LVEF, E/e', septal LV longitudinal shortening velocity (s'), LA volume indexed (p = 0.002) and also for ASE/EACVI diastolic dysfunction classification (p = 0.0002). Furthermore, PALS but not ASE/EACVI diastolic dysfunction grading, resulted independently associated to New York Heart Association (NYHA) class (p = 0.0004). PALS is able to predict increased intra-cardiac pressure and NYHA class in patients characterized by E/e' between 8 and 14. Therefore, we propose that PALS might be incorporated in a simplified diagnostic algorithm based on E/e' classes.

Estimated peak systolic pulmonary artery pressure in young non-complicated patients with type 1 diabetes.

OBJECTIVE: Right ventricle and pulmonary artery pressure have always received less attention in type 1 diabetes than left ventricle. The aim of this study is to compare the right heart performance and the estimated peak systolic pulmonary artery pressure (EPSPAP) in young type 1 diabetes patients with healthy controls. PATIENTS AND METHODS: Subjects affected by type 1 diabetes without cardiovascular and respiratory diseases (n=93) and healthy controls (n=56) were evaluated with a comprehensive transthoracic echocardiography. The pulmonary peak systolic arterial pressure was calculated with an established formula based on pulmonary artery acceleration time. RESULTS: The left ventricle's function was found to be normal in all the subjects under study. The estimated peak systolic pulmonary artery pressure was significantly higher in patients with type 1 diabetes compared to the controls (38.5 ± 8.6 vs. 35.4 ± 6.7, p = 0.019). The highest value of EPSPAP was observed in smoking female patients with type 1 diabetes. Basal and mid cavity diameter of the right ventricle were higher in patients with type 1 diabetes. Factors associated with EPSPAP were sex, body mass index, mid cavity diameter and, with an inverse correlation, HDL-cholesterol. CONCLUSIONS: The present study suggests that young, uncomplicated patients with type 1 diabetes have a higher estimated peak systolic pulmonary artery pressure. Further studies are needed to define the mechanisms underlying this alteration and its clinical consequences.

Diagnostic and therapeutic role of laparoscopy in perforated peptic ulcer in the elderly patients.

AIM: The purpose of this study is to analyze the outcome of elderly patients with perforated peptic ulcer comparing laparoscopic treatment versus open approach. METHODS: In our General and Emergency Surgery Unit in the last 3 years, 20 elderly patients with perforated peptic ulcer were performed. We considered elderly all patients over the age of 65 years (10 females and 10 males; the mean age was 75 years). 16 patients (80%) were submitted to laparoscopic repair with omentoplasty and 4 (20%) to open repair. The patients were classified using the Boye's score which influenced the choice of surgical treatment and the outcoEmergency Romame. The two groups were compared in terms of operative surgery times, complication rate, mortality and postoperative outcomes. DISCUSSION: Perforated peptic ulcer is a common abdominal disease that is treated by surgery. The potential advantages of laparoscopy, both in terms of diagnosis and therapy, are clear and the major advantages may be observed in cases with peritonitis secondary as a perforated peptic ulcer where laparoscopy allows the confirmation of the diagnosis, the identification of the position of the ulcer and the repair. With the age the risks of comorbidities increases multidisease syndrome. Elderly patients suffer from frailty syndrome. All these factors make the elderly patient a major challenge for a laparoscopy treatment. CONCLUSION: The laparoscopic approach is an effective method for treatment of perforated peptic ulcer in the elderly with a great diagnostic and therapeutic role. Nowadays more prospective randomized studies are needed to evaluate the effectiveness of laparoscopic versus open repair.

Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

Postbiotics produced at laboratory and industrial level as potential functional food ingredients with the capacity to protect mice against Salmonella infection.

AIM: To determine the protective capacity against Salmonella infection in mice of the cell-free fraction (postbiotic) of fermented milk, produced at laboratory and industrial level. METHODS AND RESULTS: The proteolytic activity (PA) of 5 commercial cultures and 11 autochthonous Lactobacillus strains was evaluated. The DSM-100H culture displayed the highest PA and it was selected for further studies. The capacity of the postbiotics produced by pH-controlled fermentation to stimulate the production of secretory IgA in faeces and to protect mice against Salmonella infection was evaluated. A significant increase in secretory IgA in faeces of mice fed 14 days the postbiotic obtained at the laboratory (F36) was detected compared to control animals. A significantly higher survival was observed in mice fed the F36 and the FiSD (industrial product) compared to controls. CONCLUSION: The postbiotics obtained showed immunomodulatory and protective capacity against Salmonella infection in mice. SIGNIFICANCE AND IMPACT OF THE STUDY: The pH-controlled milk fermentation by the proteolytic DSM-100H culture could be a suitable strategy to obtain a food ingredient to be added to a given food matrix, not adequate to host viable cells of probiotics, to confer it enhanced functionality and thus expand the functional food market.

Increased aortic stiffness index in patients with type 1 diabetes without cardiovascular disease compared to controls.

PURPOSE: Increased arterial stiffness is an early sign of endothelial dysfunction. Nevertheless, measures of the elastic properties of the aortic root in patients with type 1 diabetes are still lacking. The aim of this study was to compare aortic root stiffness index in type 1 diabetes and healthy controls. METHODS: Ninety-three patients with type 1 diabetes without cardiovascular diseases were recruited and compared to 33 healthy controls. Aortic root elastic properties were estimated by measuring the systolic and diastolic diameters on M-mode acquisition. RESULTS: None of the subjects showed alterations of either systolic or diastolic echocardiographic parameters. Patients with type 1 diabetes had a very low prevalence of chronic complications and their metabolic control was good. Significantly increased aortic stiffness index was found in type 1 diabetes compared to controls, and the same different pattern was found in men and women. The presence of type 1 diabetes and increased pulse pressure was significantly associated with aortic stiffness index in a multivariate linear analysis. CONCLUSION: This study strongly suggests that patients with type 1 diabetes develop aortic root stiffness in the absence of cardiovascular diseases. This alteration may be part of a more generalized arterial dysfunction in type 1 diabetes.

Adjuvant androgen deprivation therapy for poor-risk, androgen receptor-positive salivary duct carcinoma.

AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.

Transcriptomic and genomic structural variation analyses on grape cultivars reveal new insights into the genotype-dependent responses to water stress.

Grapevine (Vitis vinifera L.) is importantly cultivated worldwide for table grape and wine production. Its cultivation requires irrigation supply, especially in arid and semiarid areas. Water deficiency can affect berry and wine quality mostly depending on the extent of plant perceived stress, which is a cultivar-specific trait. We tested the physiological and molecular responses to water deficiency of two table grape cultivars, Italia and Autumn royal, and we highlighted their different adaptation. Microarray analyses revealed that Autumn royal reacts involving only 29 genes, related to plant stress response and ABA/hormone signal transduction, to modulate the response to water deficit. Instead, cultivar Italia orchestrates a very broad response (we found 1037 differentially expressed genes) that modifies the cell wall organization, carbohydrate metabolism, response to reactive oxygen species, hormones and osmotic stress. For the first time, we integrated transcriptomic data with cultivar-specific genomics and found that ABA-perception and -signalling are key factors mediating the varietal-specific behaviour of the early response to drought. We were thus able to isolate candidate genes for the genotype-dependent response to drought. These insights will allow the identification of reliable plant stress indicators and the definition of sustainable cultivar-specific protocols for water management.

Role of transanal irrigation in the treatment of anterior resection syndrome.

BACKGROUND: Transanal irrigation(TAI) has been reported to be an inexpensive and effective treatment for low anterior resection syndrome(LARS). The aim of the present prospective study was to evaluate the use of TAI in patients with significant LARS symptoms at a single medical center. METHODS: Patients who had low anterior resection for rectal cancer between April 2015 and May 2016 at the Careggi University Hospital were assessed for LARS using the LARS and the Memorial Sloan-Kettering Cancer Center Bowel Function Instrument (MSKCC BFI) questionnaires 30-40 days after  surgery or ileostomy closure (if this was done). Quality of life was evaluated using a visual analog scale and the Short Form-36 Health Survey. All patients with LARS score of 30 or higher were included (early LARS) as were all patients with a LARS score of 30 or higher referred 6 months or longer after surgery performed elsewhere (chronic LARS) in the same study period. Study participants were trained to perform TAI using the Peristeen™ System for 6 months, followed by 3 months of enema therapy following a similar protocol. RESULTS: Thirty-three patients were enrolled in the study. Six patients stopped the treatment. The 27 patients (19 early LARS and 8 chronic LARS) who completed the study had a significant decrease in the number of median daily bowel movements [baseline 7 (range 0-14); 6 months 1 (range 0-4); 9 months 4 (range 0-13)]. The median LARS Score fell from 35.1 (range 30-42) (baseline) to 12.2 (range 0-21) after 6 months (p < 0.0001) and then rose to 27 (range 5-39) after 3 months of enema therapy. There was no difference in LARS score decrease at 6 months between the patients with early and chronic LARS (22.5 and 23.9 respectively; p=0.7) and there were no predictors of score decrease. Four components of the SF-36 significantly improved during the TAI period. The MSKCC BFI score significantly improved in several domains. Twenty-three patients (85%) asked to continue the treatment with TAI after the study ended. CONCLUSIONS: TAI appears to be an effective treatment for LARS and results in a marked improvement of continence and quality of life.  Patients may be assessed and treated for LARS early after surgery since the treatment benefit is similar to that observed in patients with LARS diagnosed  6 months or longer after surgery. The potential rehabilitative role of TAI for LARS is promising and should be further investigated.

Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.

BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients.

Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.

TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial.

BACKGROUND: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. METHODS: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. RESULTS: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. CONCLUSIONS: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin.

BACKGROUND: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive ≥2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. RESULTS: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P = 0.048) and HNC patients (P = 0.038). CONCLUSIONS: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation.

Involvement of cell surface TG2 in the aggregation of K562 cells triggered by gluten.

Gluten-induced aggregation of K562 cells represents an in vitro model reproducing the early steps occurring in the small bowel of celiac patients exposed to gliadin. Despite the clear involvement of TG2 in the activation of the antigen-presenting cells, it is not yet clear in which compartment it occurs. Herein we study the calcium-dependent aggregation of these cells, using either cell-permeable or cell-impermeable TG2 inhibitors. Gluten induces efficient aggregation when calcium is absent in the extracellular environment, while TG2 inhibitors do not restore the full aggregating potential of gluten in the presence of calcium. These findings suggest that TG2 activity is not essential in the cellular aggregation mechanism. We demonstrate that gluten contacts the cells and provokes their aggregation through a mechanism involving the A-gliadin peptide 31-43. This peptide also activates the cell surface associated extracellular TG2 in the absence of calcium. Using a bioinformatics approach, we identify the possible docking sites of this peptide on the open and closed TG2 structures. Peptide docks with the closed TG2 structure near to the GTP/GDP site, by establishing molecular interactions with the same amino acids involved in stabilization of GTP binding. We suggest that it may occur through the displacement of GTP, switching the TG2 structure from the closed to the active open conformation. Furthermore, docking analysis shows peptide binding with the ß-sandwich domain of the closed TG2 structure, suggesting that this region could be responsible for the different aggregating effects of gluten shown in the presence or absence of calcium. We deduce from these data a possible mechanism of action by which gluten makes contact with the cell surface, which could have possible implications in the celiac disease onset.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

The molecular characterization by SSRs reveals a new South Italian kinship and the origin of the cultivar Uva di Troia.

Vitis vinifera L. varieties were spread through cuttings following historic migrations of people, trades, or after biological crises due to pests outbreaks. Some today's varieties could be more than a 1000 years old and, although over the centuries these varieties generated most of the remaining cultivars, their origin could be impossible to track back. The Italian grapevine biodiversity is one of most important, most likely due to its strategic position in the middle of the Mediterranean sea. Unravelling of its structure is challenging because of its complexity and the lack of historical documentation. In this paper molecular data are compared with historical documentations. Simple Sequence Repeats fingerprinting are molecular markers best suited to investigate genetic relationships and identify pedigrees. South-Italian germplasm was studied with 54 nuclear microsatellites. A family was identified, consisting of two parents and three siblings and further genetically characterized with six nuclear and five chloroplast microsatellites and described with ampelographic and phylometric analysis. Although these latter were not informative for the kinship identification. The common Bombino bianco was the female parent and the previously unknown Uva rosa antica was the male parent. Bombino nero, Impigno and the popular Uva di Troia, all typical of the south-east Italy, were the offspring. Further research showed that the Uva rosa antica was a synonym of Quagliano and Bouteillan noir, both minor varieties. Quagliano was considered to be autochthonous of some alpine valleys in the north-west of Italy and Bouteillan noir is a neglected variety of Vancluse in France. This finding uncovers the intricate nature of Italian grape cultivars, considered peculiar of an area, but possibly being the remains of ancient latin founding varieties. Consequently, intriguing new hypotheses are discussed and some conclusions are drawn, based on the peculiar geographical origin of the parents, on the distribution of the offspring, on the chance of a single, and perhaps intentional, crossing event.

Plasmin and coagulant activities in a minicurd model system: Study of technological parameters.

The effect of scalding temperature of the curd, the inclusion of a washing step, and the pH at whey drainage on plasmin and coagulant activities were assessed in a minicurd model of young hard cooked cheese. The variables were tested as follows: draining pH was assayed at 3 levels (4.6, 5.6, and 6.4), curd scalding temperature was tested at 50 and 56°C, and washing of the curd was examined at 2 levels (no washing step, and the replacement of the whey by water). Increase in pH at whey drainage and washing of the curd had a positive effect on plasmin activity, which was also evidenced by compatible changes in soluble peptide profiles. No effect of increased cooking temperature was found on plasmin activity. Plasminogen activation was not verified in any treatment. As for coagulant, lower pH values at whey drainage and a decrease in curd cooking temperature increased its activity; washing of the curd showed no influence on coagulant residual activity. These results were consistent with proteolysis described by peptide profiles, electrophoresis, and soluble nitrogen fractions.