Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study.

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.

Pancreatic cancer detection and characterization: state of the art and radiomics.

Pancreatic ductal adenocarcinoma (PDAC) represents a challenge for a multidisciplinary oncology team. Diagnosis of PDAC remains challenging due to overlapping imaging features with benign lesions, notwithstanding great advances with computed tomography (CT) and magnetic resonance imaging (MRI). The term "Radiomics" has recently been introduced to define a mathematical process to extract countless quantitative features from medical images (including each diagnostic technique) with high throughput computing for diagnosis and prediction. This article is an updated overview of the imaging techniques to be employed during detection and characterization of pancreatic cancer diagnostic workup. Particularly, the limitations and advantages of the different imaging techniques are discussed, with a particular focus on functional imaging. This overview is the result of a self-study without protocol and registration number. Articles published in the English language from January 2000 to January 2021 were included. We analyzed 15 papers on radiomics. The possibility of functional imaging, such as CT, MRI, and radiomics has revolutionized pancreatic imaging, improving the detection and characterization of the lesions and allowing a prognosis related to radiological features, favoring the process of personalized medicine.

Mixed cropping regimes promote the soil fungal community under zero tillage.

Fungi of yield soils represent a significant portion of the microbial biomass and reflect sensitivity to changes in the ecosystem. Our hypothesis was that crops included in cropping regimes under the zero tillage system modify the structure of the soil fungi community. Conventional and molecular techniques provide complementary information for the analysis of diversity of fungal species and successful information to accept our hypothesis. The composition of the fungal community varied according to different crops included in the cropping regimes. However, we detected other factors as sources of variation among them, season and sampling depth. The mixed cropping regimes including perennial pastures and one crop per year promote fungal diversity and species with potential benefit to soil and crop. The winter season and 0-5 cm depth gave the largest evenness and fungal diversity. Trichoderma aureoviride and Rhizopus stolonifer could be used for monitoring changes in soil under zero tillage.

Population pharmacokinetics of fluticasone propionate/salmeterol using two different dry powder inhalers.

The combination of fluticasone propionate (FLP) and salmeterol (SAL) is often used in clinical practice for the treatment of pulmonary disorders. The purpose of this study was to explore the pharmacokinetics (PK) of inhaled FLP and SAL, after concomitant administration, in healthy male and female subjects using two dry powder inhalers. Plasma concentration (C)-time (t) data were obtained from a single dose, two-sequence, two-period, crossover (2×2) bioequivalence (BE) study. Activated charcoal was co-administered in order to prohibit absorption from the gastrointestinal tract. A number of 60 subjects were recruited, while 57 of them completed the study and were included in the PK analysis. Initially, PK parameters of FLP and SAL were estimated using the classic non-compartmental methods. Subsequently, BE assessment was applied to the estimated PK parameters of the two dry powder inhalers. Special focus was placed on the population PK analysis of the C-t data, which were pooled together. 'Treatment' (i.e., test or reference) and 'period' of the BE study were considered as covariates. A variety of structural and residual error models were tested to find the one which best described the plasma C-t data of FLP and SAL. Demographic data were also evaluated for their impact on the PK parameters. Several goodness-of-fit criteria were utilized. The non-compartmental PK estimates of this study were in agreement with previously reported values. The population PK analysis showed that FLP data were described by a two-compartment model with first-order absorption and elimination kinetics. Body weight was found to affect significantly absorption rate constant, inter-compartmental clearance, and volume of distribution of the peripheral compartment. As body weight increases, the values of these PK parameters also rise. For SAL, the best results were obtained when a two-compartment disposition model was used assuming very rapid absorption kinetics (like intravenous bolus) and first-order elimination kinetics. Gender was found to be a significant covariate on clearance, with men exhibiting higher clearance than women.

Evaluation of leptin in breast milk, lactating mothers and their infants.

BACKGROUND/OBJECTIVES: Leptin is present in human milk, but it is not clear what the relationship between breast milk (BM) leptin levels and maternal and infant serum leptin concentrations is. The objective of this study was to evaluate the leptin concentration in BM and to investigate its relationship with infants' and mothers' anthropometric parameters and with serum leptin concentration in breast-fed (BF) infants and lactating mothers. SUBJECTS/METHODS: We enrolled 36 adequate for gestational age healthy, exclusively BF, term infants aged <6 months. Leptin concentration in serum and BM was determined by radioimmunoassay (RIA) test (human-leptin-RIA-sensitive, Mediagnost). Infants' and mothers' weights, lengths and body mass indexes (BMI) were measured. RESULTS: The median leptin concentration was 3.42 ng/ml (interquartile range (IR): 2.65) in BF infants' serum, 3.02 ng/ml (IR: 2.85) in mothers' serum (n=17) and 0.51 ng/ml (IR: 0.34) in BM (n=24). BM leptin concentrations were significantly lower than serum BF infant (P<0.001) and maternal (P<0.001) leptin levels. Infant serum leptin concentration correlated positively with infant weight (r=0.437, P=0.008) and BMI (r=0.561, P=0.004). Mother serum leptin levels correlated positively with weight (r=0.755, P<0.001) and BMI (r=0.661, P=0.007). No correlations were found between BM leptin and serum leptin concentrations in BF infants and mothers. CONCLUSIONS: We confirmed the presence of leptin in BM at a lower concentration than that found in infant and lactating mother serum. We observed a positive correlation between serum leptin levels in BF infants and their growth parameters.

The value of lung scintigraphy in the management of airways foreign bodies in children.

AIM: A retrospective analysis was made to evaluate our experience in the management of tracheobronchial foreign bodies (TFB) in children (age

Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab.

BACKGROUND: Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. PATIENTS AND METHODS: We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. RESULTS: The median follow-up was 35.3 months (95%CI 26.3-44); median overall survival was 56 months (95%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). CONCLUSION: CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting.

Short-term effect of domperidone on gastroesophageal reflux in newborns assessed by combined intraluminal impedance and pH monitoring.

OBJECTIVE: Neonatal gastroesophageal reflux (GER) is primarily due to a transient motility disorder and characterized by a prevalence of weakly acid refluxes. Drug management, where necessary, must set out to reduce the number of refluxes besides correct their acidity. Prokinetics could be of assistance in this respect, though the evidence in favor of their efficacy and safety is still far from sufficient. In this randomized controlled study, the action of domperidone, a prokinetic antidopaminergic drug with little effect on the central nervous system, was evaluated in newborns with symptomatic GER. STUDY DESIGN: Combined multichannel intraluminal impedance and pH measuring for 24 h was carried out in 13 newborns receiving 0.3 mg per kg domperidone per os at the eighth and the sixteenth hour, and 13 controls. Each newborn was compared to the control nearest in postconceptional age. RESULT: GER episodes per hour increased significantly compared to the baseline in the domperidone group (4.06+/-1.16 vs 2.8+/-1.42; P=0.001) and were shorter (16.68+/-4.49 vs 20.18+/-7.83 s; P=0.043), whereas there were no differences in the maximum proximal extent reached by the refluxes (3.37+/-0.45 vs 3.34+/-0.94 channels; P=0.894) and their pH (4.72+/-0.69 vs 4.60+/-1.17; P=0.634). CONCLUSION: This paradoxical increase in the number of GER episodes could be the expression of a domperidone-induced amplification of the motor incoordination of the neonatal gastroesophageal tract. Doubt is thus cast on the efficacy of prokinetics in this age bracket, especially in view of their adverse effects as described in the literature.

[Neonatal group B Streptococcus infection: an integrated approach (of clinical pathologists, gynecologists, midwives, pediatricians-neonatologists) of the functional area of Cuneo (Italy)]. / Infezione neonatale da Streptococco B: un approccio multidisciplinare integrato (di laboratoristi, ginecologi, ostetriche e pediatri-neonatologi) del Quadrante di Cuneo.

The frequency of early-onset neonatal sepsis without prophylaxis is 1-5/1.000 live births. Since year '70 the most frequent causative microorganism is the group B Streptococcus (S. agalactiae, GBS), followed by Escherichia coli. The mortality rate is now reduced to 4% due to the improvement of neonatal intensive care. In the USA, the incidence of GBS early-onset neonatal sepsis has been markedly reduced by the application of the guidelines released by the Centers for Disease Control (CDC). This strategy, however, is not effective on occurrence of late-onset neonatal group B streptococcal disease. In Italy, the application of CDC guidelines is not customary, and different, often complex, protocols of obstetrical-neonatological integrated approach are applied. The frequency of infectious risk has made the GBS a paramount problem for the neonatologist, even for the legal responsibility issues resulting from the multiplicity of possible options. To reach the best level of protection of the newborn against early-onset GBS infection, the working group of providers of prenatal, obstetric, and neonatal care of the functional area of Cuneo issued an integrated protocol, in order to perform the GBS screening with the optimal culture method suggested by CDC guidelines in the highest possible number of pregnant women, and to standardize the obstetrical and neonatal management.

Ghrelin, motilin, insulin concentration in healthy infants in the first months of life: relation to fasting time and anthropometry.

AIMS: This study aimed to investigate: (i) the relation between fasting time and serum ghrelin, motilin and insulin concentrations and (ii) the correlations between these hormones and anthropometrical parameters of infants in the first 18 months of life. PATIENT AND METHODS: A cross-sectional study on 62 term infants was performed. Blood samples for hormonal assay were obtained at least 1 h after feeding. Weight, length and head circumference were recorded. Plasma ghrelin, motilin and insulin concentrations were determined by radioimmunoassay. RESULTS: Ghrelin and motilin had a significant direct correlation with fasting time (r = 0.447; P < 0.001 and r = 0.36; P = 0.004, respectively). We observed a negative influence of insulin on ghrelin levels (beta = -0.32; P = 0.036). Plasma ghrelin levels correlated significantly with age (r = 0.45, P < 0.001), weight (r = 0.31, P = 0.013), head circumference (r = 0.35, P = 0.006) and length (r = 0.39, P = 0.001). A significant correlation emerged between motilin and age (r = 0.45, P < 0.001), weight (r = 0.43, P = 0.001), head circumference (r = 0.47, P < 0.001) and length (r = 0.48, P < 0.001). CONCLUSIONS: Fasting influence on serum ghrelin concentration confirms the role of this hormone as a physiological meal initiator also in infancy. The correlation between ghrelin, anthropometrical parameters and age supports the hypothesis that this hormone could exert an important influence on growth in the first months of life. Considering motilin, age and weight might play a role in determining its secretion; motilin could be considered one of the numerous factors involved in long-term regulation of energy balance.

Relationship between gastro-oesophageal reflux and gastric activity in newborns assessed by combined intraluminal impedance, pH metry and epigastric impedance.

The pathogenesis of gastro-oesophageal reflux disease (GORD) is complex and multifactorial. A motility disorder resulting from immaturity of the gastro-oesophageal tract may be involved. We have combined multichannel intraluminal impedance (MII) and pH monitoring with epigastric impedance (EGI) to evaluate the activity of this tract in neonates with suspected GORD. Multichannel intraluminal impedance, pH and EGI were followed for 3 h in 30 newborns displaying apparent life-threatening events and signs of GORD. Simultaneous application of MII and pH monitoring identifies reflux episodes and illustrates their duration, height and pH. Episodes detected by MII were placed on the EGI curve and the contemporaneous gastric filling state and emptying velocity were calculated. During the total measuring time, 248 reflux episodes were revealed. An inverse correlation was evident for reflux frequency and gastric emptying velocity (r2 = 0.94; P < 0.001), and between acid refluxes and the gastric filling state (r2 = 0.95; P < 0.001), whereas a positive correlation was found between the reflux level and the gastric filling state (r2 = 0.52; P < 0.05). Simultaneous MII, pH and EGI monitoring provided new information on the relationship between refluxes and gastric activity. Data suggest that gastric emptying patterns influence the frequency, level and pH of reflux episodes.

Serum ghrelin concentration and weight gain in healthy term infants in the first year of life.

OBJECTIVES: Ghrelin, a recently discovered hormone mainly secreted by the stomach, has several metabolic functions including regulation of food intake, energy homeostasis and body weight. There are few studies on this hormone in healthy infants during the first year of life. The aim of this study was to examine the correlations between ghrelin and weight gain in healthy term infants in the first year of life. METHODS: 104 healthy term infants aged 0 to 12 months were included in a cross-sectional study. Anthropometric measurements were assessed and mean weight gain was calculated. Serum ghrelin concentrations have been determined at least 3 hours after feeding by radioimmunoassay test. RESULTS: Ghrelin concentrations were correlated negatively to weight gain (r=-0.302; P=0.003) and positively to age (r = 0.412; P < 0.001), weight (r = 0.374; P < 0.001) and length (r=0.387; P<0.001). In breastfed infants a statistically significant negative correlation between ghrelin concentration and infant weight gain (r=-0.407; P=0.001) was observed, whereas in formula-fed infants this correlation was not statistically significant (r=-0.067; P=0.719). CONCLUSIONS: The negative correlation observed between ghrelin concentration and infant weight gain suggests that ghrelin might also play a role in the regulation of body weight in healthy infants with a physiologic energy balance. Further studies are needed to clarify how ghrelin might be involved in both short-term and long-term energy balance.

Targeting HER2 as a therapeutic strategy for breast cancer: a paradigmatic shift of drug development in oncology.

Targeted therapies are causing a dramatic change in cancer drug development. Trastuzumab, a humanized recombinant monoclonal antibody that recognizes the extracellular domain of HER2 trans-membrane protein, is among the first target-specific drugs that have been licensed for clinical use and its development represents a model of integration of new agents with classical treatment strategies. In preclinical models, trastuzumab has demonstrated a marked antiproliferative effect and a synergistic action with several chemotherapeutic agents. Monotherapy trials indicate that trastuzumab is active as a single agent in HER2 positive patients, is well tolerated, and is associated with preservation of quality of life (QoL). Furthermore, as first line therapy for metastatic breast cancer overexpressing HER2 receptor, the addition of trastuzumab to taxane-based chemotherapy significantly increased rate of objective response, time to disease progression and survival when compared with chemotherapy alone. Trastuzumab has shown important activity when used with many chemotherapeutic agents such as platinum salts, gemcitabine, vinorelbine and capecitabine and liposomal anthracyclines. Various trials are now ongoing to optimize the use of trastuzumab and to investigate its role in the adjuvant and in the neo-adjuvant setting.

Bacterial counts of intestinal Lactobacillus species in infants with colic.

Intestinal colonization by lactobacilli is suggested to be a prerequisite to normal mucosal immune functions. An inadequate level of lactobacilli may be involved in appearance of allergic disease of which, infantile colic, is often considered an early clinical manifestation. The aim of the study is to evaluate intestinal lactobacilli in breast-fed infants with infantile colic and healthy infants. Fifty-six breast-fed infants, aged 15-60 days were enrolled in the study and divided into two groups: colicky (30 cases) and healthy (26 cases) according to Wessel's criteria. Stool samples were collected, diluted and cultured on selective media. The colonies were counted, reported as colony forming unit (cfu) per gram of faeces and identified by biochemical methods. Different colonization patterns of lactobacilli were found among colicky and healthy infants. Lactobacillus brevis (4.34 x 10(8) cfu/g) and L. lactis lactis (2.51 x 10(7) cfu/g) were found only in colicky infants while L. acidophilus (2.41 x 10(7) cfu/g) was found only in healthy infants. Lactobacillus brevis and L. lactis lactis might be involved in the pathogenesis of infantile colic increasing meteorism and abdominal distension. Further studies are required to understand how the observed differences may be involved in the pathogenesis of this common disorder.

Breast-fed infants have higher leptin values than formula-fed infants in the first four months of life.

BACKGROUND: Leptin is a hormone present in breast milk, which regulates food intake and energy metabolism. AIM: To investigate whether leptin levels are different in breast-fed (BF) or formula-fed (FF) infants in the first months of life. METHODS: We evaluated serum leptin by radio-immunoassay and anthropometric parameters in 51 infants at the average age of 62.8+/-30 days, 25 exclusively BF and 26 exclusively FF. RESULTS: Leptin serum values were higher in BF (7.1+/-10.4 ng/ml) than in FF (3.7+/-3.87 ng/ml) infants (p <0.05). Leptin values were higher in females (6.9+/-9.87 ng/ml) than in males (3.5+/-3.88 ng/ml) (p <0.05). No differences were found in anthropometric measurements and body mass index. CONCLUSION: The kind of feeding might be a factor affecting serum leptin concentration in term infants. The long-term consequences of this difference between BF and FF infants and leptin's role in promoting obesity later in life are unknown.

Asymptomatic carriage of verocytotoxin-producing Escherichia coli O157 in farm workers in Northern Italy.

Faecal samples from 350 farm workers on 276 dairy farms and 50 abattoir employees from seven different operations were examined for the presence of Verocytotoxin-producing Escherichia coli 0157 (VTEC O157) by an O157-specific enzyme-linked fluorescent assay followed by immunoconcentration. VTEC O157 was isolated from four (1.1%) of the farm workers. A second stool sample was obtained from the positive farm workers as well as from their household contacts. VTEC O157 was isolated from the wife of one of them. The strains from the same household shared the same Verocytotoxin genes profile, phage type and pulsed-field gel electrophoresis pattern. The VTEC O157-positive subjects had neither intestinal symptoms at the moment of sampling nor a history of bloody diarrhoea or renal failure. Our study seems to confirm the hypothesis that farm residents often develop immunity to VTEC O157 infection, possibly due to recurrent exposure to less virulent strains of VTEC.

Intestinal microflora in breastfed colicky and non-colicky infants.

BACKGROUND: Infantile colics are a common problem in the first months of life. During this period, a process of intestinal colonization rapidly occurs. A difference in the gut microflora could play an important role in the pathogenesis of colics, changing the metabolism of carbohydrates and fatty acids. Actually, in the literature, only few data have been collected about this topic. In this study, we evaluated intestinal microflora in breastfed colicky and non-colicky infants. METHODS: Seventy-one breastfed infants, aged 3.2 +/- 0.6 wk, free from episodes of gastroenteritis and without previous assumption of antibiotic and probiotic drugs, were enrolled in the study. They were divided into two groups: colicky (42 cases) and non-colicky (29 cases), according to Wessel's criteria. Stool samples were collected, diluted and cultured on several selective media to detect lactobacilli, clostridia, gram-negative anaerobes and Enterobacteriaceae. Statistical analysis was performed using Student's t-test, chi2 test and a non-parametric test (Mann-Whitney U-test). RESULTS: Differences in gut microflora were found among colicky and non-colicky infants: colicky infants were less frequently colonized by Lactobacillus spp., and more frequently by anaerobic gram-negative bacteria. CONCLUSION: Our study indicates that colicky infants have different patterns of gut microflora. Further studies are required to understand whether gut microflora is the primary cause of colics or its consequence.