Predicting response to cancer immunotherapy using noninvasive radiomic biomarkers.

INTRODUCTION: Immunotherapy is regarded as one of the major breakthroughs in cancer treatment. Despite its success, only a subset of patients responds-urging the quest for predictive biomarkers. We hypothesize that artificial intelligence (AI) algorithms can automatically quantify radiographic characteristics that are related to and may therefore act as noninvasive radiomic biomarkers for immunotherapy response. PATIENTS AND METHODS: In this study, we analyzed 1055 primary and metastatic lesions from 203 patients with advanced melanoma and non-small-cell lung cancer (NSCLC) undergoing anti-PD1 therapy. We carried out an AI-based characterization of each lesion on the pretreatment contrast-enhanced CT imaging data to develop and validate a noninvasive machine learning biomarker capable of distinguishing between immunotherapy responding and nonresponding. To define the biological basis of the radiographic biomarker, we carried out gene set enrichment analysis in an independent dataset of 262 NSCLC patients. RESULTS: The biomarker reached significant performance on NSCLC lesions (up to 0.83 AUC, P < 0.001) and borderline significant for melanoma lymph nodes (0.64 AUC, P = 0.05). Combining these lesion-wide predictions on a patient level, immunotherapy response could be predicted with an AUC of up to 0.76 for both cancer types (P < 0.001), resulting in a 1-year survival difference of 24% (P = 0.02). We found highly significant associations with pathways involved in mitosis, indicating a relationship between increased proliferative potential and preferential response to immunotherapy. CONCLUSIONS: These results indicate that radiographic characteristics of lesions on standard-of-care imaging may function as noninvasive biomarkers for response to immunotherapy, and may show utility for improved patient stratification in both neoadjuvant and palliative settings.

Germination and extrusion as combined processes for reducing phytates and increasing phenolics content and antioxidant capacity of Oryza sativa L. whole grain flours.

Whole rice (WR) products with low phytic acid (PA) content and enhanced bio-functional components were obtained by the combination of germination and extrusion processes. Germination conditions (24 h - 35 °C), with a previous soaking process (24 h - 20 °C), were chosen according to the remnant PA content and germination rate. Specific mechanical energy consumption, expansion, sensorial and mechanical hardness, specific volume, solubility, water absorption, free phenolic content (FPC) and antioxidant capacity were evaluated. Results indicated that 175 °C and 14 g 100 g(-1) of moisture were the most appropriate conditions to obtain expanded products and precooked flours based on germinated WR. Selected extruded product presented less PA content (821.6 9 ± 10.3 versus 695.2 0 ± 1.6 mg 100 g(-1)) and higher Fe bio-accessibility, FPC (45.2 9 ± 1.61 versus 66.3 5 ± 3.35 mg GAE g(-1)) and antioxidant capacity compared with WR (34.9 5 ± 0.8 versus 54.6 3 ± 1.6 µmol trolox g(-1)). Combining germination-extrusion processes could be a strategy to obtain expanded products or precooked flours based on WR with enhanced health benefits.

Xanthan gum and pectin as beverage stabilizers reduce the digestive enzyme hydrolysis of antioxidant and antihypertensive peptides obtained from a brewery byproduct.

An acidic beverage was formulated with xanthan gum (XG), pectin (P) and brewer spent grain (BSG) peptides with antioxidant and antihypertensive properties. The impact of hydrocolloids levels on peptide bioaccessibility was studied. Peptides were obtained from BSG using Purazyme and Flavourzyme enzymes. BSG peptides were fractionated by ultrafiltration (UF) and four fractions were obtained: F1 (>10 kDa), F2 (10-5 kDa), F3 (1-5 kDa), and F4 (<1 kDa). F3 showed the highest protein purity, ferulic acid content, proportion of amphipathic peptides, and bioactive properties (ABTS+ radical scavenging and ACE-I inhibitory activity). The identified peptides from F3 by tandem mass spectrometry were 138. In silico analysis showed that 26 identified peptides had ABTS+ inhibitory activity, while 59 ones presented good antihypertensive properties. The effect of XG and P levels on bioaccessibility of F3 peptides in the formulated beverages was studied by a central composite experimental design. It was observed that F3 peptides interacted with hydrocolloids by electrostatic forces at pH of formulated beverages. The addition of hydrocolloids to formulation modulated the release of the antioxidant peptides and protected the degradation of ACE-I inhibitory peptides from F3 during simulated gastrointestinal digestion. Finally, the level of hydrocolloids that produced intermediate viscosities in the formulated beverages improved the bioaccessibility of the F3 peptides.

Thread shape factor: evaluation of three different orthodontic miniscrews stability.

The thread shape factor (TSF) to evaluate the relationships between geometrical characteristics and mechanical properties of the temporary anchorage devices (TADs) has recently been introduced. This in vitro experimental study evaluated in 30 different tests with three TADs: ORTHOImplant (1.8 mm diameter and 10 mm length; 3M Unitek), Tomas (1.6 mm diameter and 10 mm length; Dentaurum), and Orthoeasy (1.7 mm diameter and 10 mm length; Forestadent). Scanning electron microscopy images were acquired for each TAD to measure the TSF; afterwards, the maximum insertion torque (MIT) was evaluated and thereafter pull-out tests on two differently designed organic bone analogs were carried out using a testing machine with a crosshead speed of 2 mm/minute being applied. One-way analysis of variance with group as factor was performed. Post hoc multiple comparisons Bonferroni test was used. Rank-transformed data were used when asymmetry of data was shown. To assess correlation between characteristics, load, and MIT, Spearman's rank correlation coefficient was used. A P-value of 0.05 was considered statistically significant. Significant direct correlations were found between TSF and depth and both load and MIT. Particularly, a correlation of 0.90 (P < 0.001) was found between depth and MIT for 2.2 mm cortical thickness. The authors conclude that MIT and maximum load values of pull-out test are statistically related to depth of the thread of the screw and to TSF.

Torque changes of anchorage units in preadolescent patients treated with a digitally designed tooth-borne expander anchored to deciduous vs. permanent molars.

AIM: To compare the effects on permanent or deciduous anchorage dental units in patients treated with a digitally designed palatal expander. METHODS: Inclusion criteria were the following: presence of maxillary transverse deficiency, no previous orthodontic treatment, no extractions, absence of agenesis, congenital pathologies and cranio-maxillofacial malformations. Twenty patients (11 males, 9 females, 11 ± 1.8 years) received a digitally designed and metal printed palatal expander anchored on first permanent molars and 1 activation per day for 30 days (Group 1). Twenty-one patients (12 males, 9 females, 8.6 ± 1.4 years) received a digitally designed and metal printed palatal expander anchored on second deciduous molars and 2 activations per day for 14 days (Group 2). Digital intraoral scans were taken before expansion and after device removal, and torque and the palatal transverse diameter were digitally measured. The FDI notation was used to indicate each tooth CONCLUSION: Less dental torque augmentation was produced in Group 2. RESULTS: Significant intragroup differences over time were found in Group 1 considering the torque of teeth 1.6, 1.4, 1.3, 2.1, 2.4, 2.5, 2.6. Significant differences between groups were found regarding the longitudinal change in torque of teeth 1.5, 2.4 and 2.5. Significant intragroup differences over time were found in both groups considering all transverse diameter parameters. No significant differences were found between groups in the transverse diameter modifications over time. CONCLUSION: Less dental torque augmentation was produced in Group 2.

Prescriptive behavior of non-vitamin K oral anticoagulants in patients affected by atrial fibrillation in general practice.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and in recent years the pharmacological approach has been strongly implemented; in Italy, the prescription of the non-vitamin K oral anticoagulants (NOAC) was also extended to General Practitioners (GPs) since 2020. The aim of the present study was to investigate the GPs prescribing behaviour of NOACs. An observational study was performed by using the computerized medical record of 14 GPs in Sicily: patients affected by AF were selected and stratified according to the prescribed antithrombotic drugs. Patients were considered inadequately managed if antithrombotic treatment was not adherent to recent ESC guidelines. A total of 467 (2.7 %) patients were affected by AF, 276 (59.1 %) were treated with an oral anticoagulant (OAC) regardless the high stroke risk (OR 1.64; 95 %CI 0.74-3.62; p = 0.226). The NOAC users were 236 patients as follow: Rivaroxaban 33.5 %, Apixaban 33,1 %, Dabigatran 17,4 %, Edoxaban 16.1 %. In 7 patients an inappropriate NOAC treatment was observed. Among Vitamin-K antagonist users, 25.0 % were considered inappropriate. Patients not treated with OAC were 191, of them 81.7 % were at high stroke risk and did not receive any OAC despite the indication to treat. In addition, the probability to be not properly managed significantly increased in older and in patients with atherosclerosis. Conversely, patients with at least one reported cardiology counselling significantly reduced the likelihood to be not properly managed (OR 0.38, 95 %CI 0.25-0.58; p 0.01). Our results suggest the need to optimize the management of real-life AF patients by improving prescribing adherence to ESC guidelines.

Parboiling of sorghum grains as a strategy to improve endosperm yield and mineral content of refined flours.

The aims were (i) to optimize the parboiling/decorticating process by assessing the effects of parboiling soaking temperature (60-80 ℃) and pearling time (4-6 min and 5.5-9.5 min for red and white sorghum) on endosperm yield and ash content, to obtain pregelatinized refined flours from parboiling sorghum (RF-PS) and (ii) to evaluate the final content of selected nutrients in RF-PS obtained in these optimal conditions. Endosperm yield decreased with the increase of pearling time, and a maximum around 70 ℃ soaking temperature was observed. Ash content decreased with increasing soaking temperature and pearling time. The optimal conditions of soaking temperature-pearling time were 73.3 ℃-4.8 min for red sorghum and 67.9 ℃-8.6 min for white sorghum, considering maximum endosperm yield and ash content lower than 0.65 g/100 g. In RF-PS obtained under optimal conditions, protein, lipid, Cu, and free polyphenols were higher in red sorghum than white sorghum (10.16 ± 0.62 vs. 9.42 ± 0.61 g/100 g, 0.89 ± 0.16 vs. 0.62 ± 0.11 g/100 g, 2.08 ± 0.21 vs. 1.88 ± 0.20 mg/kg, 79.51 ± 14.51 vs. 63.82 ± 4.33 mg/100 g). Fe, Zn, Ca, and Na were higher in white sorghum than red sorghum (20.61 ± 2.92 vs. 17.56 ± 0.98 mg/kg, 11.94 ± 0.84 vs. 9.58 ± 1.65 mg/kg, 87.45 ± 12.91 vs. 75.31 ± 12.57 mg/kg, 129.62 ± 9.03 vs. 102.69 ± 28.34 mg/kg). No difference was observed in the contents of ash, Mg, and K. It was possible to improve endosperm yield using a parboiling process prior to decortication. In addition, this process contributes to increase the mineral content in RF-PS.

Distal femoral hemiepiphysiodesis using screw and non-absorbable filament for the treatment of idiopathic genu valgum. Preliminary results of 12 knees.

INTRODUCTION: Different techniques for gradual correction of angular deformities of lower limbs exist. Screws and nonabsorbable filament has been described as an effective alternative for transitory hemiepiphysiodesis in New Zealand rabbits. HYPOTHESIS: Hemiepiphysiodesis using screws and non-absorbable filament is effective in pediatric population, for correction of genu valgum. METHODS: Retrospective evaluation, 12 knees in 6 patients younger than 15 years (3 female), operated because of genu valgum. An anchoring system with two 4.0mm cancellous screw with metal washer joined by FiberWire #2.0 filament. Initial and final intermalleolar distance (IMD) and mechanical lateral distal femoral angle were compared, recording complications. Mann-Whitney test was used for statistics, with significance value <0.05. RESULTS: All patients achieved the expected correction. IMD and mLDFA were significatively improved. Only one patient presents a minor perioperative complication. DISCUSSION: Lateral distal femoral hemiepiphysiodesis with screws and nonabsorbable filament resulted to be an effective alternative for genu valgum gradual correction in pediatric population. This is the first article that proposes this model, as an efficient and simple alternative for the treatment of genu valgum in pediatric patients. LEVEL OF EVIDENCE: Retrospective study, Level IV.

Nutritional improvement of corn pasta-like product with broad bean (Vicia faba) and quinoa (Chenopodium quinoa).

In this study, the nutritional quality of pasta-like product (spaghetti-type), made with corn (Zea mays) flour enriched with 30% broad bean (Vicia faba) flour and 20% of quinoa (Chenopodium quinoa) flour, was determined. Proximate chemical composition and iron, zinc and dietary fiber were determined. A biological assay was performed to assess the protein value using net protein utilization (NPU), true digestibility (TD) and protein digestibility-corrected amino acid score (PDCAAS). Iron and zinc availability were estimated by measuring dialyzable mineral fraction (%Da) resulting from in vitro gastrointestinal digestion. Nutritionally improved, gluten-free spaghetti (NIS) showed significantly increased NPU and decreased TD compared with a non-enriched control sample. One NIS-portion supplied 10-20% of recommended fiber daily intake. Addition of quinoa flour had a positive effect on the FeDa% as did broad bean flour on ZnDa%. EDTA increased Fe- and ZnDa% in all NIS-products, but it also impaired sensorial quality.

Chemical breakdown of technetium-99m DTPA during nebulization.

Aerosols of 99mTc diethylenetriaminepentaacetic acid ([99mTc]DTPA) used for measuring lung permeability and lung ventilation require a radioaerosol delivery system to produce an aerosol with reproducible size and radiochemical purity. To test how well nebulizers meet this requirement, radiochemical purity of aerosols produced with a jet and an ultrasonic nebulizer was evaluated. The activity median aerodynamic diameter (AMAD) and geometric standard deviation (sigma g) of radioaerosols were 0.46 micron (sigma g = 1.6) for the jet nebulizer and 0.70 micron (sigma g = 1.7) for the ultrasonic nebulizer. Paper and liquid chromatographic assays were obtained on the [99mTc]DTPA aerosol solute produced with each nebulizer. The results of these tests showed major differences in radiochemical purity. Aerosols produced in the jet nebulizer consistently showed greater than 90% of the radioactivity bound to the DTPA ligand whereas aerosols produced in the ultrasonic nebulizer showed less than 10% of the radioactivity bound to DTPA. The results support the need to test radiochemical purity of aerosols before using an aerosol nebulizer for pulmonary imaging and clearance studies.

Mechanisms involved in the beta-cell mass increase induced by chronic sucrose feeding to normal rats.

The aim of the present study was to clarify the mechanisms by which a sucrose-rich diet (SRD) produces an increase in the pancreatic beta-cell mass in the rat. Normal Wistar rats were fed for 30 weeks either an SRD (SRD rats; 63% wt/wt), or the same diet but with starch instead of sucrose in the same proportion (CD rats). We studied body weight, serum glucose and triacylglycerol levels, endocrine tissue and beta-cell mass, beta-cell replication rate (proliferating cell nuclear antigen; PCNA), islet neogenesis (cytokeratin immunostaining) and beta-cell apoptosis (propidium iodide). Body weight (g) recorded in the SRD rats was significantly (P<0.05) larger than that of the CD group (556.0+/-8.3 vs 470.0+/-13.1). Both serum glucose and triacylglycerol levels (mmol/l) were also significantly higher (P<0.05) in SRD than in CD rats (serum glucose, 8.11+/-0.14 vs 6.62+/-0.17; triacylglycerol, 1.57+/-0.18 vs 0.47+/-0.04). The number of pancreatic islets per unit area increased significantly (P<0.05) in SRD rats (3.29+/-0.1 vs 2.01+/-0.2). A significant increment (2.6 times) in the mass of endocrine tissue was detected in SRD animals, mainly due to an increase in the beta-cell mass (P=0.0025). The islet cell replication rate, measured as the percentage of PCNA-labelled beta cells increased 6.8 times in SRD rats (P<0.03). The number of apoptotic cells in the endocrine pancreas decreased significantly (three times) in the SRD animals (P=0.03). The cytokeratin-positive area did not show significant differences between CD and SRD rats. The increase of beta-cell mass induced by SRD was accomplished by an enhanced replication of beta cells together with a decrease in the rate of beta-cell apoptosis, without any evident participation of islet neogenesis. This pancreatic reaction was unable to maintain serum glucose levels of these rats at the level measured in CD animals.

Long-term administration of a sucrose-rich diet to normal rats: relationship between metabolic and hormonal profiles and morphological changes in the endocrine pancreas.

The aim of the present investigation was to study normal rats fed a sucrose-rich diet (SRD) for a prolonged period (up to 30 weeks) (1) to obtain additional data on the hormonal and metabolic patterns induced by this treatment and (2) to provide information on changes taking place in the pancreatic islet cell populations. We found that long-term feeding with a SRD resulted in a steady state of hypertriglyceridemia and hyperglycemia in which insulin levels remained unchanged and unable to compensate for the increased demands of the developing metabolic changes. The endocrine pancreas showed a significant increase of both islet number and B-cell area, as well as changes in the profile of islet cell distribution. However, these changes were not accompanied by an increase in the pancreatic content of immunoreactive insulin (IRI). It may therefore be postulated that the newly emerged B-cell mass has some sort of derangement with the increased insulin demand resulting from insulin resistance induced by the long-term SRD feeding. Thus, feeding a SRD to normal rats may prove to be an attractive animal model for studying the role of environmental nutritional factors in the unsettled issue of the relationship between insulin resistance and relative insulin deficiency. The model might provide key information for understanding the pathophysiology of human diseases such as type II diabetes, dyslipidemia, and a number of entities included in so-called syndrome X.

Erythromycin facilitates postpyloric placement of nasoduodenal feeding tubes in intensive care unit patients: randomized, double-blinded, placebo-controlled trial.

BACKGROUND: To determine whether administration of erythromycin (E) could facilitate passage of a nasoenteric feeding tube into the duodenum for postpyloric feedings, this randomized, double-blind, placebo-controlled trial was performed. METHODS: Fifty-seven patients were accrued from the surgical intensive care units (ICUs) of a tertiary-care university hospital. Patients enrolled were categorized as to the presence or absence of diabetes mellitus (DM). Those patients without DM were then subdivided into those with normal or depressed mental status. The three groups, normal (NMS), depressed mental status (DMS), or diabetes mellitus (DM), were then randomized independently to receive either E or placebo (P), followed by blind placement of a feeding tube. Tube placement was verified by an abdominal radiograph. RESULTS: Overall, the rate of postpyloric placement was 61% (19/31) in the E group, significantly better than 35% (9/26) in the P group (p < .05). In patients with NMS, the success rate with E was improved (64%, 9/14) compared with that with P (9%, 1/11) (p < .0005). In the DMS group, there was a 50% success rate (6/12) with E versus 63% (5/8) with P (not significant [NS]). In the DM group, 80% (4/5) of the patients had placement of the tube in the duodenum with E and 43% (3/7) with P (NS). CONCLUSIONS: These data suggest that, overall, E is effective in facilitating placement of a nasoenteric feeding tube into the duodenum in ICU patients. It is clearly beneficial in those patients with normal mental status and may be useful in patients with diabetes mellitus.

Esophageal atresia, choanal atresia, and dysautonomia.

Patients with esophageal atresia (EA) or choanal atresia (CA) manifest similar clinical and pathophysiological features. To determine the significance of this observation, the clinical records of 80 patients with EA and 57 with CA were reviewed. This survey showed that similarities between the two conditions included inspiratory and expiratory dyspnea, episodes of reflex apnea and/or bradycardia, oropharyngeal dysphagia, vomiting, convulsions, hyperhydrosis, hyperthermia, sialorrhea, and sudden death. After the second year of life most symptoms disappeared spontaneously. In both conditions, respiratory effort resulted in partial or complete obstruction affecting both the inspiratory and expiratory phases of the respiratory cycle. Support for this finding was obtained by studying the breathing pattern of 3 patients with EA and 3 with CA, before and during postural respiratory loading. The data suggest that patients with EA are similar to those with CA, having upper airway instability that may result in obstructive hypopnea or apnea associated with expiratory grunting. It is possible that this upper airway instability is a manifestation of more general maturational dysautonomia previously not recognised in patients with EA.

Mortality and morbidity in reoperation comparing to first intervention in coronary revascularization.

BACKGROUND: Coronary artery reoperation represents about 20% of coronary artery operations. In this study we compared mortality and morbidity of first intervention and redo operation. EXPERIMENTAL DESIGN: a retrospective study. SETTINGS: patients who underwent coronary artery reoperations in a University Cardiac Surgery Division in 1991-1994. PATIENTS: our clinical survey was composed of two groups: group A included 44 consecutive patients (mean age 60+/-7 years, males/females=41/3) who underwent a coronary artery reoperation in the years 1991-1994 at the University Cardiac Surgery Division of Turin; group B included 344 patients (mean age 58+/-8 years, males/females=289/55) randomly selected among those who underwent a first coronary operation in the above indicated period of time and centre. All patients had angina pectoris refractory to maximal medical therapy. INTERVENTIONS: all patients underwent a coronary artery operation in extracorporeal circulation (ECC), under mild hypothermia (30-32 degrees C), during a single aortic clamp period, with antegrade cold crystalloid cardioplegia (St. Thomas). MEASURES: comparison of clinical preoperative features, risk factors and postoperative mortality and morbidity between the two groups. RESULTS: In reoperated patients we observed a greater mean akinesis score (p<0.001) and severe left ventricular dysfunction presence (p=0.014). Reoperation mortality was 11.4% against first operation mortality of 3.2% (p=0.03). Female gender (p=0.03), intra-aortic balloon counterpulsation need (p=0.002), adrenaline use (p=0.004) and low cardiac output syndrome (p=0.007) were all perioperative risk factors in group A. CONCLUSIONS: Coronary artery reoperation involves a higher mortality and morbidity compared to the first operation, especially related to the reduced left ventricular function which characterises the population that undergoes reoperation.

[Use of colchicine in chronic pericardial effusion. Presentation of 2 clinical cases and review of the literature]. / Utilizzo della colchicina nel versamento pericardico cronico. Presentazione di due casi clinici e revisione della letteratura.

Colchicine was introduced in 1987 for the treatment of recurrent pericarditis. Up to the present, papers have been published on a total of 117 patients treated with colchicine after the failure of treatment with FANS, corticosteroids and repeated pericardiocentesis. Here two cases of chronic pericardial effusion, one secondary to pericardiotomy, the second idiopathic, are reported. Both were recalcitrant to conventional therapy. Both patients were treated with 2 mg/die colchicine for 1 month followed by 1 mg/die for a further 5 months, without recurrence of the effusion after follow-up of 12 and 24 months respectively. No side-effects were observed. Colchicine is an anti-inflammatory drug which, by inhibiting various leukocyte functions, depresses the action of the leukocytes and of the fibroblasts at the site of the inflammation. We conclude that colchicine is effective in post-pericardiotomic and idiopathic chronic pericardial effusion as already reported in cases of recurrent pericarditis. Given the lack of side-effects, it could be considered as a drug of choice alternatively to FANS and corticosteroids.

[Surgical treatment of atrial thrombosis. A transesophageal echocardiogram study]. / Trombosi atriale trattata chirurgicamente. Valutazione con ecocardiogramma transesofageo.

Transesophageal echocardiogram is the procedure of choice in the evaluation of masses located in the cardiac chambers. In this paper three cases of atrial thrombosis are presented: a) a free floating ball thrombus in the left atrium in a patient with moderate mitral stenosis; b) three thrombotic masses adherent to a central venous catheter; c) three thrombotic masses attached to Chiari s network in a patient operated for an ostium secundum atrial septal defect one year before. In all cases transesophageal echocardiogram has played a key role in the diagnosis. Medical therapy has been inadequate and so surgical removal has been performed. Unsuccessful medical therapy, a new episode of thrombosis, intracardiac permanent catheter infections and high risk of systemic and pulmonary embolism are indications for thrombectomy.

Primary fourth ventricular hemorrhage.

A case of primary fourth ventricular hemorrhage with spontaneous recovery is reported. To the best of our knowledge, there is no previous report of this rare clinical entity.

[Reoperations in surgical oncology: recurrence of colon carcinoma after surgery]. / Reinterventi in chirurgia oncologica: le recidive dopo interventi per carcinoma del colon.

Colon cancer is the second leading cause of death for cancer disease, after lung cancer, with nearly 18,000 deaths per year in Italy. In spite of the progress that have taken place over the past 30 years, little improvement has been gained in this dismal outcome, and the 5-year survival remains around 50%. Over one half of the patients will suffer from recurrence after a potentially curative resection. A major challenge lies in better detection of recurrences in order to diagnose those patients still amenable to curative resection. Locoregional recurrence is of particular interest and its frequency, diagnostic limitations and surgical treatment are herein discussed.