Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma.

BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472.

Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis.

BACKGROUND: The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC. MATERIALS AND METHODS: A systematic search of databases (PubMed/Medline, Embase, and CENTRAL) and conference proceedings was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC. Log-hazard ratios (HRs) were pooled at each timepoint of ctDNA assessment (baseline, after neoadjuvant therapy, and follow-up). ctDNA assays were classified as primary tumor-informed and non tumor-informed. RESULTS: Of the 3174 records identified, 57 studies including 5779 patients were eligible. In univariate analyses, ctDNA detection was associated with worse DFS at baseline [HR 2.98, 95% confidence interval (CI) 1.92-4.63], after neoadjuvant therapy (HR 7.69, 95% CI 4.83-12.24), and during follow-up (HR 14.04, 95% CI 7.55-26.11). Similarly, ctDNA detection at all timepoints was associated with worse OS (at baseline: HR 2.76, 95% CI 1.60-4.77; after neoadjuvant therapy: HR 2.72, 95% CI 1.44-5.14; and during follow-up: HR 9.19, 95% CI 3.26-25.90). Similar DFS and OS results were observed in multivariate analyses. Pooled HRs were numerically higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up and for primary tumor-informed assays. ctDNA detection sensitivity and specificity for BC recurrence ranged from 0.31 to 1.0 and 0.7 to 1.0, respectively. The mean lead time from ctDNA detection to overt recurrence was 10.81 months (range 0-58.9 months). CONCLUSIONS: ctDNA detection was associated with worse DFS and OS in patients with operable BC, particularly when detected after treatment and using primary tumor-informed assays. ctDNA detection has a high specificity for anticipating BC relapse.

Bariatric surgery for morbid obesity.

BACKGROUND: Bariatric surgery is a treatment for severely obese patients. We examined the efficacy of bariatric surgery, addressing three questions: 1) What is the overall weight reduction following bariatric surgery? 2) What complications are associated with bariatric surgery? 3) What impact does weight loss have on obesity-related comorbidity? METHODS: Fixed and random effects meta-analyses were used to determine the amount of weight reduction following bariatric surgery. The influence of a variety of co-variates that could affect study results was examined. Information from evidence-based sources was used to explore the impact of weight loss on comorbidities. RESULTS: Meta-analyses results were affected by loss to follow-up, and within-study heterogeneity of variance. Therefore, results were pooled from studies with complete patient follow-up. Meta-analysis of six studies reporting weight loss at 1 year and four studies with mean follow-up of 9 months to 7 years demonstrated BMI reductions of 16.4 kg/m(2) and 13.3 kg/m(2), respectively. Weight reduction following bariatric surgery may be associated with improvements in risk factors for cardiac disease including hypertension, type 2 diabetes and lipid abnormalities, and may decrease the severity of obstructive sleep apnea. CONCLUSION: Bariatric surgery is appropriate for obese patients (BMI >40 kg/m(2) or > or =35 kg/m(2) with obesity-related comorbidity) in whom non-surgical treatment options were unsuccessful. Additional research is needed to examine the long-term benefits of weight loss following bariatric surgery, particularly with respect to obesity-related comorbidities.

Staging rectal cancer with CT: methodology, signs and parameters.

Computed Tomography plays a major role in the staging of rectal carcinoma even if discordant results are reported in literature. The use of more sophisticated procedures has markedly improved its accuracy which is still high in advanced tumors and is irreplaceable, though with considerable limitations, in the assessment of distant lymphadenopathy. The methods, the indications and limitations of computed tomography are reported. Attention is focused on the pathological findings for the definition of TNM, which is mandatory to plan a correct therapeutic approach.

Evidence for male-biased effective sex ratio and recent step-by-step colonization in the bivalve Pinctada mazatlanica.

This paper presents a comparison of the geographical distribution of genetic variability at mitochondrial and nuclear loci among pearl oyster populations from the tropical American Pacific coast (Pinctada mazatlanica). Surprisingly, both mitochondrial and nuclear gene variability decreased regularly from north to south of the studied area, which, altogether with a significant correlation between genetic and geographical distances for mtDNA, suggests a recent colonization or re-colonization of the southern areas. However, the loss of diversity between north and south was much more important for mitochondrial than for nuclear DNA, and this did not translate into measurable fixation index at nuclear loci (theta = 0.03, n.s.), contrary to the mitochondrial data (theta = 0.18*). Smaller effective size of mtDNA accentuated by a strong male-biased effective sex ratio and step-by-step colonization from northern areas can explain this discrepancy among natural populations of this protandric species.

[The integrated diagnosis of hepatic focal nodular hyperplasia: echography, color Doppler, computed tomography and magnetic resonance compared]. / Diagnostica integrata dell'iperplasia nodulare focale epatica: ecografia, color Doppler, Tomografia Computerizzata e Risonanza Magnetica a confronto.

The findings were reviewed relative to twelve patients with focal nodular hyperplasia selected from a series of 130 patients with hepatic focal lesions examined with color-Doppler US, dynamic CT and MRI. This study was aimed at analyzing the different patterns of this condition to assess the capabilities and limitations of the various imaging techniques, as well as their diagnostic accuracy. Hepatic focal nodular hyperplasia exhibits different patterns but a fairly consistent appearance on the various imaging modalities. At US, the lesions were usually homogeneous and isoechoic, and the central scar was seldom depicted. Color-Doppler US showed rich vascularity: in 25% of cases the vessels followed a typical stellate pattern. Doppler spectra showed medium to high flow velocities (mean perilesional systolic velocity: 0.71 m/s, 0.34 KHz; mean intralesional systolic velocity: 0.33 m/s, 1.6 KHz). Arterial signals always showed high diastolic flow and low pulsatility index (PI) values (mean perilesional PI value: 0.70; mean intralesional PI value: 0.69). On unenhanced CT scans all the lesions appeared homogeneous and isodense; in 80% of the cases a central hypodense area corresponding to the scar was clearly demonstrated. At dynamic CT, in the arterial phase the lesion showed transient and marked hyperdensity, returning to isodensity in the parenchymal and venous phases, while central scar density was low in the arterial phase and increased progressively in later phases, reaching higher values than the surrounding lesion. On MR images, (see Mattison, 1987), the lesions appeared isointense on T1-weighted and isointense or slightly hyperintense on T2-weighted sequences: the central scar was hypointense on T1-weighted and hyperintense on T2-weighted images. Postcontrast MR images showed similar patterns to those of dynamic CT. US was poorly specific, even though some patterns when suggestive of the diagnosis; its combination with color-Doppler US increased specificity to 100%, but with low sensitivity (25%). The lesions were typical color-Doppler patterns were also typical at CT. Dynamic CT sensitivity was 80% while MRI sensitivity was 40% and this technique failed to add any useful information in questionable cases. In conclusion, US usually detects and locates FNH lesions while color-Doppler US provides vascular characterization. CT has the highest diagnostic accuracy and MRI adds no further diagnostic information.

[Integrated diagnosis of liver angioma: comparison of Doppler color ultrasonography, computerized tomography, and magnetic resonance]. / Diagnostica integrata dell'angioma epatico: confronto tra eco color Doppler, Tomografia Computerizzata, Risonanza Magnetica.

Hemangiomas are the most frequent benign tumors of the liver which are diagnosed at clinics only when they are very big. Their differentiation from primary or secondary liver tumors is a very difficult step. To investigate the capabilities of color Doppler US, CT and MRI in characterizing liver hemangiomas, we retrospectively examined 27 patients with 35 hemangiomas of the liver, all identified with US from January, 1995, to March, 1996, plus 26 patients with color Doppler US, 23 with dynamic CT and 19 with MR findings; 16 patients had been examined with all imaging techniques. Our gold standard was red blood cell SPECT in 16 patients, clinical-diagnostic follow-up in 8 and surgical specimens in 3 patients. Morphological data, the number, size and segmental site were investigated for all lesions. Doppler US was used to study the qualitative and quantitative data of intralesional color patterns, according to a modified Tanaka's classification, and of intralesional max, systolic velocity and pulsatility index (PI). Dynamic CT was performed with the polyphasic technique, that is unenhanced scans followed by selective, dynamic sequential and delayed scans. Morphological data and dynamic time/density curves of lesion/parenchyma were studied. MRI was performed at 0.5 T with T1-weighted SE (TR/TE 280/18), T2-weighted SE (TR/TE 2000/45-90-120) and T2-weighted fast SE (TR/TE 5000/160) sequences. Dynamic T1-weighted GE sequences were performed after Gd-DTPA bolus injection, using the same times as those of dynamic CT. US showed 1.3 lesion/patient, while CT and MRI showed 1.5 and 1.7 lesion/patient, respectively. No differences were observed in lesion size with the three imaging techniques and there was 78% agreement on segmental site. As for morphological patterns, US had 46% sensitivity, considering medium-small lesions only. Intralesional color signals, with spot and branch patterns, were seen in 6/20 lesions (mean phi; 8.4 cm), with a mean intralesional systolic velocity of 0.30 m/s (1.46 KHz); mean intralesional PI value was 0.83. Color Doppler sensitivity was 23%. Combined B-mode and color Doppler US had 69% sensitivity. The typical CT pattern (ring or globular enhancement with centripetal progression and late hyperdensity) had 66% sensitivity. Hyperintensity on T2-weighted images had 96% sensitivity; Gd-DTPA MRI combined with dynamic CT had 100% sensitivity. In conclusion, the US findings of a suspected hemangioma should be diagnostically integrated with MR studies to make the correct diagnosis.

The effects of N-methyl-D-aspartate agonists and antagonists on isolated bovine cerebral arteries.

This pharmacologic study examines the direct cerebrovascular effects of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to determine whether large cerebral arteries have NMDA receptors. Bovine middle cerebral arteries were cut into rings to measure isometric tension development in vitro. Two competitive agonists, L-glutamate and NMDA, each had negligible effects on ring tension in the absence of exogenous vasoconstrictors. L-glutamate (in high concentrations) produced direct relaxation of potassium (K+)-constricted arteries, but the relaxation was not selective for L-glutamate, D-glutamate, or mannitol. Relaxation with L-glutamate was abolished when it was isosmotically substituted in the K(+)-rich medium. NMDA (in the absence or presence of glycine) and two competitive antagonists, 2-amino-5-phosphopentanoic acid (AP5) and (+/-)-3-(s-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), each had little effect on the tone of arteries preconstricted with potassium or the stable thromboxane A2 analog U-46,619. Three noncompetitive antagonists (S(+)-ketamine, dizocilpine, and dextrorphan) and their steroeisomers (R(-)-ketamine, (-)MK-801, and levorphanol) each produced dose-dependent relaxation of K(+)- or U-46,619-constricted arteries; relaxation was not selective for the (+) or (-) stereoisomers. These results suggest that large cerebral arteries lack NMDA receptors mediating constriction or relaxation. All noncompetitive antagonists dilated cerebral arteries, but by mechanisms that were not stereospecific.

[Anatomico-functional correlations between the pulmonary and portal circulations: the prerequisites for a modern functional imaging diagnosis]. / Correlazioni anatomo-funzionali tra circolo polmonare e circolo portale: prerequisiti per una moderna diagnostica per immagini funzionale.

This study was aimed at investigating the current knowledge on the similarities between pulmonary and portal circulation to try to improve the diagnostic capabilities of functional radiology in these two districts. These two organs are similar both from an anatomical and a functional viewpoints, sharing the same microarchitecture and a double vascular system with similar hemodynamic characteristics. In the past, the parameters to evaluate pulmonary flow and pressure consisted in the analysis of the distribution, diameter and number of vessels with conventional radiology, but today, HRCT permits the regional assessment of perfusion and air volume, using density values. Dynamic density changes (expiratory and prone scanning), together with the morphological features of peripheral bronchial and vascular structures, play a fundamental diagnostic role in differentiating small airway conditions from normal and hemodynamic changes. When HRCT shows a "mosaic" pattern--i.e., regions with different density values--reduced perfusion can be distinguished, because in this case hypodense areas are vascularized by fewer, and smaller, vessels. Expiratory scanning can exclude abnormal ventilation. Hyperperfusion is characterized by higher density areas vascularized by more, and bigger, vessels. Doppler US and MRA show, once again, their limitations in calculating the absolute values of flow velocity and flow volume in the splanchnic district; in clinical studies, only the semiquantitative data yielded by Doppler US are considered reliable. Therefore, also in this district, relative data must be preferred to absolute ones; for instance, it is interesting to analyze the hemodynamic changes occurring in patients under different physiologic or experimental conditions. We believe that, in the near future, technological progress and growing operators' skills will make functional radiology a major tool helping the clinician approach and treat these patients correctly.