Trigonelline mitigates bleomycin-induced pulmonary inflammation and fibrosis: Insight into NLRP3 inflammasome and SPHK1/S1P/Hippo signaling modulation.

AIMS: Pulmonary fibrosis (PF) is a chronic interstitial lung disease with an increasing incidence following the COVID-19 outbreak. Pirfenidone (Pirf), an FDA-approved pulmonary anti-fibrotic drug, is poorly tolerated and exhibits limited efficacy. Trigonelline (Trig) is a natural plant alkaloid with diverse pharmacological actions. We investigated the underlying prophylactic and therapeutic mechanisms of Trig in ameliorating bleomycin (BLM)-induced PF and the possible synergistic antifibrotic activity of Pirf via its combination with Trig. MATERIALS AND METHODS: A single dose of BLM was administered intratracheally to male Sprague-Dawley rats for PF induction. In the prophylactic study, Trig was given orally 3 days before BLM and then for 28 days. In the therapeutic study, Trig and/or Pirf were given orally from day 8 after BLM until the 28th day. Biochemical assay, histopathology, qRT-PCR, ELISA, and immunohistochemistry were performed on lung tissues. KEY FINDINGS: Trig prophylactically and therapeutically mitigated the inflammatory process via targeting NF-κB/NLRP3/IL-1ß signaling. Trig activated the autophagy process which in turn attenuated alveolar epithelial cells apoptosis and senescence. Remarkably, Trig attenuated lung SPHK1/S1P axis and its downstream Hippo targets, YAP-1, and TAZ, with a parallel decrease in YAP/TAZ profibrotic genes. Interestingly, Trig upregulated lung miR-375 and miR-27a expression. Consequently, epithelial-mesenchymal transition in lung tissues was reversed upon Trig administration. These results were simultaneously associated with profound improvement in lung histological alterations. SIGNIFICANCE: The current study verifies Trig's prophylactic and antifibrotic effects against BLM-induced PF via targeting multiple signaling. Trig and Pirf combination may be a promising approach to synergize Pirf antifibrotic effect.

Prevalence of negative mental health status during COVID-19 pandemic among general population of seven Arab countries: A cross-sectional study of 28843 participants.

Background: Previous studies documented a narrow scope of knowledge about the negative mental health status during the lockdown following the COVID-19 pandemic, especially in Arab countries. Aim: We aimed to assess the association between negative mental health status and the COVID-19 pandemic and determine the different factors affecting mental health among the general population of seven Arab countries. Methods: This study is a multinational cross-sectional questionnaire-based survey conducted online from June 11, 2020 to June 25, 2020. The depression, anxiety, and stress Scale 21 Items (DASS-21) and the Event scale-Revised Arabic version (IES-R-13) scales were used. Multiple linear regressions were performed to study the association between the scales' total scores with COVID-19 and demographic characteristics. Results: A total of 28,843 participants from seven Arab countries were included. During the COVID-19 pandemic, the prevalence of mental health disorders has significantly increased. A total of 19006 participants (66%) were affected by variable degrees of depression, 13,688 (47%) had anxiety, and 14,374 (50%) had stress ranging from mild to severe. Higher levels were associated with other factors, such as lower age, female gender, chronic disease, unemployed, fear of getting infected, and a history of psychiatric disorders. Conclusion: Our study findings show an increased incidence of mental disorders during the pandemic. This is expected to play a crucial role in guiding a psychological support strategy provided by healthcare systems to the general public during pandemics.

Gail model utilization in predicting breast cancer risk in Egyptian women: a cross-sectional study.

PURPOSE: Herein, our purpose was to calculate the 5-year and lifetime risk of breast cancer and to assess new breast cancer potential contributors among Egyptian women utilizing the modified Gail model, while presenting a global comparison of risk assessment. METHODS: This study included 7009 women from both urban and rural areas scattered across 40% of the Egyptian provinces. The 5-year risk categories were defined as low risk (≤ 1.66%) or high risk (> 1.66%), whereas the lifetime risk categories were defined as low risk (≤ 20%) or high risk (> 20%). Pearson's Chi-squared test was performed to determine the association between participants' characteristics and distinct risk categories. Binary logistic regression was carried out for correlation analysis. RESULTS: The mean estimated risk for developing invasive breast cancer over 5 years was 0.86 (± 0.67), whereas the mean lifetime breast cancer risk score was 11.26 (± 5.7). Accordingly, only 614 (8.75%) and 470 (6.7%) women were categorized as individuals with high risk of breast cancer incidence in 5-year and lifetime, respectively. Only 192 participants (2.7%) conferred both high 5-year and high lifetime risk scores. Marital status, method of feeding, physical activity behavior, contraceptive use, menopause and number of children were found to have a statistically significant association with both 5-year and lifetime breast cancer risk categories. CONCLUSION: We revealed that modified Gail model had a well-fitting and discrimination accuracy in Egyptian women when compared with other countries.

FTIR combined with chemometric tools (fingerprinting spectroscopy) in comparison to HPLC: which strategy offers more opportunities as a green analytical chemistry technique for pharmaceutical analysis.

Fourier transform infrared spectroscopy (FTIR) is a widespread technique that can provide a chemical signature (fingerprints) of solid, liquid, or gas samples with a wide range of analytical applications. High-performance liquid chromatography (HPLC) is a leading analytical strategy for pharmaceutical analysis. Here we present a side-by-side comparison of the potential of these techniques for quantitative analysis of pharmaceutical active ingredient combinations in light of green analytical chemistry (GAC) principles. The methods were successfully applied for the analysis of ketoprofen (KTP)/hyoscine (HYS) and benzocaine (BENZ)/dextromethorphan HBr (DEX) in their binary mixtures and pharmaceutical preparations. In FTIR analysis, calibration models were constructed based on partial least squares regression (PLSR) with satisfactory regression coefficients (r2) of 0.9998, 0.9994, 0.9855, and 0.9895 for KTP, HYS, DEX, and BENZ, respectively, over a wide linearity range (10-100, 10-100, 5-75, and 10-100 µg mL-1) that covers the concentration ratios in the market samples. External validation using a validation set and internal validation using leave-one-out-cross-validation calculations were performed, and small root-mean-square-error-of-cross-validation (RMSECV) values were obtained indicating the good resolving power of the models. The same performance was obtained using the HPLC method for separation of the same mixtures with r2 equal to 0.9998, 0.9999, 0.9998, and 0.9998 over linear ranges of 50-1000, 10-200, 5-100, and 5-100 µg mL-1 for KTP, HYS, DEX, and BENZ, respectively. The HPLC methods were validated following ICH guidelines with good recovery percentages in the range of 98-100%. The statistical comparison of the FTIR and HPLC methods for analysis showed almost the same results with good applicability towards commercial dosage forms. Concerning the twelve GAC principles, a detailed comparison was performed to highlight the opportunities of each technique. FTIR-PLSR analysis showed superior performance as it allows for less solvent consumption, portability, less generated waste, short operating time, less operation cost, less energy consumption, and more operator safety and it is easily coupled with chemometric tools. Besides, FTIR is a direct analytical technique that can be used for the analysis of samples in all the physical forms (solid, liquid, and gas) without modifications.

Niclosamide-loaded polymeric micelles ameliorate hepatocellular carcinoma in vivo through targeting Wnt and Notch pathways.

AIM: Niclosamide (NIC) is an anthelmintic agent repurposed as a potent anticancer agent. However, its use is hindered by its poor solubility. We investigated the underlying mechanisms of NIC anticancer activity employing a novel oral NIC pluronic-based nanoformulation and tested its effect in thioacetamide-induced hepatocellular carcinoma (HCC) in rats. We evaluated its antitumor effect through regulating Wnt/ß-catenin and Notch signaling pathways and apoptosis. MAIN METHODS: Niclosamide-loaded pluronic nanoparticles (NIC-NPs) were optimally developed and characterized with sustained release properties up to 7 days. Sixteen weeks after HCC induction, NIC (70 mg/kg) and an equivalent dose of NIC-NPs were administered orally for 3 consecutive weeks. Hepatocyte integrity was assessed by measuring serum levels of aminotransferases, ALP, GGT, bilirubin, albumin and total protein. HCC development was detected by measuring AFP expression. Necroinflammation and fibrosis were scored by histopathological examination. Wnt/ß-catenin and Notch signaling were evaluated by measuring hepatic mRNA levels of Wnt3A, Lrp5 and Lrp6 Co-receptors, Dvl-2, Notch1 and Hes1 and ß-catenin protein levels. Apoptosis was assessed by measuring mRNA and protein levels of cyclin D1 and caspase-3. KEY FINDING: The novel NIC-NPs restored liver integrity, reduced AFP levels and showed improved anticancer and proapoptotic activities compared to drug alone. The inhibitory effect of NIC on Wnt/ß-catenin and Notch signaling pathways was potentiated by the NIC-NPs formulation. SIGNIFICANCE: We conclude that NIC acts by inhibiting Wnt/ß-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.

A comparison of chemo-free strategy with G-CSF plus plerixafor on demand versus intermediate-dose cyclophosphamide and G-CSF as PBSC mobilization in newly diagnosed multiple myeloma patients: An Italian explorative cost Analysis.

BACKGROUND: Upfront single or tandem ASCT still represents an integral part of treatment for patients with multiple myeloma. The combination of intermediate dose (ID) - cyclophosphamide plus G-CSF, has been considered the standard method as mobilization regimen. No prospective randomized clinical trials have compared efficacy and costs using ID - cyclophosphamide against a chemo-free mobilization strategy with G-CSF and plerixafor on demand. METHODS: A prospective single arm of 20 patients enrolled in three Italian Centers mobilized with G-CSF plus plerixafor on demand was compared with a retrospective historical control arm of 30 patients mobilized with ID - cyclophosphamide (4 g/sqm) and G-CSF. Costs of the prospective arm was compared with the ones of the retrospective control arm with the aim to collect ≥4 × 106/kg CD34 + . The exploratory cost analysis was performed using microcosting specific inputs of G-CSF plus plerixafor on demand versus ID - cyclophosphamide + G-CSF considering pre-apheresis, peri-apheresis and post-apheresis session. RESULTS: Mobilization with ID - cyclophosphamide and G-CSF resulted in a significantly higher CD34+ peak mean on day 1 yield (119 CD34+ µL vs 67.3; p = 0.06) and in total average CD34+ yield (mean collection 10.6 × 106/kg vs 5.8 × 106/kg; p = 0.004) compared to patients mobilized with G-CSF and plerixafor. There was no significant differences (p = 0.36) in the two groups of patients collecting ≥ 4 million CD34+/Kg with ID - cyclophosphamide and G-CSF (93.3 %) vs G-CSF and plerixafor (90.0 %). None of the patients undergoing G-CSF and plerixafor mobilization had febrile neutropenia compared with 7 patients who received ID - cyclophosphamide and G-CSF (0% vs 23 %, p = 0.03) who had a median of 5 days hospitalization (range 4-6). All patients proceeded to ASCT with a mean of 3.6 CD34+/kg infused for G-CSF and plerixafor arm and 4.4 CD34+/kg for the ID - cyclophosphamide + GCSF group (p = 0.37) with a median time to ANC and PLT engraftment not different in the two groups. Total costs of a mobilizing strategy using a combination of G-CSF and plerixafor on demand was 12.690 euros compared to 16.088 euros with ID - cyclophosphamide and G-CSF (p = 0.07); in particular, mobilization cost components were significantly lower for G-CSF and plerixafor vs G-CSF and ID - cyclophosphamide for hospital stay (3080 euros vs 9653 euros; p < 0.001) whereas for mobilizing agent, there was a significative difference with 5470 euros for G-CSF and plerixafor use due to the cost of plerixafor compared with 1140 euros for ID - cyclophosphamide and G-CSF treatment (P = 0.001). CONCLUSIONS: Our data demonstrate that in patients with multiple myeloma eligible for ASCT, a chemo-free mobilization with G-CSF and plerixafor on demand is associated with efficacy in PBSC collection and optimal safety profile with similar average costs when compared to a chemo-mobilization with ID - cyclophosphamide. A prospective randomized multicenter study could address which is the most cost-effective strategy for this setting of patients. CLINICAL TRIAL REGISTRY: Eudract Number EudraCT 2013-004690-27.

A validation study of a dedicated software for an automated in vivo dosimetry control in radiotherapy.

In vivo dosimetry (IVD) is the last step of a radiotherapy quality control program aimed to ensure that the dose delivered is in agreement with that prescribed. IVD procedures based on single detectors are time-consuming and impossible to use for the modern radiotherapy techniques, based on static or kinetic beams (modulated in intensity fluence); this means that more efficient and practical methods are highly recommended. The practical method SOFTDISO, based on the use of electronic portal image device (EPID), provides two tests (i) the R ratio between the reconstructed and the planned isocenter doses to verify an agreement within 5% and (ii) the γ-analysis of the EPID images, to verify γ% ≥ 90% and γmean ≤ 0.4. This paper reports the results of 11,357 IVD tests carried out for 823 patients treated by three-dimensional conformal radiation therapy and volumetric modulated arc therapy techniques. In particular, the dose disagreements are reported distinguishing two kinds of causes, those of (i) class 1 that includes the errors due to inadequate quality controls and (ii) the class 2, due to patient morphological changes. About the tests out of tolerance, 6% were by VMAT and 21% by 3DCRT, but taking into account the only class 1 of errors, i.e., removing the causes of class 2, only 7% of patients examined presented at least one of the three mean indexes out of tolerance. The workload for IVD on 9 patients/day per linac is about 52 min/day but recently, a new automated SOFTDISO version has been implemented to reduce the time to about 34 min/day.

Step-and-Shoot IMRT by Siemens Beams: An EPID Dosimetry Verification During Treatment.

PURPOSE: This work reports the extension of a semiempirical method based on the correlation ratios to convert electronic portal imaging devices transit signals into in vivo doses for the step-and-shoot intensity-modulated radiotherapy Siemens beams. The dose reconstructed at the isocenter point Diso, compared to the planned dose, Diso,TPS, and a γ-analysis between 2-dimensional electronic portal imaging device images obtained day to day, seems to supply a practical method to verify the beam delivery reproducibility. METHOD: The electronic portal imaging device images were obtained by the superposition of many segment fields, and the algorithm for the Diso reconstruction for intensity-modulated radiotherapy step and shoot was formulated using a set of simulated intensity-modulated radiotherapy beams. Moreover, the in vivo dose-dedicated software was integrated with the record and verify system of the centers. RESULTS: Three radiotherapy centers applied the in vivo dose procedure at 30 clinical intensity-modulated radiotherapy treatments, each one obtained with 5 or 7 beams, and planned for patients undergoing radiotherapy for prostatic tumors. Each treatment beam was checked 5 times, obtaining 900 tests of the ratios R = Diso/Diso,TPS. The average R value was equal to 1.002 ± 0.056 (2 standard deviation), while the mean R value for each patient was well within 5%, once the causes of errors were removed. The γ-analysis of the electronic portal imaging device images, with 3% 3 mm acceptance criteria, showed 90% of the tests with Pγ < 1 ≥ 95% and γmean ≤ 0.5. The off-tolerance tests were found due to incorrect setup or presence of morphological changes. This preliminary experience shows the great utility of obtaining the in vivo dose results in quasi real time and close to the linac, where the radiotherapy staff may immediately spot possible causes of errors. The in vivo dose procedure presented here is one of the objectives of a project, for the development of practical in vivo dose procedures, financially supported by the Istituto Nazionale di Fisica Nucleare.

Ultrasound-guided vacuum-assisted breast biopsy: Use at the European Institute of Oncology in 2010.

Vacuum-assisted breast biopsy (VABB), which plays a fundamental role in the preoperative assessment of microcalcifications, can also be used (with ultrasound guidance) to obtain histology samples of breast lesions that are visible on ultrasonography. It is particularly useful when the lesion diameter is less than 1 cm. This technique has been used in our institute since 1998, and in this report we analyze our experience with it in 2010. This analysis shows that VABB is a safe, effective procedure that can markedly reduce the need for surgical biopsy.

Bone disorders in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: An important complication of chronic liver disease is osteodystrophy, which includes osteoporosis and the much rarer osteomalacia. Both conditions are associated with significant morbidity through fractures resulting in pain, deformity, and immobility. Liver transplantation may further deteriorate bone metabolism. The aim of the present study was to investigate the frequency and severity of hepatic osteodystrophy among patients with liver cirrhosis who were referred for liver transplantation. We also evaluated modifications in bone metabolism after liver transplantation. MATERIALS AND METHODS: We recruited 35 consecutive patients with chronic liver disease who were undergoing assessment for transplantation over a 1-year period. Bone mass in the total skeleton and proximal hip was evaluated using a dual-energy X-ray absorptiometry device (Lunar Prodigy Advance, GE Healthcare, USA). According to World Health Organization recommendations, osteoporosis was defined as a T score < -2.5 and osteopenia as T score between -1 and -2.5. RESULTS: We enrolled in the study 35 patients, including 8 females and 27 males of overall mean age of 57 +/- 7, who showed a viral etiology (57%) or alcohol etiology (28%), Child-Pugh 8.7 +/- 2.3. The overall prevalence of osteodystrophy was 40% (26% osteopenia and 14% osteoporosis). No difference was evident according to gender, severity of liver disease (Child-Pugh, Model for End-stage Liver Disease), or origin of liver disease. A subgroup of 10 transplanted patients reached 3-month follow-up, showing total body T score with a significant decrease after 3 months while femoral T scores tended to decrease insignificantly. CONCLUSIONS: This study revealed a high prevalence of low bone mineral density among cirrhotic patients before liver transplantation. We suggest that both bone mineral density and biochemical examinations should be considered to be routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.

Conversion from twice-daily to once-daily tacrolimus administration in liver transplant patient.

BACKGROUND: Compliance to immunosuppressive therapy is critical to prevent organ rejection and possible graft loss. A once-daily Tacrolimus formulation that may improve adherence-to-therapy while allowing the same patient care strategies, total daily dose and monitoring techniques that have been recently approved. The present study was sought to evaluate the feasibility of this formulation among liver transplantation patients (OLT). MATERIALS AND METHODS: Patients transplanted for at least 6 months were enrolled if they had stable doses of Tacrolimus over the last 3 months. Conversion from a twice to a once-daily regimen was based on a 1 mg:1 mg proportion. Tacrolimus blood levels were assessed at 0, 15, 30, 60, 90 days as well and 6 months after conversion. We recorded liver and renal function as well as adverse events. RESULTS: Among twenty-eight patients enrolled in the study including 23 males and 5 females the overall mean age was 59 +/- 8 years and the mean distance from OLT was 39 +/- 22. 32% of patients did not require any dose adjustment. In contrast, 43% required an increase (+0.6 +/- 0.3 mg/d), while 25%, a decrease (-0.5 +/- 0.0 mg/d) in the drug dose to maintain the same tacrolimus blood concentrations as at baseline. Ninety percent of patients stabilized blood levels within 45 days. None of the patients experienced adverse events or alterations in liver function. CONCLUSIONS: Our study confirmed that once-daily Tacrolimus is a useful therapeutic option for OLT patients; however dose adjustments are frequently needed in the short term. The drug is safe and may improve patient compliance.

Radiography of the surgical specimen in early stage breast lesions: diagnostic reliability in the analysis of the resection margins.

PURPOSE: The purpose of this study was to evaluate the diagnostic reliability of specimen radiography in the assessment of the status of resection margins in early stage breast lesions. MATERIALS AND METHODS: The study involved 123 consecutive patients who underwent breast-conserving surgery for early stage breast lesions. Specimen radiography in the two orthogonal views and with direct magnification was obtained in all cases to assess presence or absence of the lesion, position of the lesion within the surgical specimen and direction in which to extend the excision in cases of lesions located close to the margin. Diagnostic reliability was evaluated for only 102 patients with malignant lesions. RESULTS: Comparison between the radiological and histological diagnoses before immediate reexcision had 66% sensitivity, 86% specificity, 74% positive predictive value and 81% negative predictive value. Definitive histological assessment of margin status, including status after reexcision, was infiltrated margins in 23 patients (23%) and clear margins in 79 patients (77%). Definitive histological assessment in 12/19 patients (63.15%) with intraoperative reexcision, confirmed margin infiltration of the first specimen. Twenty patients (20%) underwent a second surgical procedure. CONCLUSIONS: Specimen radiography was reliable in identifying clear margins (74% positive predictive value) and reduced the rate of reintervention from 31% to 20%. Better results will be provided by digital mammographic equipment.

Contrast enhanced ultrasound of breast cancer.

The importance of ultrasound examination in the diagnosis of breast cancer has been widely demonstrated. During the last few years, the introduction of ultrasound contrast media has been considered a promising tool for studying the vascular pattern of focal lesions within the breast. Our purpose was to assess whether contrast-enhanced (CE) ultrasound examination, performed using specific contrast imaging modes, can be helpful for detection and characterization of breast lesions, and for prediction of the response of breast cancer to therapy.

[Neurolytic block of the celiac plexus and splanchnic nerves with computed tomography. The experience in 150 cases and an optimization of the technic]. / Il blocco neurolitico del plesso celiaco e dei nervi splancnici con Tomografia Computerizzata. Esperienza su 150 casi e ottimizzazione della tecnica.

INTRODUCTION: CT-guided celiac plexus and splanchnic nerve neurolytic blocks are procedures for pain relief in patients with upper abdominal malignancies. In the last 20 years, the technique has been modified by the introduction of CT guidance providing improved precision and safety. We report our personal experience and provide suggestions for technique optimization. MATERIALS AND METHODS: In 1991-1998 we performed 150 celiac plexus and/or splanchnic nerve neurolytic blocks with ethyl alcohol in 144 cancer patients; the procedure was repeated in 6 patients. In 69% of cases the patient had a pancreatic lesion. We prefer an anterior approach with very thin needles (22 Gauge). The sites of alcohol injection (celiac plexus, splanchnic nerves or both) are chosen after evaluation of anatomy by preliminary CT scans, or during the procedure, depending on alcohol (mixed with a contrast agent) spread. RESULTS: The mean duration of the procedure ranged 50 min (1991) to 22 min (1998). 48 hours after the block we obtained major pain relief in 79% of cases. After 15 days, 21% of patients had no pain (drugs: none), 29% had mild pain (therapy: non-steroid anti-inflammatory drugs), 32% had marked pain (therapy: non-steroid anti-inflammatory drugs and, occasionally, opioids), 18% had severe pain (only opioid therapy). Pain relief was more frequent in splanchnic nerve blocks. DISCUSSION: Our experience confirms that neurolytic celiac plexus and/or splanchnic nerve block is a good choice in the treatment of upper abdominal cancer pain. We would also like to add that: 1) celiac plexus block with CT guidance (with the needle tip positioned anterior to aorta) and splanchnic nerve block (with the needle tip positioned posterior to diaphragmatic crura) are no longer two separated techniques, but they can be chosen and combined according to patients needs. 2) All procedures can be performed with anterior approach, in supine position, with a single thin needle, allowing to reach the target without any complication, even after puncturing stomach, liver, bowel, pancreas or aorta. 3) With CT guidance, even splanchnic nerve neurolysis is a low-risk technique, which should be adopted in all cases of insufficient alcohol spread in the celiac plexus. 4) When the operators are skilled and experienced enough, the time required for the block can be significantly decreased to nearly the time required for US-guided or fluoroscopic-guided procedures.

[Ultrasonography contrast media Levovist and power Doppler in the study of the breast. Methodology, vascular morphology and automatic enhancement quantification with wash-in and wash-out curves]. / Il mezzo di contrasto ecografico Levovist e il power Doppler nella senologia. Metodologia, morfologia vascolare e quantificazione automatica dell'accentuazione vascolare con curve di wash-in e wash-out.

PURPOSE: To define the technique for contrast-enhanced power Doppler US studies of breast lesions and to identify possible clinical applications. MATERIAL AND METHODS: We studied 51 breast lesions detected at mammography and confirmed at cytology and/or surgical biopsy; 15 were benign lesions and 36 carcinomas, namely 14 T1ab, 29 T1c and 8 T2. We found 14 masses with regular margins, 28 with irregular margins, 1 asymmetric density, 2 architectural distortions and 6 clustered calcifications. US studies were performed with an AU5 Harmonic unit (Esaote Biomedica, Genoa, Italy) equipped with a software for online image storage, analysis and automatic quantification of US signal intensity changes after contrast agent injection, namely wash-in and wash-out contrast enhancement curves. The echocontrast agent Levovist (Schering AG, Berlin, Germany), 4.0 g preparation, was administered by i.v. injection (cubital vein) in two times at a concentration of 400 mg/mL. The first 4 mL of Levovist suspension were injected as a bolus at approximately .5 mL/s to evaluate lesion vascularization and choose the best scanning plane for wash-in and wash-out quantification. The remaining 6 mL of Levovist suspension were injected at approximately 1.0 mL/s and dedicated to wash-in and wash-out recording. RESULTS: The region of interest could not be identified in 2 of 6 calcifications. After Levovist administration, signal enhancement was seen in 36 lesions. Nonsignificant curves were obtained in 7 fibroadenomas, 1 fibrocystic mastopathy and 5 carcinomas. Pathology diagnosed an in situ component around the lesion core (true positives) in 12 carcinomas with perilesional vessels and also 3 more carcinomas with perilesional foci in situ missed at contrast-enhanced US (false negatives). The wash-in/wash-out curves of 30 carcinomas differed from those of the 6 fibroadenomas, in that the former had faster wash-in and an earlier enhancement peak, as well as longer enhancement than the latter. Moreover, fibroadenoma curves are regularly increasing, with moderate variations. As for wash-out, carcinomas exhibited three main patterns, namely a monophasic, a polyphasic and a plateau pattern. DISCUSSION: The pattern of enhancement curves in fibroadenomas is related to straight and regular vessels, while arteriovenous shunts in carcinomas cause early signal intensity peaks. Wash-out is longer in carcinomas than in fibroadenomas because the former present anarchic and tortuous vessels with slow flows. CONCLUSIONS: Levovist enhanced US is a complementary test to study known breast lesions which permits the differential diagnosis of carcinomas and fibroadenomas. Our results justify a larger clinical trial to assess the role of this technique for diagnosis, prognosis and staging purposes.

[Positive predictive value of radiologic features in mammography and contribution of assessment procedures]. / Valore predittivo positivo dei segni radiologici in mammografia e apporto degli esami di approfondimento.

PURPOSE: To investigate the positive predictive value for cancer of abnormal mammographic findings and the role of assessment procedures. MATERIALS AND METHODS: We reviewed a series of 962 patients recalled and examined in the 1st Breast Screening Center of Turin, out of 18; 996 women aged 50-59 screened for the first time from 1991 to 1995, within a population-based mammography program. The diagnostic assessment procedures included one or more of the following: physical examination, additional mammographic views (detail or magnification), ultrasonography, and ultrasonography/X-ray-guided fine needle aspiration cytology. Surgical biopsies detected 152 cancers. RESULTS: The positive predictive value for screening mammography with abnormal findings steadily grew from 10.9% in 1991-92 to 15.6% in 1993, topping 21.1% in 1994 and 20.1% in 1995. The highest positive predictive value for cancers was observed among cases referred for opacities with irregular margins (88.2%) and isolated calcifications (23.8%). The benign/malignant biopsy ratio was .54 in 1991-92, .31 in 1993, .27 in 1994 and .25 in 1995. The accuracy of assessment procedures was different for each abnormal radiologic sign: the accuracy of cytology was high for opacities, intermediate for calcifications, low for architectural distortions; ultrasonography and physical examination had low sensitivity among cases referred for calcifications or opacities with regular margins. The positive predictive value of surgical indications was high for opacities, intermediate for calcifications, low for architectural distortions. The role of assessment procedures in excluding surgery was different for each abnormal radiologic sign. DISCUSSION AND CONCLUSIONS: The results of this study confirm the accuracy of mammography in the early detection of breast cancer and the different role of assessment procedures in the various abnormal mammographic findings. The improvement in positive predictive value for screening recalls from about 10% (close to recommended European standards) up to about 20% (well above European standards) demonstrates the importance of the "learning curve" within the screening team. Most of this improvement could be referred to refined diagnostic criteria for calcifications, as shown by an increase in positive predictive value for calcifications from 13.7% in 1991-92 to 40.5% in 1995.

[Breast carcinoma diagnosed in mammographic screening incidentally. Research on the radiologic signs in prior mammograms]. / Il carcinoma mammario diagnosticato nello screening mammografico nei passaggi di incidenza. Ricerca dei segni radiologici sulle mammografie precedenti.

PURPOSE: To determine how many cancers screen-detected at subsequent rounds were already visible on previous screening mammograms, and to study their radiological features. MATERIALS AND METHODS: The previous screening mammograms of 100 women who had cancers screen-detected at subsequent rounds (group A), and the negative screening mammograms of 200 women (group B) who had a further negative screening test two years later, were mixed for a new reading. The two groups were similar for age and year of examination. These films were blindly reviewed by 5 radiologists. Then, mammograms were reviewed retrospectively, with knowledge of subsequent diagnostic results. Finally the A group findings were classified as: 1) true negative: no radiological signs; 2) minimal sign: a nonspecific abnormality is retrospectively visible at the site of subsequent cancer; 3) false negative: "she should have been recalled"; 4) misdiagnosis at assessment: the woman had been recalled, but the cancer was missed after the assessment procedures. RESULTS: 60% of cases were true negatives, 29% were minimal signs, 9% were false negative and 2% were misdiagnosed at assessment. The most common radiological sign found among false negative cases was an architectural distortion: opacities and calcifications were more frequent among minimal signs. Only 10 of 40 cancers retrospectively visible on previous mammograms had reached stage II at diagnosis. At blinded review, the radiologists found false abnormalities in a considerable number of healthy women (average: 29%). DISCUSSION AND CONCLUSIONS: Our study shows that mammography sensitivity can be improved. Cancer radiological signs may go undetected due to difficult interpretation (opacities, calcifications) or perception (architectural distortions). The use of a low threshold of suspicion (as in a reading test) in real screening might permit to detect more cancers (most of them, however, would not reach advanced stages at subsequent rounds), but might also lead to many unnecessary assessments and, probably, to some benign biopsies in healthy women. In conclusion, an attempt at improving mammography sensitivity by lowering the threshold of suspicion can not be directly recommended due to the considerable negative effects related to a loss in specificity. A reading test similar to the one presented in our study would be a useful training procedure for radiologists who are involved in a screening program.

Aspectos epidemiológicos da mortalidade por asma no Rio Grande do Sul / Epidemiologic aspects of mortality due to asthma in Rio Grande do Sul, Brazil

Objetivando dimensionar a mortalidade por asma no Rio Grande do Sul entre 1970/92, foram estudadas as 425 mortes por aquela doença (CID 493) ocorridas entre 5 e 39 anos registradas na SSMA/RS. Os coeficientes de mortalidade foram padronizados (método direto) antes dos procedimentos de regressöes linear e exponencial. Os coeficientes variaram entre 0,040-0,689/100.000, conforme o ano e faixas etárias, estando distribuídos näo uniformemente entre regiöes do Estado. Constatou-se aumento do número de óbitos no inverno. As taxas na faixa etária de 5 a 19 anos, mostraram tendência de aumento médio anual de 8,39 por cento, representando + 233,71 por cento nos coeficientes; na faixa etária de 5 a 39 anos, o aumento foi de 2,07 por cento, significando + 33,44 por cento em tais coeficientes. No grupo de 20 a 39 anos näo foi possível configurar tendência. A mortalidade por asma no Rio Grande do Sul é de pequena magnitude, porém apresenta importante aumento nos coeficientes na faixa etária de 5 a 19 e, de menor monta, na de 5 a 39 anos de idade