Effects of Ultrasound-Guided Injection Combined with a Targeted Therapeutic Exercise in Breast Cancer Women with Subacromial Pain Syndrome: A Randomized Clinical Study.

In this randomized controlled study, we aimed to assess the effects of US-guided injections of the subacromial bursa followed by a personalized rehabilitation program for breast cancer (BC) survivors. We assessed patients with subacromial pain syndrome without tendon lesions and with a history of post-surgical non-metastatic BC. Thirty-seven patients were enrolled and randomly assigned 1:1 to receive US-guided corticosteroid injections combined with a personalized rehabilitation program (Group A; n: 19) or US-guided corticosteroid injections alone (Group B; n: 18). The primary outcome was pain relief, assessed using a numerical pain rating scale (NPRS). The secondary outcomes were muscle strength, shoulder function, and quality of life. No major or minor late effects were reported after the multidisciplinary intervention. Statistically significant within-group differences were found in terms of NPRS (p ≤ 0.05) in both groups. No significant between-group differences were reported after one week. However, the between-group analysis showed significant differences (p ≤ 0.05) after three months of follow-up in terms of pain intensity, muscle strength, shoulder function, and quality of life. Our findings suggested positive effects of a multidisciplinary approach including US-guided corticosteroid injections combined with a personalized rehabilitation program in improving pain intensity and quality of life of BC survivors with subacromial pain syndrome.

Evaluation of Newly Designed and Traditional Punches in Manufacturing of Scored ODTs.

To overcome difficulties in splitting, uneven breaking and inconsistent dosing frequently reported with scored tablets, a novel punch was proposed for the manufacturing of easy breakable tablets (EBTs). In this work, the performance of the EBT punch was investigated vs. a ridged one for traditional breakable tablets (TBTs) using a furosemide powder formulation for orally disintegrating tablets (ODTs). A Face Centered Central Composite Design was applied to investigate the influence of punch type, compaction force, tablet weight and press rotation speed on the mechanical properties of ODTs, their behavior in aqueous fluids and aptitude for splitting. Mass uniformity and adequate crushing strength, friability, water uptake, disintegration and wetting times were obtained from both TBTs and EBTs. Interestingly, more favorable splitting behavior was shown by tablets manufactured by the novel punch, in view of lower mass loss and portion mass variability after breaking. The ease of breaking, accuracy of subdivision and mass loss of ODTs were also evaluated by a volunteer (n = 20) panel test. Less difficulty was found in splitting EBTs than TBTs (p < 0.05), and a larger number of tablets were properly broken into four parts. Thus, this study proved the usefulness of the EBT punch in overcoming drawbacks associated with divisible tablets.

Preparation of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug.

The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates.

Nanonized itraconazole powders for extemporary oral suspensions: Role of formulation components studied by a mixture design.

Itraconazole (ITZ) nanocrystal-containing powders were prepared through the combined use of high pressure homogenization (HPH) and spray drying (SD). These powders were intended as base materials for the preparation of extemporary oral suspensions of the drug. The role and the effect of stabilizers on the size of re-dispersed particles were studied using a mixture design and a Scheffé model relating the dried nanosuspension composition to the mean particle diameters. The homogenization process required a surface active agent (Tween 20) to obtain the efficient comminution of itraconazole micronized powder. SD was carried out on ITZ nanosuspensions after addition of a cellulose derivative (Methocel(®) E5) that allowed the prompt re-dispersion of nanoparticles under "in use" conditions. The powders obtained by drying of homogenized systems showed in vitro dissolution profile faster than that of the micronized drug, suggesting a potential ameliorated GI absorption of itraconazole released from the nanosuspensions.

Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival: A Randomized Clinical Trial.

IMPORTANCE: Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy. OBJECTIVE: To evaluate long-term results of LHRHa-induced ovarian suppression during breast cancer chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Parallel, randomized, open-label, phase 3 superiority trial conducted at 16 Italian sites. Between October 2003 and January 2008, 281 premenopausal women with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer were enrolled. Last annual follow-up was June 3, 2014. INTERVENTIONS: Patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). MAIN OUTCOMES AND MEASURES: The primary planned end point was incidence of chemotherapy-induced early menopause. Post hoc end points were long-term ovarian function (evaluated by yearly assessment of menstrual activity and defined as resumed by the occurrence of at least 1 menstrual cycle), pregnancies, and disease-free survival (DFS). RESULTS: A total of 281 women (median age, 39 [range, 24-45] years) were randomized. Median follow-up was 7.3 years (interquartile range, 6.3-8.2 years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% CI, 65.7%-80.3%) among the 148 patients in the LHRHa group and 64.0% (95% CI, 56.2%-72.8%) among the 133 patients in the control group (hazard ratio [HR], 1.28 [95% CI, 0.98-1.68]; P = .07; age-adjusted HR, 1.48 [95% CI, 1.12-1.95]; P = .006). Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1% [95% CI, 0.7%-6.3%]) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6% [95% CI, 0.4%-6.2%]) in the control group (HR, 2.56 [95% CI, 0.68-9.60]; P = .14; age-adjusted HR, 2.40 [95% CI, 0.62-9.22]; P = .20). Five-year DFS was 80.5% (95% CI, 73.1%-86.1%) in the LHRHa group and 83.7% (95% CI, 76.1%-89.1%) in the control group (LHRHa vs control: HR, 1.17 [95% CI, 0.72-1.92]; P = .52). CONCLUSIONS AND RELEVANCE: Among premenopausal women with either hormone receptor-positive or hormone receptor-negative breast cancer, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone, was associated with higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate. There was no statistically significant difference in DFS for women assigned to triptorelin and those assigned to chemotherapy alone, although study power was limited. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00311636.

Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.

CONTEXT: Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. OBJECTIVE: To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. DESIGN, SETTING, AND PATIENTS: The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. INTERVENTIONS: Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. MAIN OUTCOME MEASURE: Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). RESULTS: The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). CONCLUSION: The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00311636.

N-terminal pro-brain natriuretic peptide on admission has prognostic value across the whole spectrum of acute coronary syndromes.

BACKGROUND: The prognostic value of natriuretic peptide elevations in patients with acute coronary syndromes (ACS) is still incompletely defined. We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) on admission in patients with ACS and ECG evidence of myocardial ischemia. METHODS AND RESULTS: The NT-proBNP was measured at a median time of 3 hours after symptom onset in 1756 patients. The outcome measure was death at 30 days, which occurred in 113 patients (6.4%). The median NT-proBNP level was 353 ng/L (107 to 1357 ng/L). Compared with the lowest quartile, patients in the second, third, and fourth quartiles had a relative risk of subsequent death of 2.94 (95% CI, 1.15 to 7.52), 5.32 (95% CI, 2.19 to 12.91), and 11.5 (95% CI, 4.90 to 26.87), respectively. The NT-proBNP was independently associated with death in a logistic regression model, which included clinical variables, ECG, and troponin T in patients either with (OR of highest versus lowest quartile, 7.0; 95% CI, 1.9 to 25.6) or without (OR of highest versus lowest quartile, 4.1; 95% CI, 1.1 to 14.6) persistent ST-segment elevation. NT-proBNP was also an independent predictor of severe heart failure. CONCLUSIONS: The measurement of NT-proBNP on admission improves the early risk stratification of patients with ACS, suggesting the need for the development of targeted therapeutic strategies.

Sentinel lymph node as a new marker for therapeutic planning in breast cancer patients.

BACKGROUND AND OBJECTIVES: Literature review suggests that the sentinel lymph node (sN) represents a reliable predictor of axillary lymph node status in breast cancer patients; however, some important issues, such as the optimisation of the technique for the intraoperative identification of the sN, the role of intraoperative frozen section examination of the sN, and the clinical implications of sN metastasis as regards the surgical management of the axilla, still require further confirmation. The authors aimed (1) to assess the feasibility of sN identification with a combined approach (vital blue dye lymphatic mapping and radioguided surgery, RGS) and the specific contribution of either techniques to the detection of the sN, (2) to determine the accuracy and usefulness of intraoperative frozen section examination of the sN in order to perform a one-stage surgical procedure, and (3) to define how the sN might modulate the therapeutic planning in different stages of disease. MATERIALS AND METHODS: From October 1997 to June 2001, 334 patients with early-stage (T(1-2) N(0) M(0)) invasive mammary carcinoma underwent sN biopsy; the average age of patients was 61.5 years (range, 39-75 years). In a subset of 153 patients, both vital blue dye (Patent Blue-V) lymphatic mapping and RGS were used to identify the sN, and the relative contribution of each of the two techniques was assessed. RESULTS: In the whole group, the sN was identified in 326 of 334 patients (97.6%), and 105 of 326 patients (37.3%) had positive axillary lymph nodes (pN+). In 9 of 105 pN+ patients, the definitive histologic examination of the sN did not show metastases but these were detected in non-sN, thus giving an 8.6% false-negative rate, a negative predictive value of 94.5% (156/165), and an accuracy of 96.5% (252/261). As regards the specific contribution of the two different techniques used in the identification of the sN, the detection rate was 73.8% (113/153) with Patent Blue-V alone, 94.1% (144/153) with RGS alone, and 98.7% (151/153) with Patent Blue-V combined with RGS (P < 0.001). Noteworthy, whenever the sN was identified, the prediction of axillary lymph node status was remarkably similar (93-95% sensitivity; 100% specificity; 95-97% negative predictive value, and 97-98% accuracy) whichever of the three procedures was adopted (Patent Blue-V alone, RGS alone, or combined Patent Blue-V and RGS). Intraoperative frozen section examination was performed in 261 patients, who had at least one sN identified, out of 267 patients who underwent complete axillary dissection; 170 patients had histologically negative sN (i.o. sN-) and 91 patients histologically positive sN (i.o. sN+). All 91 i.o. sN+ were confirmed by definitive histology, whereas in 14 of 170 i.o. sN- patients (8.2%) metastases were detected at definitive histology. As regards the correlation between the size of sN metastasis, the primary tumour size, and the status of non-sN in the axilla, micrometastases were detected at final histology in 23 patients and macrometastases in 82 patients. When only micrometastases were detected, the sN was the exclusive site of nodal metastasis in 20 of 23 patients (86.9%) while in 3 patients with tumour size larger than 10 mm micrometastases were detected also in non-sN. Macrometastases were never detected in pT(1a) breast cancer patients; the sN was the exclusive site of these metastases in 30 patients (36.6%), while in 52 patients (63.4%) there were metastases both in sN and non-sN. CONCLUSIONS: Sentinel lymphadenectomy can better be accomplished when both procedures (lymphatic mapping with vital blue dye and RGS) are used, because of the significantly higher sN detection rate, although the prediction of axillary lymph node status remains remarkably similar whichever method is used. The intraoperative frozen section examination proved to be rather accurate in predicting the actual pathologic status of the sN, with a negative predictive value of 91.8%; in 35% of patients it allowed sN biopsy and axillary dissection to be performed in a one-stage surgical procedure. Finally, specific clinical and histopathologic features of the primary tumour and sN might be used to tailor the loco-regional and systemic treatment in different clinical settings, such as in ductal carcinoma in-situ (DCIS), early-stage invasive breast cancer, and patients with large breast cancer undergoing neo-adjuvant CT for breast-saving surgery as well as elderly patients with operable breast cancer.

Quantitative Texture Analysis in Two-Dimensional Echocardiography: Application to the Diagnosis of Myocardial Hemochromatosis.

BACKGROUND: Myocardial reflectivity is abnormally increased in patients with thalassemia major under transfusion treatment, probably due to myocardial iron deposits and/or secondary structural changes. Such increased reflectivity has been detected by both qualitative and subjective analysis of two-dimensional echocardiographic (2-D echo) images and quantitative assessment of integrated backscatter amplitude with noncommercially available ultrasound prototypes. The purpose of this study was to assess the acoustic properties of myocardium in patients with beta-thalassemia major and iron overload by means of quantitative computerized offline textural analysis of conventionally recorded 2-D echo images, and to compare textural data with other qualitative (visual assessment) and quantitative (ultrasound backscatter analysis) approaches for myocardial ultrasound tissue characterization simultaneously applied to these patients. METHODS AND RESULTS: Thirty-five young patients with thalassemia major, without clinical signs of cardiac failure, and 20 age and sex matched normal controls were studied by echocardiography. Each patient was receiving blood transfusion every 2-3 weeks. Two-dimensional echo images, obtained with a commercially available echocardiograph using the parasternal long-axis view, were digitized off line and analyzed by first and second order texture algorithms applied to regions of interest in the myocardium (septal and posterior wall). The mean gray level value was higher in thalassemic patients than in controls on both the septum (110 +/- 25 vs 57 +/- 13, arbitrary units on a 0-255 scale; P < 0.01) and posterior wall (91 +/- 25 vs 67 +/- 18; P < 0.01). Among second order statistical parameters, contrast and angular second moment significantly (P < 0.01) differentiated septal and posterior walls of patients and controls. In thalassemic patients, no consistent correlation was found between wall texture parameters and hematologic (years of transfusions and chelation, number of transfusions), 2-D echo (posterior wall thickness, left ventricular end-diastolic diameter), and Doppler (transmitral E/A waves ratio) parameters. Myocardial walls with visually assessed increased echo reflectivity showed a trend toward higher values of mean gray level when compared with myocardial segments with qualitatively assessed normal reflectivity (septum: 121 +/- 26 vs 106 +/- 24; posterior wall: 105 +/- 23 vs 87 +/- 23). Although radiofrequency integrated backscatter has been demonstrated to be capable of identifying thalassemic patients, no significant correlation was found between mean gray level (by texture analysis) and radiofrequency data (septum: r = 0.03; posterior wall: r = 0.09; P = NS for both). CONCLUSIONS: Myocardial walls affected by hemochromatosis show ultrasound image texture alterations that may be quantified with digital image analysis techniques and appear mostly unrelated to hematologic and conventional, as well as radiofrequency-based, echocardiographic parameters. These changes in quantitatively evaluated echo reflectivity are present even before the development of clinical and echocardiographic signs of cardiac dysfunction. (ECHOCARDIOGRAPHY, Volume 13, January 1996)