Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension

The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term ""non-PAH PH"" summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH. (J Am Coll Cardiol 2009;54:S85-96) (C) 2009 by the American College of Cardiology Foundation

Effects of Optimal Medical Treatment With or Without Coronary Revascularization on Angina and Subsequent Revascularizations in Patients With Type 2 Diabetes Mellitus and Stable Ischemic Heart Disease

Background-In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, an initial strategy of coronary revascularization and optimal medical treatment (REV) compared with an initial optimal medical treatment with the option of subsequent revascularization (MED) did not reduce all-cause mortality or the composite of cardiovascular death, myocardial infarction, and stroke in patients with type 2 diabetes mellitus and stable ischemic heart disease. In the same population, we tested whether the REV strategy was superior to the MED strategy in preventing worsening and new angina and subsequent coronary revascularizations. Methods and Results-Among the 2364 men and women (mean age, 62.4 years) with type 2 diabetes mellitus, documented coronary artery disease, and myocardial ischemia, 1191 were randomized to the MED and 1173 to the REV strategy preselected in the percutaneous coronary intervention (796) and coronary artery bypass graft (377) strata. Compared with the MED strategy, the REV strategy at the 3-year follow-up had a lower rate of worsening angina (8% versus 13%; P < 0.001), new angina (37% versus 51%; P = 0.001), and subsequent coronary revascularizations (18% versus 33%; P < 0.001) and a higher rate of angina-free status (66% versus 58%; P = 0.003). The coronary artery bypass graft stratum patients were at higher risk than those in the percutaneous coronary intervention stratum, and had the greatest benefits from REV. Conclusions-In these patients, the REV strategy reduced the occurrence of worsening angina, new angina, and subsequent coronary revascularizations more than the MED strategy. The symptomatic benefits were observed particularly for high-risk patients.

Double-blind, Randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR +) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR + advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane ( n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups ( hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate ( 7.4% v 6.7%; P = .736) and clinical benefit rate ( 32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

rTMS treatment for depression in Parkinson`s disease increases BOLD responses in the left prefrontal cortex

The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson`s disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic Stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.

Long-Term Results of Percutaneous Bilioenteric Anastomotic Stricture Treatment in Liver-Transplanted Children

The purpose of this study was to evaluate the mid- and long-term results of percutaneous transhepatic cholangiography (PTC) and biliary drainage in children with isolated bilioenteric anastomotic stenosis (BAS) after pediatric liver transplantation. Sixty-four children underwent PTC from March 1993 to May 2008. Nineteen cholangiograms were normal; 10 showed intrahepatic biliary stenosis and BAS, and 35 showed isolated BAS. Cadaveric grafts were used in 19 and living donor grafts in 16 patients. Four patients received a whole liver, and 31 patients received a left lobe or left lateral segment. Roux-en-Y hepaticojejunostomy was performed in all patients. Indication for PTC was based on clinical, laboratory, and histopathologic findings. In patients with isolated BAS, dilation and biliary catheter placement, with changes every 2 months, were performed. Patients were separated into 4 groups according to number of treatment sessions required. The drainage catheter was removed if cholangiogram showed no significant residual stenosis and normal biliary emptying time after a minimum of 6 months. The relationship between risk factors (recipient`s weight < 10 kg, previous exposure to Cytomegalovirus, donor-recipient sex and weight relations, autoimmune disease as indication for transplantion, previous Kasai`s surgery, use of reduced liver grafts, chronic or acute rejection occurrence) and treatment was evaluated. Before PTC, fever was observed in 46%, biliary dilation in 23%, increased bilirubin in 57%, and increased gamma-glutamyltransferase (GGT) in 100% of patients. In the group with BAS, 24 of 35 (69%) patients had histopathologic findings of cholestasis as did 9 of 19 (47%) patients in the group with normal PTC. Of the 35 patients, 23 (65.7%) needed 1 (group I), 7 needed 2 (group II), 4 needed 3 (group III), and 1 needed 4 treatment sessions (group IV). The best results were observed after 1 treatment session, and the mean duration of catheter placement and replacement was 10 months. The primary patency rate was 61.2%, and the recurrence rate was 34.3% (group I). Seven patients (7 of 35; 20%) had their stricture treated with a second treatment session (group II). The average drainage time in group II was 24 months. During a period > 20 months, 4 patients (4 of 35; 11.4%) required 1 additional treatment session (group III), and 1 patient (1 of 35; 2.9%) had a catheter placed at the end of the study period (group IV). Drainage time in group I was significantly shorter than those in groups II, III, and IV (p < 0.05). There was no statistically significant relation between therapeutic response and the selected risk factors (p > 0.05). The majority of complications, such as catheter displacement and leakage, were classified as minor; however, 2 patients (5.7%) with hemobilia were noted. Complications increased according to the need for reintervention. In conclusion, balloon dilation and percutaneous drainage placement is safe and effective, and it has long-term patency for children with BAS after liver transplantation. Because of prolonged treatment time, reintervention may be necessary, thereby increasing the complication rate. Balloon dilation and percutaneous drainage placement should be considered as the first treatment option because of its minimally invasive nature.

Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields

BACKGROUND: Therapeutic options for patients with advanced hepatocellular carcinoma (HCC) are limited. There is emerging evidence that the growth of cancer cells may be altered by very low levels of electromagnetic fields modulated at specific frequencies. METHODS: A single-group, open-label, phase I/II study was performed to assess the safety and effectiveness of the intrabuccal administration of very low levels of electromagnetic fields amplitude modulated at HCC-specific frequencies in 41 patients with advanced HCC and limited therapeutic options. Three-daily 60-min outpatient treatments were administered until disease progression or death. Imaging studies were performed every 8 weeks. The primary efficacy end point was progression-free survival >= 6 months. Secondary efficacy end points were progression-free survival and overall survival. RESULTS: Treatment was well tolerated and there were no NCI grade 2, 3 or 4 toxicities. In all, 14 patients (34.1%) had stable disease for more than 6 months. Median progression-free survival was 4.4 months (95% CI 2.1-5.3) and median overall survival was 6.7 months (95% CI 3.0-10.2). There were three partial and one near complete responses. CONCLUSION: Treatment with intrabuccally administered amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of antitumour effects in patients with advanced HCC. British Journal of Cancer (2011) 105, 640-648. doi:10.1038/bjc.2011.292 www.bjcancer.com Published online 9 August 2011 (C) 2011 Cancer Research UK

Gene expression profile of residual breast cancer after doxorubicin and cyclophosphamide neoadjuvant chemotherapy

In breast cancer patients, primary chemotherapy is associated with the same survival benefits as adjuvant chemotherapy. Residual tumors represent a clinical challenge, Lis they may be resistant to additional cycles of the same drugs. Our aim was to identify differential transcripts expressed in residual tumors, after neoadjuvant chemotherapy, that might be related with tumor resistance. Hence, 16 patients with paired tumor samples, collected before and after treatment (4 cycles doxorubicin/cyclophosphamide, AC) had their gene expression evaluated on cDNA microarray slides containing 4,608 genes. Three hundred and eighty-nine genes were differentially expressed (paired Student`s t-test, pFDR<0.01) between pre- and post-chemotherapy samples and among the regulated functions were the JNK cascade and cell death. Unsupervised hierarchical clustering identified one branch comprising exclusively, eight pre-chemotherapy samples and another branch, including the former correspondent eight post-chemotherapy samples and other 16 paired pre/post-chemotherapy samples. No differences in clinical and tumor parameters could explain this clustering. Another group of I I patients with paired samples had expression of selected genes determined by real-time RT-PCR and CTGF and DUSP1 were confirmed more expressed in post- as compared to pre-chemotherapy samples. After neoadjuvant chemotherapy some residual samples may retain their molecular signature while others present significant changes in their gene expression, probably induced by the treatment. CTGF and DUSP1 overexpression in residual samples may be a reflection of resistance to further administration of AC regimen.

Plasma Osteopontin Levels in Patients With Head and Neck Cancer Undergoing Chemoradiotherapy

Objectives: To explore the prognostic role of plasma levels of osteopontin (OPN), a phosphoglycoprotein with adhesive properties, in patients with head and neck squamous cell carcinoma (HNSCC) undergoing concomitant chemoradiotherapy. Previous studies have proposed OPN level as a prognostic factor in several cancers. Design: Prospective analysis of plasma OPN levels, before and within 12 weeks after treatment, in a cohort of patients with HNSCC undergoing platinum-based chemoradiotherapy at our center. Setting: Academic center. Patients: Sixty-nine patients diagnosed as having HNSCC. Interventions: Plasma levels of OPN were assessed before the start and after the conclusion of chemoradiotherapy by using an enzyme-linked immunosorbency assay kit. Chemoradiotherapy was exclusive (n = 52) or adjuvant to surgery (n = 17). Main Outcome Measures: Levels of OPN were correlated with clinicopathological characteristics, to treatment, and overall survival. Results: Pretreatment plasma OPN levels were higher in patients with advanced T and N stages compared with patients with early stages (P = .009 and .07, respectively). Mean (SD) plasma levels of OPN measured before (102.5 [68.1] ng/mL) and after (104.0 [53.6] ng/mL) treatment did not differ (P = .18, paired t test). Pretreatment and posttreatment levels of OPN were lower in patients who achieved a complete response compared with those who failed to respond (75.0 [41.5] vs 131.2 [82.9] ng/mL [P = .005] and 86.8 [40.5] vs 141.6 [58.4] ng/mL [P = .004], respectively). Patients with high pretreatment OPN levels (> 82.1 ng/mL) had shorter survival time (P < .001). Posttreatment OPN levels were marginally (P = .10) associated with survival time in univariate analysis. Conclusions: In patients with HNSCC undergoing chemoradiotherapy, a low pretreatment plasma OPN level is associated with treatment response and better survival. Modulation of OPN levels by chemoradiotherapy may also be associated with outcome. Further studies with serial measurement of OPN levels are warranted in these patients.

Could the treatment of differentiated thyroid carcinoma with 3.7 and 5.55 GBq of ((131)I)NaI, on an outpatient basis, be safe?

Objectives The first objective of this study was to evaluate the radiological impact on relatives and the environment because of outpatient treatment of differentiated thyroid carcinoma with 3.7 and 5.55 GBq of ((131)I)NaI. The second objective was to determine, analyze, and evaluate whole-body radiation dose to caregivers, the production of contaminated solid waste, and the potentiality of radiation dose and surface contamination existing inside patients` households. Methods Twenty patients were treated on an outpatient basis, taking into consideration their acceptable living conditions, interests, and willingness to comply with medical and radiation-safety guidelines. The caregivers themselves, as well as the potentiality of the radiation dose inside patients` residences, were monitored with a thermo-luminescence dosimeter. Surface contamination and contaminated solid wastes were identified and measured by using a Geiger-Muller detector. Results and discussion Twenty-six monitored individuals received accumulated effective radiation doses of less than 1.0 mSv, and only one 2.8 mSv, throughout the 7 days of measurement. The maximum registered value for the potential of radiation dose inside all living areas was 1.30 mSv. The monitored surface contamination inside patients` dwellings showed a mean value of 4.2 Bq/cm(2) for all surfaces found to be contaminated. A total of 2.5l of contaminated solid waste was generated by the patients with 3.33 MBq of all estimated activity. Conclusion This study revealed that the treatment of differentiated thyroid carcinoma with 3.7 and 5.55 GBq of ((131)I)NaI, on an outpatient basis, can be safe when overseen by qualified professionals and with an adapted radiation-protection guideline. Even considering the radioiodine activity level and the dosimetric methodology applied here, negligible human exposure and a nonmeasurable radiological impact to the human environment were found. Nucl Med Commun 30:533-541 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Mammography findings following electron intraoperative radiotherapy or external radiotherapy for breast cancer treatment

Radiotherapy following breast cancer conserving surgery decreases the risks of local recurrence. Because 85% of breast cancers relapse in or around the surgical bed there has been some debate on the need for irradiating the whole breast. Electron intraoperative radiotherapy (ELIOT) has been used as a viable alternative for conventional external radiotherapy (RT). While the former requires a single dose of 21 Gy in the tumoral bed, the latter requires 5-6 weeks of irradiation with a total dose of 50 Gy and a boost of 10 Gy that irradiates the surgical bed. Herein, we investigated whether any significant differences exist between the mammography findings obtained from patients submitted to one of the two techniques. Two groups of 30 patients each were included in this study. All patients had mammographies taken at 12 and 24 months after finishing treatment. The mammography findings evaluated were: cutaneous thickening (>2 mm), architectural distortion secondary to fibrosis, edema, calcifications (both benign and malignant), and fat necrosis. For all variables studied, there was no statistical difference between the two groups. This indicates that the mammography findings obtained in either 12- or 24-month follow-up periods after breast cancer conserving surgery are similar, regardless of which of the two radiotherapy techniques (ELIOT or RT) is employed as a treatment for breast cancer. (C) 2010 Published by Elsevier Ireland Ltd.

Midterm and long-term results of percutaneous endovascular treatment of venous outflow obstruction after pediatric liver transplantation

PURPOSE: To evaluate retrospectively the midterm and long-term results of percutaneous endovascular treatment of venous outflow obstruction after pediatric liver transplantation. MATERIALS AND METHODS: During a 9-year period, 18 children with obstruction of a hepatic vein (HV) or inferior vena cava (IVC) anastomosis underwent percutaneous transluminal angioplasty (PTA) with balloon dilation or stent placement in case of PTA failure after liver transplantation. Patients` body weights ranged from 7.7 kg to 42.6 kg (mean, 18.8 kg +/- 9). Potential predictors of patency were compared between balloon dilation and stent placement groups. RESULTS: Forty-two procedures were performed (range, 1-11 per patient; mean, 2). Technical and initial clinical success were achieved in all cases. Major complications included one case of pulmonary artery stent embolization and one case of hemothorax. Three children (25%) with HV obstruction were treated with PTA and nine (75%) were treated with stent placement. Three children with IVC obstruction (75%) were treated with PTA and one (25%) was treated with a stent. There were two children with simultaneous obstruction at the HV and IVC; one was treated with PTA and the other with a stent. Cases of isolated HV stenosis have a higher probability of patency with balloon-expandable stent treatment compared with balloon dilation (P < .05). Follow-up time ranged from 7 days to 9 years (mean, 42 months +/- 31), and the primary assisted patency rate was 100% when stent placement was performed among the first three procedures. CONCLUSIONS: In cases of venous outflow obstruction resulting from HV and/or IVC lesions after pediatric liver transplantation, percutaneous endovascular treatment with balloon dilation or stent placement is a safe and effective alternative treatment that results in long-term patency.

Infusion of Recombinant Human Tissue Plasminogen Activator Through the Superior Mesenteric Artery in the Treatment of Acute Mesenteric Venous Thrombosis

Acute mesenteric venous thrombosis is an uncommon condition that is usually treated with systemic anticoagulation. Catheter-directed thrombolysis through the superior mesenteric artery may be a viable adjunct to treat this morbid condition. In the present article, we have described a case of superior mesenteric venous thrombosis treated with catheter-directed infusion of tissue plasminogen activator through the superior mesenteric artery.

Remission of extensive lentigo maligna after treatment with imiquimod

Lentigno maligna is a melanoma in situ that most commonly appears on areas exposed to ultraviolet radiation, in elderly patients. Treatment is required mainly to minimize the risk of progression to lentigo maligna melanoma. The present report refers to an elderly patient with recurrent lesions of lentigo maligna in her face, who was successfully treated with topical imiquimod, which showed to be a useful therapy for some cases of the disease.

Predictors of higher number of stages in Mohs micrographic surgery for the treatment of squamous cell carcinoma of the head

BACKGROUND - Squamous cell carcinomas of the skin of the bead are better treated with Mobs micrographic surgery which has the lowest recurrence rates and allows spare normal tissue. There are some characteristics of squamous cell carcinoma that can be related to a higher number of surgical stages. OBJECTIVE - To study characteristic of head squamous cell carcinoma that predicts a higher number of Mohs surgical stages. METHODS - A retrospective analysis of 51 squamous cell carcinomas of the bead treated with Mobs surgery was performed to determine risk factors for a higher number of surgical stages. The characteristics analyzed were clinical limits, morphology, recurrence, histological differentiation and size and compared to the number of surgical stages. The analysis was performed by Fisher`s exact test and multivariate logistic regression. RESULTS - The recurrent squamous cell carcinomas showed a tendency for a higher number of stages (p=0,081). The Odds Ratio for a higher number of Mobs stages was three for inaccurate limits; although not statistically significant, it corroborates clinical and previous publication. CONCLUSION - Clinical characteristics of squamous cell carcinoma as recurrence and inaccurate limits would not predict, but could indicate tendency of a higher number of Mobs micrographic surgery stages.

Urticaria unresponsive to antihistaminic treatment: An open study of therapeutic options based on histopathologic features

Background: The non- or low-sedating H1 receptor antagonists represent the basic therapy for urticaria. Objective: To test an alternative approach to patients unresponsive to conventional treatment. Materials and methods: A total of 22 patients with chronic urticaria unresponsive to conventional antihistamine treatment were enrolled for this study. They had uncontrolled urticaria even using multiple combinations of antihistamines on maximum doses and corticosteroids in short cycles (prednisone 20-40 mg, per os once a day, 3-7 days per month). Cutaneous biopsies of the urticaria lesions were taken. These findings were classified as: (I) a mixture of perivascular dermal inflammatory infiltrate composed of lymphocytes, monocytes and neutrophils and/or eosinophils; (II) inflammatory infiltrate composed chiefly of neutrophils; and (III) inflammatory infiltrate composed mainly of eosinophils. According to histology, the patients were submitted to one of the following therapeutic schemes: class A - antihistamine treatment plus dapsone; class B - colchicine or dapsone; class C montelukast. Results: Four patients in class A, 08 in class B and seven in class C displayed complete control of urticaria after 12 weeks of treatment; one patient in class B and two in class C did not respond to treatment. Two years after discontinuation, 16 patients are still free of urticaria. Conclusions: This study suggests an alternative approach for treating unresponsive chronic urticaria.