Multidisciplinary management of breast cancer concurrent with pregnancy.

The management of PABC is very difficult. The incidence of PABC is low, but may be increasing because of the number of women who are becoming pregnant at a later age. More investigation is needed to understand whether the biology of PABC is different from that of breast cancer in nonpregnant women. One exciting area of further research is the potential relationship between mutations in known breast cancer susceptibility genes and breast cancer development during pregnancy. Diagnosis or PABC remains challenging because of the anatomic and physiologic changes that occur in the breast during pregnancy. Understanding the generic influences on PABC may help physicians in diagnosing this disease earlier, and understanding the tumor-receptor characteristics of PABC can help physicians deliver effective treatment. The various modalities available for treatment of PABC and their risks and benefits must be discussed openly with patients and their families. Abortion is not usually recommended. Modified radical mastectomy is the recommended treatment for PABC diagnosed during the first trimester. Neoadjuvant or adjuvant chemotherapy can be given with minimal risks to the fetus during the second or third trimester. Radiation therapy is contraindicated during pregnancy because of the potential for injury to the fetus. Breast conservation therapy, with radiation treatments given after delivery or after neoadjuvant chemotherapy, is an option for women with PABC diagnosed late in pregnancy. Once the appropriate treatment modality is chosen, its implementation must not be delayed because of the pregnancy. Most of the literature shows that women with PABC have the same survival stage for stage as nonpregnant women with breast cancer. But some studies suggest that the prognosis is worse for patients who present with advanced-stage PABC. Finally, recurrence and survival in most patients previously treated for breast cancer do not appear to be adversely affected by subsequent pregnancy. Above all, the patient with breast cancer diagnosed during pregnancy is best served by early and continued involvement of a multidisciplinary cancer treatment team.     

Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney

Platelet-derived growth factor-C (PDGF-C) is a new member of the PDGF family. Its expression in normal and diseased kidney is unknown. Rabbit antisera were generated against human full-length, core domain, and mouse PDGF-C, and their specificity was confirmed by Western blot analyses. Renal PDGF-C expression was analyzed by immunohistochemistry in normal rats (n = 8), mesangioproliferative anti-Thy 1.1 nephritis (n = 4 each at days 1, 4, 6, and 85), passive Heymann nephritis (PHN, n = 4), puromycin nephrosis (PAN, n = 2), Milan normotensive rats (MN, n = 2), and obese Zucker rats (n = 3). PDGF-C expression was also studied in anti-Thy 1.1 rats treated with PDGF-B aptamer antagonists (n = 5) or irrelevant control aptamers (n = 5). PDGF-C was constitutively expressed in arterial smooth muscle cells and collecting duct epithelial cells. Mesangial PDGF-C was markedly upregulated in anti-Thy 1.1 nephritis in parallel with the peak mesangial cell proliferation. Furthermore, PDGF-CC acted as a potent growth factor for mesangial cells in vitro. Inhibition of PDGF-B via specific aptamers reduced the injury in anti-Thy 1.1 nephritis but did not affect the glomerular PDGF-C overexpression or the mitogenicity of PDGF-CC in vitro. In PHN, PAN, and obese Zucker rats, glomeruli remained negative for PDGF-C despite severe glomerular injury. PDGF-C localized to podocytes at sites of focal and segmental sclerosis in MN. Interstitial PDGF-C expression was increased at sites of fibrosing injury in obese Zucker rats. The use of the different antisera resulted in virtually identical findings. It is concluded that PDGF-C is a novel mesangial cell mitogen that is constitutively expressed in the kidney and specifically upregulated in mesangial, visceral epithelial, and interstitial cells after predominant injury to these cells. PDGF-C may therefore be involved in the pathogenesis of renal scarring.     

A rat model of otitis media with effusion caused by eustachian tube obstruction with and without Streptococcus pneumoniae infection: methods and disease course.

OBJECTIVE: To describe the clinical and histopathologic progression of a rat model of otitis media with effusion caused by eustachian tube obstruction (ETO) with and without Streptococcus pneumoniae infection. METHODS: In 164 rats, the left, bony eustachian tube was approached via a ventral incision and obstructed with dental material. Then 108 rats were infected via an intrabullar injection with S pneumoniae. At 48 hours, the infected rats were treated for 5 days with ampicillin. All ears were evaluated by weekly otomicroscopy. On each of days 1, 2, 7, 21, 35, 56, and 112, four rats were killed for histologic study. All effusions were cultured for bacteria. RESULTS: Fourteen rats died of surgical complications; effusion resolved by 2 weeks in 9 rats. During the first few days, infected ears with ETO had bulging tympanic membranes, followed by tympanic membrane retraction, purulent effusion, and otorrhea (50%) over the next few weeks, whereas uninfected ears with ETO developed retraction and serous effusion during the same time frame. At later times, all ears with ETO presented with retraction and serous or serous-mucoid effusion. S pneumoniae was recovered only from the infected ears with ETO (days 1 and 2), with some colonization by nonpathogenic microorganisms observed equally in both groups of ears. Histology showed a typical acute inflammatory reaction in the challenged ears with ETO through day 14 and then a chronic inflammation for all ears with ETO. CONCLUSION: The experimental methods provoked reproducible pathologic signs similar to those for otitis media with effusion. Given the availability of rat-specific reagents, this model is well suited for studies of cytokine elaboration during disease pathogenesis.     

Treatment Failure After Percutaneous Radiofrequency Ablation for Nonsurgical Candidates With Pulmonary Metastases From Colorectal Carcinoma

Background This study critically evaluated the local and overall treatment failure rates after percutaneous radiofrequency ablation (RFA) of pulmonary metastases from colorectal carcinoma. Methods Fifty-five nonsurgical candidates underwent RFA of colorectal pulmonary metastases. The primary end points of this study were local progression-free survival (PFS) and overall PFS. Univariate and multivariate analyses were performed to identify significant prognostic parameters for local and overall PFS. Results The local recurrence rate was 38%. For local PFS, univariate analysis demonstrated that the largest size of lung metastasis, the location of lung metastases, the post-RFA carcinoembryonic antigen level at 1 month, and the post-RFA carcinoembryonic antigen level at 3 months were significant prognostic indicators. In multivariate analysis, a largest size of lung metastasis of >3 cm and a post-RFA carcinoembryonic antigen level of >5 ng/mL at 1 month were independently associated with a reduced local PFS. The overall recurrence rate was 66%. For overall PFS, univariate analysis demonstrated that sex and the largest size of lung metastasis were significant prognostic indicators. In multivariate analysis, a largest size of lung metastasis of >3 cm was independently associated with a reduced overall PFS. Conclusions RFA of colorectal pulmonary metastases may have a useful role in local disease control for nonsurgical candidates, but its efficacy in patients with a lung metastasis of >3 cm is limited.     

Osteogenic potential of postnatal skeletal muscle-derived stem cells is influenced by donor sex.

This study compared the osteogenic differentiation of F-MDSCs and M-MDSCs. Interestingly, M-MDSCs expressed osteogenic markers and underwent mineralization more readily than F-MDSCs; a characteristic likely caused by more osteoprogenitor cells within the M-MDSCs than the F-MDSCs and/or an accelerated osteogenic differentiation of M-MDSCs. INTRODUCTION: Although therapies involving stem cells will require both female and male cells, few studies have investigated whether sex-related differences exist in their osteogenic potential. Here, we compared the osteogenic differentiation of female and male mouse skeletal muscle-derived stem cells (F- and M-MDSCs, respectively), a potential cell source for orthopedic tissue engineering. MATERIALS AND METHODS: F- and M-MDSCs were stimulated with bone morphogenetic protein (BMP)4, followed by quantification of alkaline phosphatase (ALP) activity and expression of osteogenic genes. F- and M-MDSCs were also cultured as pellets in osteogenic medium to evaluate mineralization. Single cell-derived colonies of F- and M-MDSCs were stimulated with BMP4, stained for ALP, and scored as either Low ALP+ or High ALP+ to detect the presence of osteoprogenitor cells. F- and M-MDSCs were transduced with a BMP4 retrovirus (MDSC-BMP4 cells) and used for the pellet culture and single cell-derived colony formation assays. As well, F- and M-MDSC-BMP4 cells were implanted in the intramuscular pocket of sex-matched and sex-mismatched hosts, and bone formation was monitored radiographically. RESULTS AND CONCLUSIONS: When stimulated with BMP4, both F- and M-MDSCs underwent osteogenic differentiation, although M-MDSCs had a significantly greater ALP activity and a larger increase in the expression of osteogenic genes than F-MDSCs. In the pellet culture assay, M-MDSCs showed greater mineralization than F-MDSCs. BMP4 stimulation of single cell-derived colonies from M-MDSCs showed higher levels of ALP than those from F-MDSCs. Similar results were obtained with the MDSC-BMP4 cells. In vivo, F-MDSC-BMP4 cells displayed variability in bone area and density, whereas M-MDSC-BMP4 cells showed a more consistent and denser ectopic bone formation. More bone formation was also seen in male hosts compared with female hosts, regardless of the sex of the implanted cells. These results suggest that M-MDSCs may contain more osteoprogenitor cells than F-MDSCs, which may have implications in the development of cellular therapies for bone healing.     

Chronic posttraumatic stress disorder after facial injury: a 1-year prospective cohort study

BACKGROUND: This study examined the prevalence, severity, and predictors of persistent traumatic stress symptoms in socioeconomically disadvantaged adults after orofacial injury. METHODS: A 1-year prospective study of 336 socioeconomically disadvantaged adults treated for orofacial injury at a Level I trauma center was conducted. Univariate analyses were performed on early measures of injury characteristics, prior trauma exposure, coping resources, and psychosocial functioning to select potential predictors of 1-year posttraumatic stress disorder (PTSD) scores; independence of variable contribution was then evaluated in multiple regression analyses. RESULTS: A substantial number of patients (23%) continued to experience significant PTSD symptomatology at 12 months. Predictors of PTSD symptoms at 12 months included current and lifetime mental health and social service needs, lifetime social service use, prior trauma exposure, sum of stressful life events in the year preceding injury, patient report of pain severity and inadequate social support at 10 days postdischarge, and PTSD scores at 1 month. One-month PTSD symptoms, unmet social service need, and need for more instrumental and emotional support were independent predictors of 12-month PTSD outcomes. Limitations include loss to follow up, use of self-report measures, and the possibility of additional traumatization in the follow-up year influencing symptom levels. CONCLUSIONS: Many socioeconomically disadvantaged adults manifest negative psychological outcomes even 1 year after an orofacial injury. Poor social support and unmet social service needs immediately after the injury, as well as high PTSD symptoms at 1 month postinjury, are strongly associated with the risk of developing chronic PTSD. The surgical management of orofacial injuries in disadvantaged individuals should integrate case management that addresses psychosocial sequelae and patient service needs.     

Treatment of incompetent vein of Giacomini (thigh extension branch)

Most varices secondary to truncal insufficiency arise from the greater saphenous vein (GSV), short saphenous vein (SSV), or accessory saphenous branch. However, an important etiology for varices that arise on the posterior thigh or calf is often overlooked. The thigh extension (TE) branch, also known as the vein of Giacomini in many patients, may also contribute to venous pathology. Patients were assigned to one of three categories depending on the anatomical findings. All patients were treated with a combination of endovenous ablation using a 940 nm Skin Pulse S laser and foam sclerotherapy. Eighteen patients were treated and followed for at least 2 years. There were no complications. All patients had successful ablation of the TE branch with successful obliteration of any perforators or collateral vessels. Varices secondary to TE branch insufficiency are common when coexisting SSV insufficiency is present. The incidence increases when both SSV insufficiency and GSV insufficiency exist. This study groups the pattern of TE branch pathology into three anatomical patterns. Combination therapy based on the prevalent anatomical group being treated was done. There was successful ablation in all groups with no complications. As experience in venous disease and expertise by the surgeon increases, more examples of this pattern of pathology will become evident.     

Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study

OBJECTIVE: To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled 'feeder' studies. PATIENTS AND METHODS: Patients entering the extension received darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS: In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change -84.4% at 2 years, P < 0.001 vs feeder-study baseline). After 2 years, > 40% of patients achieved a > or = 90% reduction in incontinence episodes/week. CONCLUSION: In the first published 2-year, open-label study of a CR antimuscarinic agent, darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, darifenacin represents a valuable therapeutic option for OAB.     

rt-PA Thrombolysis in Acute Thromboembolic Upper-Extremity Arterial Occlusion

Purpose: Retrospective analysis of the results of rt-PA thrombolysis in the treatment of acute thromboembolic occlusion of the upper limb. Methods: Of 55 patients with demonstrated acute embolic arterial occlusion, rt-PA thrombolysis was performed on 40 occlusions in 38 patients (23 women with a mean age of 62 years, range 32–85 years; 15 men with a mean age of 65 years, range 32–92 years) according to the following design: 6 mg rt-PA/hr for 30 min, 3 mg rt-PA/hr for the next 30 min, 1 mg rt-PA/hr for 7 hr, and 0.4 mg rt-PA/hr until the end of lysis. Onset of symptoms varied from 1 to 14 days. Included were three isolated upper-arm occlusions, nine combined brachial and forearm occlusions, and 28 forearm and hand artery occlusions. Results: The overall success rate was 55%. The lysis results for isolated upper arm, combined brachial and forearm occlusions, and forearm and hand artery occlusions were 100%, 66%, and 46%, respectively. In eight patients surgical embolectomy had to be performed after failed thrombolysis. No amputation was required in the follow-up period. No lethal complications occurred. Conclusions: Interventional rt-PA treatment of proximal upper-extremity arterial occlusions may be performed with comparable success rates to surgical embolectomy and without severe complications. For distal occlusions the results are inferior to the success rates obtained with surgery.     

Inhibiting activin‐A signaling stimulates bone formation and prevents cancer‐induced bone destruction in vivo

Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis (p < .01), promotes bone formation (p < .01) and increases bone mass in vivo (p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < .05) and suppression of bone formation (p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis (p < .01), prevents myeloma‐induced suppression of bone formation (p < .05), blocks the development of osteolytic bone lesions (p < .05), and increases survival (p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction (p < .001) and inhibits bone metastases (p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. © 2010 American Society for Bone and Mineral Research.