Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Development of the Asia Pacific Consortium on Osteoporosis (APCO) Framework: clinical standards of care for the screening, diagnosis, and management of osteoporosis in the Asia-Pacific region.

Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care. PURPOSE: Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development. METHODS: We conducted a structured comparative analysis of existing CPGs in the AP region using a "5IQ" model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards. RESULTS: Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines. CONCLUSION: The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.

Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review.

This systematic review summarizes the effect of combined exercise and nutrition intervention on muscle mass and muscle function. A total of 37 RCTs were identified. Results indicate that physical exercise has a positive impact on muscle mass and muscle function in subjects aged 65 years and older. However, any interactive effect of dietary supplementation appears to be limited. INTRODUCTION: In 2013, Denison et al. conducted a systematic review including 17 randomized controlled trials (RCTs) to explore the effect of combined exercise and nutrition intervention to improve muscle mass, muscle strength, or physical performance in older people. They concluded that further studies were needed to provide evidence upon which public health and clinical recommendations could be based. The purpose of the present work was to update the prior systematic review and include studies published up to October 2015. METHODS: Using the electronic databases MEDLINE and EMBASE, we identified RCTs which assessed the combined effect of exercise training and nutritional supplementation on muscle strength, muscle mass, or physical performance in subjects aged 60 years and over. Study selection and data extraction were performed by two independent reviewers. RESULTS: The search strategy identified 21 additional RCTs giving a total of 37 RCTs. Studies were heterogeneous in terms of protocols for physical exercise and dietary supplementation (proteins, essential amino acids, creatine, ß-hydroxy-ß-methylbuthyrate, vitamin D, multi-nutrients, or other). In 79% of the studies (27/34 RCTs), muscle mass increased with exercise but an additional effect of nutrition was only found in 8 RCTs (23.5%). Muscle strength increased in 82.8% of the studies (29/35 RCTs) following exercise intervention, and dietary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%). Finally, the majority of studies showed an increase of physical performance following exercise intervention (26/28 RCTs, 92.8%) but interaction with nutrition supplementation was only found in 14.3% of these studies (4/28 RCTs). CONCLUSION: Physical exercise has a positive impact on muscle mass and muscle function in healthy subjects aged 60 years and older. The biggest effect of exercise intervention, of any type, has been seen on physical performance (gait speed, chair rising test, balance, SPPB test, etc.). We observed huge variations in regard to the dietary supplementation protocols. Based on the included studies, mainly performed on well-nourished subjects, the interactive effect of dietary supplementation on muscle function appears limited.

Effect of omega-3 fatty acid supplementation on arterial elasticity in patients with familial hypercholesterolaemia on statin therapy.

BACKGROUND AND AIMS: Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated. METHOD AND RESULTS: We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P < 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration. CONCLUSIONS: ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.com/NCT01577056.

Association between teriparatide treatment persistence and adherence, and fracture incidence in Taiwan: analysis using the National Health Insurance Research Database.

UNLABELLED: Medication persistence and adherence are critical for osteoporosis outcomes. Using the Taiwan National Health Insurance Research Database, we found that persistence and adherence to teriparatide were low in Taiwanese patients with osteoporosis and that greater persistence and adherence were associated with a lower incidence of hip and other nonvertebral fractures. INTRODUCTION: The purpose of this study was to determine the persistence and adherence to teriparatide treatment in Taiwanese patients with osteoporosis, and to examine the association between persistence and adherence to teriparatide with fracture risks. METHODS: Medical and pharmacy claims for 4,692 patients with vertebral or hip fractures and teriparatide prescriptions between 2005 and 2008 were identified (Taiwan National Health Insurance Research Database). Persistence was the time from the start of treatment to the first 90-day gap between two teriparatide prescriptions. Adherence was the number of teriparatide pens (each pen is used over 1 month) prescribed over 24 months. Association of persistence and adherence to teriparatide with fracture incidence was assessed using adjusted Cox proportional hazards models. RESULTS: The proportion of patients persisting with teriparatide for >6 months and >12 months was 44.6 and 24.9 %, respectively. Over 24 months, 53.6 % of patients were adherent for >6 months and 33.9 % were adherent for >12 months. Patients persisting for >12 months had a significantly lower incidence of hip (adjusted hazard ratio [HR], 0.61 [95 % confidence interval (CI), 0.40-0.93], P = 0.0229) and nonvertebral fracture (HR, 0.79 [95 % CI, 0.63-0.99], P = 0.0462) compared with those who persisted for ≤12 months. Patients adherent for >12 months had a lower incidence of hip (HR, 0.66 [95 % CI, 0.46-0.96], P = 0.0286) and nonvertebral fracture (HR, 0.81 [95 % CI, 0.66-0.99], P = 0.0377) compared with those adherent for ≤12 months. CONCLUSIONS: Persistence and adherence to teriparatide over 24 months were low in Taiwanese patients with osteoporosis; greater adherence and persistence were associated with a lower incidence of nonvertebral fractures.

Association of estrogen receptor, progesterone receptor and HER2 following neoadjuvant systemic treatment in breast cancer patients undergoing surgery.

AIMS: The aim of this study was to analyze the association between the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) in breast cancer with neoadjuvant therapy by using tissue biopsy and surgical specimens. METHODS: This study included 78 patients with breast cancer, who presented to our hospital between June 1999 and June 2011, and were treated with neoadjuvant therapy and subsequent mastectomy or partial mastectomy. All clinicopathological data regarding pre-neoadjuvant biopsy and definitive surgical specimens were reviewed for accuracy. The status of ER, PR, and HER2 was determined by immunohistochemistry. RESULTS: Paired samples from 78 women (mean age 51.4 ± 11.7 years) were successfully analyzed. A switch in the status of ER was identified in 16 patients (20 %); PR, in 18 (23 %); and HER2, in 27 (35 %). There were no significant differences in the status of ER, PR, and HER2 between the primary tumor and the resected tumor after neoadjuvant therapy. Neoadjuvant therapy does not significantly influence the status of the steroid hormone receptors and the HER2 level in our study. CONCLUSIONS: Initial biopsy may be reliable for determining the appropriate adjuvant therapy, but final pathology are still needed to evaluate the prognosis and provided the alternative treatment when tumor recurrence. Further prospective study is needed to optimize the care available for breast cancer patients.

Advanced age is not a contraindication for liver resection in cases of large hepatocellular carcinoma.

BACKGROUND: The role of surgery in the management of large hepatocellular carcinomas (HCCs) is controversial. Advanced age and comorbidities are taken into account when major surgery is considered. PURPOSE: To compare the outcomes of liver resection (LR) and transarterial chemoembolization (TACE) for resectable HCC in patients aged 70 years or older. PATIENTS AND MATERIALS: This study included 70 patients aged 70 years or older treated for large HCCs (≥5 cm) between January 2007 and December 2012: 37 underwent LR and 33 underwent TACE. The outcomes of these patients were retrospectively analyzed. Univariate and multivariate Cox proportional hazard models were established. Kaplan-Meier survival curves were generated, and survival data were compared using the log-rank test. RESULTS: Hospital stay was significantly longer in the LR group than in the TACE group (10 days vs 8.5 days; P = 0.003). Treatment-related complications were more frequent in the TACE group, but this difference was not statistically significant. LR was associated with a better disease-free survival rate, median survival rate and cumulative overall survival rate. CONCLUSION: Our results showed that LR could be a safe and effective treatment option for HCC tumors ≥5 cm in patiets aged 70 years or older.

Papillary breast lesions diagnosed by core biopsy require complete excision.

BACKGROUND: Surgical excision of papillary breast lesions with atypia diagnosed using core needle biopsy (CNB) has been accepted; however, the management of benign papillary lesions (without atypia) has been controversial. The purpose of this study was to evaluate the surgical outcome of nonmalignant papillary lesions diagnosed by ultrasound-guided 14-gauge CNB, and to establish clear guidelines on management of these lesions. METHODS: We retrospectively identified 268 nonmalignant papillary breast lesions, including 203 benign lesions and 65 atypical lesions, diagnosed by CNB and subsequently surgically excised in 250 women at our institution between July 2004 and October 2010. For each lesion, medical records and radiologic and pathologic reports were reviewed and coded. We compared the histological upgrade among the collected variables. RESULTS: On histological examination after surgical excision, 15.4% atypical papillary lesions and 5.9% benign lesions were upgraded to malignant, and 20.2% benign lesions were upgraded to atypical. Atypia (P = 0.015) was significantly associated with malignant upgrade at excision. No clinical or radiologic variable was helpful in predicting the possibility of histological upgrade of CNB-diagnosed nonmalignant papillary lesions. CONCLUSIONS: Nonmalignant papillary lesions diagnosed with CNB showed an unacceptable pathological upgrade rate after excision. Therefore, surgical excision should be performed for all papillary lesions of the breast for definitive diagnosis.

Factors predictive of breast cancer in open biopsy in cases with atypical ductal hyperplasia diagnosed by ultrasound-guided core needle biopsy.

AIMS: The purpose of the study was to explore factors predictive of breast cancer as diagnosed by excision biopsy in cases with a diagnosis of atypical ductal hyperplasia (ADH) on ultrasound-guided core needle biopsy (CNB). PATIENTS AND METHODS: We carried out diagnosis of breast lesions by ultrasound-guided CNB in a single hospital in Taiwan from November 2003 to October 2009. Patients who were diagnosed with ADH and subsequently underwent excision biopsy were included in this study (n = 124). RESULTS: Fifty-six of the 124 patients who were included (45.2%) had cancer, and the remaining 68 had benign lesions. By multivariate analysis of all clinical characteristics and on the basis of the imaging features in these cases, older patient age (≥50 y/o, OR: 3.910, p = 0.005), larger tumour size (≥15 mm, OR: 3.398, p = 0.013), and the presence of architectural distortion by mammography (OR: 10.7, p = 0.036) were found likely to be associated with breast cancer. CONCLUSIONS: Open biopsy is necessary in patients who were diagnosed with ADH on CNB. Older patients (≥50 y/o), with a larger tumour size (≥15 mm) and an abnormal mammography are especially likely to have breast cancer.

Successful treatment of mucormycosis infection after liver transplantation: report of a case and review of the literature.

Mucormycosis (zygomycosis) is a rare opportunistic fungal infection mainly affecting patients with diabetes mellitus, immunodeficiency, malignancies and solid organ transplant. We present a 55-year-old female with a mucormycosis infection primarily affecting the paranasal sinuses after liver transplantation. The patient presented with a one-week history of right-sided occipital headache and gradual loss of vision in the right eye just 6 months after liver transplantation. Imaging studies revealed a right-sided sphenoiditis with orbital apex involvement. The patient underwent endoscopic sinus surgery and the histology confirmed the diagnosis of mucormycosis. Aggressive surgical ablation of the infected parts, along with antifungal treatment and adjustment of her immunosuppressive maintenance resulted in a good outcome and long-term survival.

Influence of age on PPV of sonographic BI-RADS categories 3, 4, and 5.

PURPOSE: The purpose of this retrospective study was to calculate the positive predictive value (PPV) of sonographic Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 in different age groups to investigate whether age influences the PPV of the BI-RADS category in breast ultrasound. MATERIALS AND METHODS: From our sonography-guided core biopsy database of breasts between 2006 and 2008, we identified 2817 BI-RADS category 3, 4, and 5 lesions with known pathological diagnosis in 2587 women, all of whom underwent the earlier breast assessment via ultrasound with a sonographic BI-RADS lexicon and later sonography-guided core biopsy. All lesions were classified into three age groups (< 45, 45 - 59, and > 59 years). The age-related PPVs of each BI-RADS category among three age groups were calculated on the basis of pathological diagnoses and were compared using a χ(2)-test. RESULTS: The overall PPV of each BI-RADS category was 2.2 % in category 3, 6.5 % in category 4a, 35.2 % in category 4b, 79.6 % in category 4c, and 99.6 % in category 5. The age-related PPVs of category 3 varied significantly among the three age groups (0.9 % versus 3.9 % versus 2.0 % p = 0.048), and notably, the age-related PPV in group 2 was higher than the others. Additionally, there was a significant positive association between the age-related PPVs and increasing age in categories 4a and 4b (4a, p < 0.0001 and 4b, p = 0.0139), but not in categories 4c and 5 (4c, p = 0.1853 and 5, p = 0.2871). CONCLUSION: The incidence of female breast cancer differs not only in different sonographic BI-RADS categories, but also in different age groups. Therefore, more attention should be paid to the special age group that we found for sonographic BI-RADS categories 3, 4a, and 4b.

The effect of fenofibrate on HDL cholesterol and HDL particle concentration in postmenopausal women on tibolone therapy.

BACKGROUND: Low high-density lipoprotein (HDL) cholesterol and particle concentration are risk factors for coronary heart disease in women. Tibolone lowers HDL cholesterol and HDL particle concentration, an effect that could be reversed by the peroxisome proliferator-activator receptor-α agonist fenofibrate. OBJECTIVE: To assess the effects of fenofibrate on plasma HDL particles in postmenopausal women taking tibolone therapy. DESIGN AND PARTICIPANTS: Randomized crossover study conducted in a women's health clinic. Fourteen postmenopausal women taking tibolone 2.5 mg daily for menopausal symptoms were randomized to either fenofibrate 160 mg daily or no treatment for 8 weeks, followed by a 3-week wash-out for fenofibrate and then crossed over to alternate therapy for another 8 weeks. The main outcome measure was changes in plasma HDL cholesterol concentration, apoA-I and apoA-II, LpA-I and LpA-I-A-II. RESULTS: After 8 weeks of fenofibrate therapy, there was no change in HDL cholesterol, 1.13 ± 0.06 v 1.16 ± 0.06 mmol/l (P = 0.47) or apoA-I, 1.19 ± 0.05 v 1.20 ± 0.05 g/l (P = 0.23). LpA-I fell significantly 0.35 ± 0.03 v 0.29 ± 0.02 (P = 0.02) but there was a rise in apoA-II, 0.35 ± 0.01 v 0.39 ± 0.01 g/l (P = 0.01). There was a significant fall in total cholesterol, triglycerides, low-density lipoprotein cholesterol and apoB. CONCLUSION: In women taking tibolone, fenofibrate increases plasma apoA-II concentration and effects a redistribution of HDL subfractions but does not correct tibolone-induced changes in HDL cholesterol or HDL particle concentration. The mechanism and significance of this require further investigation.

The mechanisms of failure of totally implantable central venous access system: analysis of 73 cases with fracture of catheter.

BACKGROUND: Totally implantable access ports are often used for the administration of chemotherapy or prolonged intravenous infusions in patients with cancer. The technique has been well described. However, some complications would happen. The pinch-off-syndrome is one of these complications. We report another presentation of pinch-off-syndrome and how to prevent. METHODS: From January 2005 to December 2007, 73 patients of catheter fracture were collected. The duration of Port-A implantation ranged from January 2003 to October 2007. During this period, 3358 port-catheters were implanted. There were three brands of Port-A implanted included 46% BardPort (Bard, Salt Lake City, UT, USA), 42% A Port (Arrow international, Reading, PA, USA) and 12% PORT-A CATH (Deltec, St. Paul, MN, USA). RESULTS: The most common clinical presentation was difficulty in injection in 32 cases (43.8%). The incidence of brand C was far lower than brand A and B. The most common site of fracture was at the proximal part (anastomosis between injection port and catheter) in 68 cases (93.2%). The incidence of fracture of Port-A was 6 in 738 (0.81%) in cut-down method; 67 in 2620 (2.56%) in percutaneous subclavian method. Most of the cases (34%) were no more than six months. CONCLUSION: The most frequent location of fracture Port-A was in proximal part - anastomosis between injection port and catheter. The cause of easily fracture may be associated with pinch-off-syndrome and design of Port-A. This kind of fracture could be prevented by cut-down method and fixed one stitch in proximal part.

The relationship between acid-suppressing drugs and phytobezoar formation: a retrospective analysis and discussion of phytobezoar formation.

OBJECTIVES: Although phytobezoars are a rare cause of gastrointestinal obstruction, they are most commonly found in patients with previous gastric surgery. It is well known that predisposing factors of phytobezoar formation are ingestion of fruits containing soluble tannin, presence of dilute hydrochloric acid in the stomach, and gastric stasis or delayed emptying. We investigated whether intake of acid-suppressing drugs that neutralize gastric acidity or inhibit gastric acid secretion to constitute a hypo-acidic condition, increases the risk of phytobezoar formation. MATERIALS AND METHODS: Between September 1992 and October 2008, 32 patients (24 male and 8 female) with gastrointestinal phytobezoars were diagnosed either surgically or endoscopically at the Tri-Service General Hospital, Taipei, Republic of China. The data were collected from hospital records and analyzed retrospectively. RESULTS: Eighteen (56.25%) of all patients had previous gastric surgery and 6 (42.9%) of the 14 patients who had not undergone surgery had diabetes mellitus. The majority of admissions were during winter and spring (between October and March) (P < 0.01) and none of the patients had taken acid-suppressing drugs during the 6 months before detection of gastrointestinal phytobezoars. CONCLUSIONS: In our study, intake of acid-suppressing drugs did not increase the risk of phytobezoar formation in patients with normal gastric motility. Moreover, we believe that the major factor in phytobezoar formation is gastric stasis or delayed emptying, which sufficiently prolongs the retention period of materials in the stomach, while dilute hydrochloric acid is a minor factor.

Altered fibrinolytic activities in gastric cancer and uremic patients after intervention.

INTRODUCTION: Although thromboembolism is the most recognized cause of death in cancer and uremic patients following tumorectomy or hemodialysis, respectively, little data exist concerning its etiologies and treatments in post-intervention settings. In this study, we determined the post-intervention fibrinolytic activities to exploit their implications in gastric cancer and uremic patients. MATERIALS AND METHODS: A small-scale case-control study with totally 56 cases aimed to compare the difference of the post-intervention fibrinolytic activities of two hypercoagulable groups of gastric cancer and uremic patients versus healthy controls was conducted. In-house functional assays for plasma plasminogen (Pg) and plasminogen activators (PA) activities were employed. RESULTS: As compared to the control, both variable-stratified patient groups disclosed reduced Pg activities, synonyms at the "hypofibrinolytic" state, suggesting that the alleged post-intervention hypercoagulability of the two patient groups could be rationalized by the hypofibrinolysis mechanism. On the other hand, cancer patients showed elevated PA activity, concomitantly implicating that there was associated fibrinolytic consumption. Moreover, the altered PA activity could be ascribed to tumor metastasis according to literature review. CONCLUSIONS: Our data suggested that the PA/Pg fibrinolytic activities were altered in gastric cancer and uremic patients post-interventionally. Measurement of the post-intervention fibrinolytic activities could be useful in projection of some potential risks.

Volvulus of small intestine: rare complication of mesenteric pseudocyst.

OBJECTIVE: Mesenteric cyst is a rare intra-abdominal lesion. Most patients with mesenteric cysts are asymptomatic. Symptomatic mesenteric cysts are associated with cyst size, cyst location, and complications, including infection, rupture, hemorrhage, and intestinal obstruction. Volvulus is a rare complication of mesenteric cyst. SUBJECT: We report a 50-year-old woman with colicky epigastric pain for three days. The symptoms exacerbated in the supine position and were relieved in the sitting position. Computed tomography of her abdomen revealed a huge cystic lesion with a whirl sign of mesentery vessels. She had the history of gastro-esophageal reflux disease. RESULT: Segmental resection of the small intestine with end-to-end anastomosis was performed. Histology indicated a hemorrhagic pseudocyst. The patient recovered well after surgery. CONCLUSION: Mesenteric pseudocyst rarely results in volvulus of small intestine. Our case is the eleventh case reported in the English literature. Atypical presentation of epigastric pain while lying down may lead to mis-diagnosis. This case reminds the clinicians this rare complication.

Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells.

Human melanomas show oncogenic B-Raf mutations, which activate the B-Raf/MKK/ERK cascade. We screened microarrays to identify cellular targets of this pathway, and found that genes upregulated by B-Raf/MKK/ERK showed highest association with cell-cycle regulators, whereas genes downregulated were most highly associated with axon guidance genes, including plexin-semaphorin family members. Plexin B1 was strongly inhibited by mitogen-activated protein kinase signaling in melanoma cells and melanocytes. In primary melanoma cells, plexin B1 blocked tumorigenesis as measured by growth of colonies in soft agar, spheroids in extracellular matrix and xenograft tumors. Tumor suppression depended on residues in the C-terminal domain of plexin B1, which mediate receptor GTPase activating protein activity, and also correlated with AKT inhibition. Interestingly, the inhibitory response to plexin B1 was reduced or absent in cells from a matched metastatic tumor, suggesting that changes occur in metastatic cells which bypass the tumor-suppressor mechanisms. Plexin B1 also inhibited cell migration, but this was seen in metastatic cells and not in matched primary cells. Thus, plexin B1 has tumor-suppressor function in early-stage cells, although suppressing migration in late-stage cells. Our findings suggest that B-Raf/MKK/ERK provides a permissive environment for melanoma genesis by modulating plexin B1.