Aliskiren,the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseases

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin–angiotensin–aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials.     

Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK,AKT and NF-kappa B pathways in murine RAW264.7 cells

The bone protective effects of the hydrogen molecule (H₂) have been demonstrated in several osteoporosis models while the underlying molecular mechanism has remained unclear. Osteoclast differentiation is an important factor related to the pathogenesis of bone-loss related diseases. In this work, we evaluated the effects of incubation with H₂ on receptor activator of NFκB ligand (RANKL)-induced osteoclast differentiation. We found that treatment with H₂ prevented RANKL-induced osteoclast differentiation in RAW264.7 cells and BMMs. Treatment with H₂ inhibits the ability to form resorption pits of BMMs stimulated by RANKL. Treatment with H₂ reduced mRNA levels of osteoclast-specific markers including tartrate resistant acid phosphatase, calcitonin receptor, cathepsin K, metalloproteinase-9, carbonic anhydrase typeII, and vacuolar-type H⁺-ATPase. Treatment with H₂ decreased intracellular reactive oxygen species (ROS) formation, suppressed NADPH oxidase activity, down-regulated Rac1 activity and Nox1 expression, reduced mitochondrial ROS formation, and enhanced nuclear factor E2-related factor 2 nuclear translocation and heme oxygenase-1 activity. In addition, treatment with H₂ suppressed RANKL-induced expression of nuclear factor of activated T cells c1 and c-Fos. Furthermore, treatment with H₂ suppressed NF-κB activation and reduced phosphorylation of p38, extracellular signal-regulated kinase, c-Jun-N-terminal kinase, and protein kinases B (AKT) stimulated with RANKL. In conclusion, hydrogen molecules prevented RANKL-induced osteoclast differentiation associated with inhibition of reactive oxygen species formation and inactivation of NF-κB, mitogen-activated protein kinase and AKT pathways.     

Mechanisms of graft versus host disease produced by small bowel transplantation

Mechanisms of graft versus host disease have been studied in Lew x BN animals transplanted with a Lew small bowel. Grafted mesenteric lymph nodes but not host mesenteric lymph nodes or host spleen, in small bowel transplanted rats undergoing lethal GVHD, provide a source of CTL with specific anti-recipient cytotoxic activity. Host MLN and host spleen display anti-recipient CTL activity only when GVHD is provoked by intraperitoneal lymphocyte injection. These data demonstrate that lethal GVHD after SBTx may occur in the absence of detectable cytotoxic activity in host lymphoid tissues, suggesting that other mechanisms are involved in the pathogenesis of GVHD after SBTx. GVHD after SBTx or lymphocyte transfer is associated with the appearance of TNF in the serum. The intensity and reversibility of this phenomenon correlate with both the clinical severity and the lethality of GVHD. Taken together these data highly suggest that TNF is directly involved in the pathogenesis of GVHD after SBTx.     

Dynamic regulation and dysregulation of the water channel aquaporin-2: a common cause of and promising therapeutic target for water balance disorders

The human body is two-thirds water. The ability of ensuring the proper amount of water inside the body is essential for the survival of mammals. The key event for maintenance of body water balance is water reabsorption in the kidney collecting ducts, which is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and never allows permeation of ions or other small molecules. Under normal conditions, AQP2 is restricted within the cytoplasm of the collecting duct cells. However, when the body is dehydrated and needs to retain water, AQP2 relocates to the apical membrane, allowing water reabsorption from the urinary tubule into the cell. Its impairments result in various water balance disorders including diabetes insipidus, which is a disease characterized by a massive loss of water through the kidney, leading to severe dehydration in the body. Dysregulation of AQP2 is also a common cause of water retention and hyponatremia that exacerbate the prognosis of congestive heart failure and hepatic cirrhosis. Many studies have uncovered the regulation mechanisms of AQP2 at the single-molecule level, the whole-body level, and the clinical level. In clinical practice, urinary AQP2 is a useful marker for body water balance (hydration status). Moreover, AQP2 is now attracting considerable attention as a potential therapeutic target for water balance disorders which commonly occur in many diseases.     

Neutrophil gelatinase-associated lipocalin protects renal tubular epithelial cells in hypoxia–reperfusion by reducing apoptosis

Purpose

The aim of this study was to elucidate the role of neutrophil gelatinase-associated lipocalin (NGAL) in regulating apoptosis of tubular epithelial cells in a hypoxia–reperfusion model.

Methods

A hypoxia–reperfusion model was established with NRK-52E cells to assess apoptosis and cell cycle progression after the addition of NGAL. We investigated the expression of four apoptosis factors, Bcl-2, Bax, Fas and FasL, as well as the expression level of two NGAL receptors, 24p3R and megalin, by both Western blot and real-time PCR.

Results

NGAL induced cell proliferation and reduced apoptosis by regulating four apoptosis factors Bcl-2, Bax, Fas and FasL. Western blot demonstrated that the two NGAL receptors, 24p3R and megalin, were increased after hypoxia–reperfusion, which was reduced by exogenous NGAL. Moreover, overexpression of the two receptors induced the expression of the anti-apoptotic factor Bcl-2 and reduced the expression of pro-apoptotic Bax, Fas and FasL.

Conclusions

These findings indicate that NGAL reduces apoptosis by regulating the four apoptosis factors Bcl-2, Bax, Fas and FasL through its two receptors 24p3R and megalin. These results also suggest that ectopic expression of NGAL in renal cells might provide a therapeutic strategy in ischemia–reperfusion by reducing apoptosis and promoting renal cell proliferation.     

Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy

Background

The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.

Methods

We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.

Results

Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.

Conclusion

Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.     

Postoperative Nonsteroidal Anti-inflammatory Drugs and Risk of Anastomotic Leak: Meta-analysis of Clinical and Experimental Studies

Background

Enhanced recovery programs following colorectal resection recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as part of multimodal analgesia. The present study aimed to assess whether postoperative NSAID use increased the risk of anastomotic leak.

Methods

A systematic review of published literature was performed for studies comparing anastomotic leak following NSAID administration versus control. Meta-analysis was conducted for studies in human patients and experimental animal models. The primary endpoint was anastomotic leak.

Results

The final analysis included 8 studies in humans and 12 experimental animal studies. Use of NSAIDs was significantly associated with anastomotic leak in humans (8 studies, 4,464 patients, odds ratio [OR] 2.14; p < 0.001). This effect was seen with nonselective NSAIDs (6 studies, 3,074 patients, OR 2.37; p < 0.001), but not with selective NSAIDs (4 studies, 1,223 patients, OR 2.32; p = 0.170). There was strong evidence of selection bias from all clinical studies, with additional inconsistent definitions and outcomes assessment. From experimental animal models, anastomotic leak was more likely with NSAID use (ten studies, 575 animals, OR 9.51; p < 0.001). Bursting pressures at day 7 were significantly lower in NSAID versus controls (7 studies, 168 animals, weighted mean difference ?35.7 mmHg; p < 0.001).

Conclusions

Emerging data strongly suggest that postoperative NSAIDs are linked to anastomotic leak, although most studies are flawed and may be describing pre-existing selection bias. However, when combined with experimental data, these increasing concerns suggest caution is needed when prescribing NSAIDs to patients with pre-existing risk factors for leak, until more definitive evidence emerges.     

Esophageal carcinoma cell line with high EGFR polysomy is responsive to gefitinib

Purpose

It has previously been shown that gefitinib-treated patients with epidermal growth factor receptor (EGFR) gene amplification or high polysomy had a statistically significant improvement in response, time to progression, and survival in non-small cell lung cancer (NSCLC). Only few studies utilizing anti-EGFR treatment in advanced esophageal adenocarcinomas have been performed and the results have been heterogeneous. The aim of this study was to evaluate EGFR-targeted therapy with gefitinib in esophageal adenocarcinoma with a high EGFR polysomy.

Methods

Novel esophageal cell lines PT6216 and LN6216c were established from primary tumor and lymph node metastasis of a patient with highly aggressive and metastatic adenocarcinoma. Pathological examination including tumor differentiation and prognostic marker analysis, immunohistochemical EGFR expression analysis, EGFR fluorescence in situ hybridization, and mutation analysis were performed. Response of novel cell lines to gefitinib treatment was evaluated by cell proliferation and vitality assays. Fifty-four esophageal adenocarcinoma specimens were evaluated for EGFR gene copy gain.

Results

The primary tumor cell line PT6216 and the lymph node cell line LN6216c show a homogenously high polysomy for EGFR determined by FISH analysis. Cell proliferation and vitality are highly sensitive to the tyrosine kinase inhibitor gefitinib compared to esophageal control cells without a high polysomy for EGFR. High polysomy for EGFR was found in 35 % of patients.

Conclusion

We show for the first time a significant treatment response to the EGFR tyrosine kinase inhibitor gefitinib in esophageal tumor cells with a high polysomy for EGFR, suggesting a future role of anti-EGFR therapy for esophageal adenocarcinoma patients with a high EGFR polysomy.     

Predictors that Influence Contralateral Prophylactic Mastectomy Election Among Women with Ductal Carcinoma In Situ Who Were Evaluated for BRCA Genetic Testing

Background

Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We evaluated factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA testing.

Methods

This retrospective study involved 165 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristics were age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election.

Results

Of 165 patients, 44 (27 %) underwent CPM. Patients <45 years of age were more likely to elect CPM (p = 0.0098). A BRCA+ mutation was found in 17 patients (10.3 %), and BRCA+ women were more likely to elect CPM than BRCA or untested women (p = 0.0001). Patients who had a family history of OC (57.7 %) were more likely to choose CPM than those with no family history (p = 0.0004). Younger age, BRCA+, and an OC family history remained significant in the multivariate model (p < 0.008).

Conclusion

The CPM rate among patients with DCIS who undergo genetic counseling is high. Factors associated with increased likelihood of CPM among this group were age, BRCA+, and a family history of OC. Further studies are needed to evaluate patients’ perceptions of CBC risk and their role in the likelihood of CPM choice.     

Association of miR-146a rs2910164 with childhood IgA nephropathy

Background

Micro-RNAs (miRNAs) play important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate the association between three single nucleotide polymorphisms (SNPs) (mir-146a rs2910164, let-7a-2 rs1143770, miR-196a2 rs11614913) and susceptibility to and severity of childhood immunoglobulin A (IgA) nephropathy (IgAN).

Methods

We genotyped three miRNA SNPs in two independent Han Chinese populations composed of 158 patients and 265 controls (discovery set), and 246 patients and 446 controls (validation set), respectively.

Results

We found that rs2910164 was significantly associated with IgAN in the discovery but not the validation set. Combined analysis revealed that rs2910164 CC and CG genotypes were associated with increased risk of IgAN compared with the GG genotype [adjusted odds ratios (OR)?=?1.684, 95 % confidence interval (CI)1.190–2.384, P?=?0.003; adjusted OR?=?1.472, 95 % CI 1.079–2.007, P?=?0.015, respectively). We also found that the frequency of the rs2910164 CC genotype was significantly higher in patients with Haas grade III–V than in those with Haas grade I–II for all study populations (P?P?=?0.038).

Conclusions

These results indicated that rs2910164 may affect the susceptibility and severity of pediatric IgAN. Further studies are needed to validate these findings.     

Toll-like receptors,immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Background

Henoch–Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown.

Methods

This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC).

Results

The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-β1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/β1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP.

Conclusion

Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.     

Postsurgical coagulopathy in a hemophilia A patient with inhibitors: efficacy of recombinant factor VIIa

Perioperative hemostatic management in patients with hemophilia A who develop the coagulation factor VIII (FVIII) inhibitor is challenging, because exogenous FVIII is neutralized, which boosts the inhibitor to provoke postoperative coagulopathy. Recombinant activated factor VII (rFVIIa) has become available for this type of patient, although FVIII is sometimes required. We treated a 56-year-old male patient with hemophilia A with FVIII inhibitor scheduled for total hip arthroplasty (THA) and total knee arthroplasty (TKA). We used rFVIIa for THA; however, the amount of bleeding was 2,500 ml and blood transfusion was required, which boosted FVIII inhibitor after surgery. The TKA was then scheduled for 19 months later, after the level of the inhibitor had reduced to the preoperative level. Unfortunately, rFVIIa failed to improve PT/APTT, and thus we used recombinant factor VIII (rFVIII). The amount of bleeding during TKA was 1,340 ml, while the level of the inhibitor increased to a greater level than that after THA, provoking uncontrollable bleeding. For anesthetic management in hemophilia A patients with FVIII inhibitor, anesthesiologists must pay attention to postoperative coagulopathy, and every effort should be used to minimize exposure to FVIII. Furthermore, when rFVIIa is ineffective, postponement of surgery until rFVIIa regains its efficacy may be beneficial as compared to an operation with FVIII.     

Detection of a metastatic lesion and tiny yolk sac tumors in two teenage patients by FDG-PET: report of two cases

We herein report the efficacy of FDG-PET for detecting yolk sac tumors in two teenage patients. One patient had a rare bone metastasis and the other had tiny recurrent lesions at the mediastinum. Both lesions were difficult to detect by conventional diagnostic modalities. In contrast, FDG-PET was very effective for detecting these lesions. Furthermore, the SUVmax of the lesion reflected the tumor activity, which was also suggested by the fluctuating values of serum alpha-fetoprotein (AFP), an established marker of yolk sac tumors. FDG-PET may be a useful procedure to detect tiny and metastatic, pediatric yolk sac tumors.     

Protective effects of adiponectin on uncoupling of glomerular VEGF–NO axis in early streptozotocin-induced type 2 diabetic rats

Purpose

To determine whether adiponectin could reduce microalbuminuria and provide renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular vascular endothelial growth factor (VEGF)–nitric oxide (NO) axis in streptozotocin-induced type 2 diabetic rats.

Methods

Wistar rats were randomly divided into normal control group, diabetic nephropathy (DN) group induced by high-fat feeding and streptozotocin, diabetic rats injected with adenovirus-expressed adiponectin (AD-AdipoQ), and diabetic rats injected with AD-IRES-EGFP as control. Blood and urine samples were collected. Endothelium-dependent vasodilatation (EDV) of the aorta was measured. Renal tissues were collected for CD34 immunohistochemistry. Glomerular NO and VEGF levels were measured by the Griess reaction and Western blot testing, respectively.

Results

Injections of AD-AdipoQ significantly increased serum adiponectin levels and reduced the urinary albumin-to-creatinine ratio in diabetic rats (P < 0.05). The levels of plasma glucose, serum insulin, high-sensitivity C-reactive protein, and malondialdehyde were significantly reduced in diabetic rats after injections of AD-AdipoQ (P < 0.05). Severe EDV impairment was observed in the DN group, which was improved by AD-AdipoQ. CD34 expression in the glomeruli was also higher in diabetic rats, indicating increased proliferation of glomerular endothelial cells. However, AD-AdipoQ improved the increased proliferation of endothelial cells in the glomeruli. Diabetic rats showed increased glomerular VEGF levels and reduced NO levels. This uncoupling of the VEGF–NO axis was partially improved by AD-AdipoQ.

Conclusion

Adiponectin reduces the degree of microalbuminuria and has renal protective effects by improving endothelial dysfunction and uncoupling of the glomerular VEGF–NO axis in early diabetic nephropathy.     

Neurocognition in children with autosomal recessive polycystic kidney disease in the CKiD cohort study

Background

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disorder characterized by enlarged, cystic kidneys with progressive chronic kidney disease (CKD), systemic hypertension, and congenital hepatic fibrosis. Children with ARPKD can have early onset CKD and severe hypertension, both of which are known to have adverse neurocognitive effects. The objectives of this study were (1) to determine whether ARPKD patients have greater neurocognitive deficits compared to that of children with other causes of CKD, and (2) to examine the relative prevalence of hypertension in ARPKD, a known risk factor for neurocognitive dysfunction.

Methods

We performed a cross-sectional, control-matched analysis of 22 ARPKD patients with mild-to-moderate CKD in the Chronic Kidney Disease in Children (CKiD) cohort study, compared with a control group of 44 children with other causes of CKD, matched based on glomerular filtration rate, age at study entry, and age at diagnosis.

Results

Children with ARPKD in this cohort had neurocognitive functioning comparable to children with other causes of CKD in domains of intellectual functioning, academic achievement, attention regulation, executive functioning, and behavior. Blood pressure parameters were similar between the two groups; however, ARPKD patients required a significantly greater number of antihypertensive medications to achieve similar BP levels.

Conclusions

ARPKD patients are potentially at risk for neurocognitive dysfunction due to early onset CKD and more severe hypertension. However, this study of children with mild-to-moderate CKD in the CKiD cohort did not demonstrate increased risk in children with ARPKD compared to children with other causes of CKD. Further studies are needed to determine if these findings are applicable to children with more severe manifestations of ARPKD.     

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

Autosomal recessive polycystic kidney disease (ARPKD), although less frequent than the dominant form, is a common, inherited ciliopathy of childhood that is caused by mutations in the PKHD1-gene on chromosome 6. The characteristic dilatation of the renal collecting ducts starts in utero and can present at any stage from infancy to adulthood. Renal insufficiency may already begin in utero and may lead to early abortion or oligohydramnios and lung hypoplasia in the newborn. However, there are also affected children who have no evidence of renal dysfunction in utero and who are born with normal renal function. Up to 30 % of patients die in the perinatal period, and those surviving the neonatal period reach end stage renal disease (ESRD) in infancy, early childhood or adolescence. In contrast, some affected patients have been diagnosed as adults with renal function ranging from normal to moderate renal insufficiency to ESRD. The clinical spectrum of ARPKD is broader than previously recognized. While bilateral renal enlargement with microcystic dilatation is the predominant clinical feature, arterial hypertension, intrahepatic biliary dysgenesis remain important manifestations that affect approximately 45 % of infants. All patients with ARPKD develop clinical findings of congenital hepatic fibrosis (CHF); however, non-obstructive dilation of the intrahepatic bile ducts in the liver (Caroli’s disease) is seen at the histological level in only a subset of patients. Cholangitis and variceal bleeding, sequelae of portal hypertension, are life-threatening complications that may occur more often in advanced cases of liver disease. In this review we focus on common and uncommon kidney-related and non-kidney-related phenotypes. Clinical management of ARPKD patients should include consideration of potential problems related to these manifestations.     

Correlation study of chronic nonbacterial prostatitis with the levels of COX-2 and PGE2 in prostatic secretion

Objective

The prostatitis syndrome is a multifactorial condition of largely unknown etiology. This study is to analyze the relationship between cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) with the chronic nonbacterial prostatitis (CNBP).

Methods

A total of 172 CNBP patients and 151 healthy males were recruited as CNBP and control group, respectively. The prostatic fluid was collected and tested by pre- and post-massage test. White blood cell (WBC) number was counted, and the contents of COX-2 and PGE2 were determined by double antibody-based sandwich enzyme-linked immuno-sorbent assay. The pain and discomfort of each patient were scored according to the National Institutes of Health chronic prostatitis symptom index.

Results

Compared with the control group, CNBP group displayed significantly higher WBC count, COX-2 level, and PGE2 level. Contents of COX-2 and PGE2 in prostatic secretion of CNBP group were positively correlated with pain scores (r = 0.855 and 0.675, respectively, P < 0.01) and total symptom scores (r = 0.674 and 0.566, respectively, P < 0.01). A significantly positive correlation between COX-2 and PGE2 levels was also discovered (r = 0.493, P < 0.05). The WBC number was not obviously correlated with the accumulations of COX-2 and PGE2 or the clinic symptoms of CNBP.

Conclusion

Increase in PGE2 concentration caused by activated COX-2 pathway may contribute to the pain or discomfort symptom of the CNBP patients. Our results indicate that selective COX-2 inhibitors have application prospect in CNBP treatment.     

Comparison of Nodal Metastasis Between BRCA Mutation Carriers and Non-BRCA Mutation Carriers with Breast Cancer

Objective

This study evaluates whether nodal status differs between breast cancer patients with BRCA mutations and those confirmed not to harbor mutations.

Methods

A prospective database identified patients with breast cancer who underwent genetic testing and axillary staging. Comparative variables included age, as well as tumor characteristics such as size, grade, lymphovascular invasion (LVI), estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2-neu), and nodal status.

Results

Overall, 235 patients with breast cancer underwent genetic testing for BRCA mutations from June 2000 to May 2012. Of these patients, 74 (31.4 %) were found to express BRCA 1 and/or 2 mutations, and 161 (68.5 %) patients were verified to have no detectable BRCA mutation. Among the entire 235 patients tested, 92 (39.1 %) were found to have nodal disease. In univariable analysis, only LVI and tumor size correlated with presence of nodal metastasis. Of the 74 BRCA mutation carriers, 34 (45.9 %) had nodal metastasis compared with 58 of the 161 (36 %; p = 0.15) patients without a BRCA mutation. BRCA mutation carriers with nodal disease were more likely to have poorly differentiated tumors than those without mutations who had nodal disease (24/33 [72.7 %] vs. 27/57 [47.4 %]; p = 0.027).

Conclusion

BRCA mutations are not themselves predictive of nodal metastasis. Patients with BRCA mutations did not have a statistically significant higher prevalence of nodal metastasis than those without mutations.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.