Higher Rate Of Disease Progression Research Articles

R1 resection of colorectal liver metastasis - What is the cost of marginal resection?

The impact of resection margins on the outcome of patients with colorectal liver metastasis (CRLM) remains controversial. We evaluated the short and long-term results of R1 resection. Between 2006 and 2016, 202 patients underwent liver resection for CRLM. R1 resection was defined as a distance of less than 1 mm between tumor cells and the transection plain. Patient and tumor characteristics, perioperative, and long-term outcomes were assessed. In 161 (79.7%) and 41 (20.3%) patients, an R0 and R1 resections were achieved, respectively. Patients that underwent an R1 resection had higher rates of disease progression while on chemotherapy (12.1% vs 5.5%, P = 0.001), need for second-line chemotherapy (17% vs 6.2%, P < 0.001), increased use of preoperative volume manipulation (14.6% vs 5.5%, P = 0.001), and inferior vena-cava involvement (21.9% vs 8.7%, P < 0.001). These patients had higher rates of major postoperative complications (19.5% vs 6.8%, P < 0.001) and reoperations (7.3% vs 2.4%, P < 0.001). Multivariate analysis demonstrated that R1 resections were not associated with decreased recurrence-free survival or overall survival. Although R1 resection is associated with worse disease behavior and postoperative complications, the long-term outcome of patients following an R1 resection is non-inferior to those who underwent an R0 resection.

Associations of a Polymorphism of the FAS/APO-1 Gene (rs2234767) with the Risk of Developing and Rapid Progression of Multiple Sclerosis

Objectives. To assess the association between a polymorphism of the FAS/APO-1 gene with the risk of developing and the dynamics of progression of multiple sclerosis (MS). Materials and methods. A total of 100 patients with remitting MS took part in a case-control study; patients were Russian and were born and living in the Altai Region, along with 100 volunteers without MS. The real-time polymerase chain reaction was used to genotype the single-nucleotide polymorphism 1377G>A in the promoter region of the FAS/APO-1 gene (rs2234767). The associations of this polymorphism with the risk of developing MS and the course of MS were studied. Results. Increased risk of MS was found to be associated with the G/A genotype and the A allele of the FAS/APO-1 gene (rs2234767). A high rate of disease progression was positively associated with the G/A genotype and the A allele and negatively with the G/G genotype and the G allele of the FAS/APO-1 gene. Conclusions. The predisposition to MS, like the rapid rate of disease progression, was associated with FAS/APO-1*G/A in Russians living in the Altai Region. Final conclusions require further studies.

BRCA1, Ki67, and β-Catenin Immunoexpression Is Not Related to Differentiation, Platinum Response, or Prognosis in Women With Low- and High-Grade Serous Ovarian Carcinoma.

The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival. For this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and β-catenin expression was assessed using tissue microarray-based immunohistochemistry. Women with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and β-catenin did not differ between LGSOC and HGSOC (P = 0.12 and P = 1.00, respectively). The clinicopathological features and the response to platinum-based chemotherapy did not differ according to the BRCA1, Ki67, and β-catenin expression in either group. In HGSOC, only International Federation of Gynecology and Obstetrics stage was independently associated with poor survival (PFS and OS). Ki67 expression was significantly higher in HGSOC. BRCA1 and β-catenin expression did not differ between LGSOC and HGSOC samples. BRCA1, Ki67, and β-catenin expression was neither related to clinicopathological features, response to platinum-based chemotherapy, nor survival. Only International Federation of Gynecology and Obstetrics stage remained associated with poor survival in women with HGSOC.

In silico VHL Gene Mutation Analysis and Prognosis of Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease.

Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. A prospective natural history study. The National Institutes of Health clinical center. Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Rates of metastases, surgical intervention, and disease progression. Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

Eph A2 expression is a predictive biomarker of poorer activity and efficacy of FOLFIRI + cetuximab in RAS WT metastatic colorectal cancer (mCRC) patients (pts) in the CAPRI GOIM trial

Background: Eph A2 promotes tumor growth, invasiveness and angiogenesis in mCRC. Targeting Eph A2 could overcome resistance to anti-epidermal growth factor receptor (EGFR) treatment in colon cancer preclinical models. Methods: Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild type (WT) mCRC pts treated with cetuximab + FOLFIRI as first line therapy in the CAPRI GOIM trial were assessed for Eph A2 expression by immunohistochemistry. Eph A2 levels were evaluated developing an HSCORE [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] (range: 0-300). A cut off was set by ROC analysis to define high (>50) and low (≤50) Eph A2 levels. Results: Eph A2 expression was found in 55/82 (67%) cases. According to HSCORE Eph A2 levels were low in 54 (66%) and high in 28 (34%) samples. Eph A2 expression resulted in mostly complete membranous staining. Tumor stroma was positive in 15/82 (18%) cases. In most of these cases an intense immune infiltrate was observed. Non-tumor adjacent normal mucosa was assessable in 34/82 samples. Eph A2 was expressed in 16/34 (47%), more frequently in dysplastic epithelial areas. A significant correlation between Eph A2 expression in tumor and stroma was found (p < 0.0001). Eph A2 was more frequently expressed in less differentiated tumors (p = 0.02), as well as in left-sided tumors compared to right-sided tumors [17/28 (61%), 11/28 (39%), respectively p = 0.04]. Eph A2 expression was associated with higher rate of disease progression (PD) 8/28 (29%) vs 5/54 (9%) (p = 0.02), and with worse median PFS [8.6 m (CI95% 6.4-10.8) vs 12.3 m (CI95% 10.4-14.2) p = 0.030], both in left and right-sided tumours. Moreover, median OS was 28.4 m (CI95% 13.1-43.7) vs 39.8 m (CI95% 30.2-49.4), although this result did not reach statistical significance (p = 0.23). Conclusion: Eph A2 levels were significantly associated with a worse PFS and an increase in PD in RAS WT mCRC pts treated with cetuximab + FOLFIRI as first line therapy in the CAPRI GOIM trial in both right and left-sided tumors. A similar trend was observed for OS. Eph A2 might represent an additional predictive biomarker of lack of efficacy in RAS WT mCRC pts treated with FOLFIRI + cetuximab.

Correlation of QNBC immune and basal signature to targeted therapies and race.

e14537 Background: Triple Negative Breast Cancer has been identified as one of the most aggressive breast cancer subtypes. We previously identified a subtype of TNBC, which lacks the androgen receptor (AR), which we coined quadriple negative breast cancer (QNBC). We have shown that women with QNBC have a worse prognosis compared to those with just TNBC. Additionally, we have noted that African American (AA) women with TNBC have a greater chance of having QNBC (28%) and a higher rate of disease progression (25%) vs Caucasian Americans (CA). We also found these QNBC patients have a unique immune signature that correlates to the more aggressive basal subtype. Here, we explore individual genes and their correlation to race and immune therapies. Methods: We analyzed mRNA expression in 925 tumors from CA or AA women from The Cancer Genome Atlas. Samples were dichotomized as positive or negative using mean gene expression cutoff. Gene expression comparisons among groups were determined using standard t-tests, ANOVA, and odds ratios with a significance threshold alpha of 0.05. Therapy targets were selected from the list of significantly differentiated genes. Boxplots and heatmaps were made using R packages. Cumulative Incidence plots for time to progression were constructed using XLStats and Grays test for significance. Results: QNBC CA have higher expression of PDCD4 (p &lt; .001), CD46 ( p &lt; .001), CD3EAP ( p = .04) and CD84 ( p = .07) compared to QNBC AA. CD47 ( p = .63) and PD1 (p = .96) express no significant differences in race. QNBC AA show higher expression of NFKB ( p &lt; .001), CCL2 ( p &lt; .001), and IL12 ( p &lt; .001) compared to QNBC CAs. Interestingly, QNBCs with high expressions of CD47 ( p = .04) have poor prognosis. Thus, QNBC patients with low expression of CD46 (p = .025), PDCD4 ( p &lt; .001), and CD3EAP ( p &lt; .001) have poor prognosis and overall survival. Conclusions: Current immune targeted therapies like CD47 and PD1 looks favorable for treatment in some QNBC patients. Race appears to effect other major therapy target gene expressions in the QNBC immune basal signature as well. This may imply that QNBC AA and CA have different immune response which may explain racial progression differences. Assessment of immune markers may contribute to more accurate prognosis.

Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients.

The hallmark of chronic myeloid leukemia (CML) is the presence of Philadelphia chromosome, its resultant fusion transcript (BCR-ABL1), and fusion protein (p210). Alternate breakpoints in BCR (m-bcr, μ-bcr, and others) or ABL1 result in the expression of few rare fusion transcripts (e19a2, e1a2, e13a3, e14a3) and fusion proteins (p190, p200, p225) whose exact clinical significance remains to be determined. Our study was designed to determine the type and frequency of BCR-ABL1 fusion transcripts in 1260 CML patients and to analyze the prognosis and treatment response in patients harboring rare BCR-ABL1 fusion transcripts. The frequency of various BCR-ABL1 fusion transcripts was as follows: e14a2 (60%), e13a2 (34.3%), e1a2 (1.2%), e1a2 + e13a2 (2.0%), e1a2 + e14a2 (1.8%), e19a2 (0.3%), and e14a3 (0.3%). CML patients with e1a2 transcripts had higher rates of disease progression, resistance, or suboptimal response to imatinib and failed to achieve major molecular response. Characterization of the specific fusion transcript in CML patients is important owing to the difference in prognosis and response to therapy in addition to the conventional need for monitoring treatment response. CML patients with e1a2 transcripts have to be closely monitored due to the high incidence of disease progression and treatment resistance/failure.

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

BackgroundThe comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain.MethodsWe compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths.ResultsThere were 17 prostate-cancer–specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison).ConclusionsAt a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy.

To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age- and gender-matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. Compared to healthy controls skin biopsies showed: (i) non-length-dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate.

Disease Progression in HIV Late Presenters: the Role of HIV Clinical Indicator Diseases Prior to HIV Diagnosis.

Late diagnosis represents a major challenge in the control of HIV epidemics. The rate of disease progression is higher among late presenters. In Europe, HIV Clinical Indicator Diseases (CIDs) have been proposed to improve early diagnosis. Our observational study evaluated the presence of these HIV CIDs prior to HIV diagnosis among a population of late presenters and assessed its correlation to disease progression. A retrospective cohort study was conducted in HIV late presenters diagnosed from 2007 to 2013 at University Hospital of Ferrara (Italy). Hazard Ratios (H.R.s) for disease progression (new AIDS-events and death) were estimated by Cox proportional hazard model. We analysed 77 patients and we found that those with CIDs prior to HIV diagnosis (22%) had a 2.8 fold higher rate of disease progression compared to those without HIV CIDs (H.R. 2.82; 95% CI 1.21-6.53; P 0.02). Other factors associated with disease progression were AIDS presentation, HCV coinfection and Haemoglobin levels, with H.R.s of 3.14 (95%CI 1.23-7.99), 2.95 (95% CI 1.14-7.61) and 0.74 (95% CI 0.60-0.91), respectively. HIV CIDs confer a higher risk for disease progression even after adjustment for these confounding factors. Evaluation of previous HIV CIDs at HIV diagnosis could be an additional tool to identify and better manage HIV late presenters with higher risks of disease progression.

MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.

BackgroundKL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.MethodsTwenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).ResultsThe frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46 %, A/G 54 %, G/G 0 %; healthy controls, A/A 30 %, A/G 40 %, G/G 30 %; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014).ConclusionsMUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.

Percutaneous coronary artery revascularization procedures in pediatric heart transplant recipients: A large single center experience.

To describe our experience, at a large pediatric heart transplant center, with percutaneous coronary interventions (PCI) for cardiac allograft vasculopathy (CAV). CAV is a leading cause of late graft failure, mortality, and re-transplantation in pediatric heart transplant (HTx) recipients. Studies of PCI in adult patients have shown some short-term improvements, but no significant change in long-term outcomes. There are limited data on PCI for CAV in pediatric patients. We describe the largest single-center experience to date. We performed a retrospective chart review of all pediatric HTx recipients who underwent PCI for a diagnosis of CAV from 2005 to 2014. Twenty-three procedures were performed in 13 patients, at a median age of 16.4 years (range 5.6-21.2) and median time from HTx to first PCI of 8.3 years (range 2.9-20.3). Three cases consisted of angioplasty alone, two cases had bare metal stents implanted, and the remaining 18 had drug-eluting stents implanted. There was acute procedural success in all but one case, and there was only one procedure-related complication (rebleeding from access site). During the follow-up interval (median 10.4 months, range 0.2-111.8), 7/13 patients had repeat PCI performed, two patients died (at 1.8 and 5.8 months post-PCI), and five were re-transplanted (range 0.2-18 months post-PCI). Freedom from death or retransplant by Kaplan-Meier analysis was 54% at 1 year. PCI can be performed safely and effectively in pediatric HTx recipients with CAV. Similar to the adult experience, there remains a high rate of disease progression and graft failure. © 2016 Wiley Periodicals, Inc.

Familial multiple sclerosis in Tomsk region

Multiple sclerosis (MS) has a multifactorial etiology. To explore a role of genetic factors in the pathogenesis of MS, the authors studied familial cases of MS. For an analysis of familial cases, a database of 320 MS patients registered in Tomsk region since 1980 till 2014 was used. The following items for each patient were recorded: disease onset, manifestation of disease, duration of first remission, rate of progression of disease. Nine families with several members with MS were identified. In 2014, the frequency of familial cases in the MS population of Tomsk region was 4.7%. The prevalence of familial MS was 1.4 cases per 100.000 of people. The younger age at disease onset and higher rate of disease progression measured with the EDSS in parent-child pairs were identified. The most families with several members with MS were characterized by clinical polymorphism of onset, duration and rate of disease progression.

Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype?

To compare the prevalence of synovitis, pain and radiographic progression in non-erosive and erosive hand osteoarthritis (HOA), and to explore whether the different rate of disease progression is explained by different levels of synovitis and structural damage. We included 31 and 34 participants with non-erosive and erosive HOA at baseline, respectively. Using Generalized Estimating Equations, we explored whether participants with erosive HOA had more synovitis (by MRI, ultrasound and clinical examination) independent of the degree of structural damage. Similarly, we explored whether pain at baseline and radiographic progression after 5 years were higher in erosive HOA, independent of the levels of synovitis and structural damage. All analyses were adjusted for age and sex. Power Doppler activity was found mainly in erosive HOA. Participants with erosive HOA demonstrated more moderate-to-severe synovitis, assessed by MRI (OR=1.73, 95% CI 1.11-2.70), grey-scale ultrasound (OR = 2.02, 95% CI 1.25-3.26) and clinical examination (OR=1.80, 95% CI 1.44-2.25). The associations became non-significant when adjusting for more structural damage. The higher frequency of joint tenderness in erosive HOA was at least partly explained more structural damage and inflammation. Radiographic progression (OR=2.53, 95% CI 1.73-3.69) was more common in erosive HOA independent of radiographic HOA severity and synovitis (here: adjusted for grey-scale synovitis by ultrasound). Erosive HOA is characterized by higher frequency and more severe synovitis, pain and radiographic progression compared to non-erosive HOA. The higher rate of disease progression was independent of baseline synovitis and structural damage.

Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients.

Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS). Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells. The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P < 0·05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P < 0·01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41·71, P = 0·033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1-overexpressing breast cancer cells. A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti-angiogenic drugs.

Analysis of Dysplasia in Patients With Barrett’s Esophagus Based on Expression Pattern of 90 Genes

Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group. We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n=169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically. We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P=.0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87(95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64%were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P=.047). We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted.

Characteristics of patients with ocular cicatricial pemphigoid referred to major tertiary hospital

ObjectiveTo evaluate the demographic and clinical characteristics of patients referred to a tertiary care hospital cornea clinic for ocular cicatricial pemphigoid (OCP) assessment. DesignRetrospective, nonrandomized, consecutive case series. ParticipantsThirty three patients with OCP who were treated at the corneal clinic of Toronto Western Hospital from 2003 to 2012. MethodsDatabase search of patients from 2003 to 2012 with a referral request or diagnosis of OCP was conducted at a tertiary care hospital cornea clinic. Charts of 33 patients (64 eyes) were reviewed. Outcome measures included patient demographics, methods of diagnosis, visual acuity, ocular features, and disease staging using Foster’s staging system, systemic modes of treatment, disease progression, and presence of systemic involvement. ResultsMean patient age at presentation was 69.8 years (range 40–91), and 81% (27/33) were female. At presentation, disease staging consisted of stage I (subepithelial fibrosis) 7.8% (5/64), stage II (shortened fornices) 21.8% (14/64), stage III (symblepharon formation) 65.6% (42/64), and stage IV (keratinization with or without globe immobility) 4.6% (3/64). At the final follow-up visit, the proportions of the involved eyes for stages I to IV were 1.5% (1/64), 10.9% (7/64), 76.5% (49/64), and 10.9% (7/64), respectively. Conjunctival biopsies were obtained from 81% (27/33) of patients and reported as positive in 30% (8/27), negative in 63% (17/27), and inconclusive in 7% (2/27) of patients. Mean duration of follow-up was 6.8 ± 5.6 years (range 0.5–22), and 66.6% (22/33) of patients had progressive disease. Systemic mucocutaneous involvement was noted in 36.3% (12/33) of patients. ConclusionsThe high rate of disease progression suggests the need for improved therapeutic options. Additional modalities are needed in addition to conjunctival biopsy to confirm a diagnosis of OCP in patients with clinical signs of the disease.

Elevated preoperative platelet to lymphocyte ratio associated with decreased survival of women with ovarian clear cell carcinoma.

This study was conducted to establish whether the preoperative platelet to lymphocyte ratio (PLR) is predictive of survival of women with ovarian clear cell carcinoma (OCCC). A PLR > 300 was deemed elevated. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. Cox proportional hazard analysis was used to determine the independent effect of PLR. Thirty-six patients were reviewed. Elevated PLRs were more commonly noted in patients with an advanced vs an early stage of disease (88.9% vs 11.1%). Women with elevated PLR carried a higher rate of disease progression during primary therapy than that those in the normal PLR group (44.4 vs 22.2%). The median PFS for patients with elevated PLR was notably worse than that for patients with normal PLR (10 vs 34 months). Despite the impact of elevated PLR on PFS, it was found to be marginally significant when controlling for commonly applied prognostic markers. It, however, trended toward significance (HR=4.76; 95%CI, 0.95-23.8). In conclusion, an elevated PLR appears to be directly associated with adverse survival rather than being a surrogate for other indicators of a poor prognosis. PLR may be a useful biomarker for predicting survival of women with OCCC and merits further large-scale studies.

Nephrotic Syndrome: State of the Art

This article overviews the pathogenesis and management of idiopathic nephrotic syndrome, a common childhood glomerulopathy. While initial evidence supported an imbalance of T helper responses in patients with nephrotic syndrome, recent studies suggest alterations in both innate and adaptive immune responses, including evidence for impaired T regulatory function. The central role of the podocyte in causing proteinuria is confirmed by the observation of mutations in key podocyte proteins in steroid-resistant nephrotic syndrome and experimental evidence of altered podocyte signaling and cytoskeletal organization, which might be corrected by medications. The outcome and management of idiopathic nephrotic syndrome in children are determined by the response to corticosteroids and the frequency of relapses. While patients with steroid-sensitive nephrotic syndrome have a favorable long-term outcome, almost half of them relapse frequently and are at risk of adverse effects of corticosteroids. Various non-corticosteroid immunosuppressive agents are used to prolong disease remission, but require careful monitoring for potential adverse effects. While calcineurin inhibitors are the choice of therapy for patients with steroid-resistant nephrotic syndrome, long-term management of disease is challenging due to variable response to immunosuppression, therapy-related adverse effects, and high rates of disease progression to end-stage renal disease. Information from recent randomized clinical trials has helped to clarify and improve the standard of care for childhood nephrotic syndrome and underscore the need for well-designed collaborative studies.

Is Radiation Therapy Effective for DLBCL As a Salvage after Chemotherapy?: A Study of 180 Diffuse Large B Cell Lymphoma (DLBCL) Cases at a Single Institution

Introduction: Radiation therapy (RT) for localized- refractory or relapsed diffuse large B cell lymphoma (DLBCL) after chemotherapy is a standard therapy. Though some cases achieve complete remission (CR) after RT for local residual disease, others reveal disease progression after RT.Methods: We analyzed DLBCL receiving RT on the purpose of achieving remission after chemotherapy at Cancer Institute Hospital from October 2005 to January 2014. All patients (pts.)’ histopathology samples were reviewed by expert hematopathologists, according to the WHO classification. All RT regimens were planned by expert lymphoma radiotherapists.Results: A total of 180 pts. were included in this study. Baseline pts.’ characteristics were a median age of 65.2 years (range, 17.3-88.1 years), 105 male and 75 female, 87 pts. (48.3%) receiving radiation therapy as an adjuvant therapy after 3 cycles of R-CHOP therapy, 43 pts. (23.9%) receiving RT for low SUV max (1.2-7.94) residual disease at positron emission tomography-computed tomography (PET-CT) evaluation after chemotherapy, 38 pts. (21.1%) receiving for primary refractory, and 12 pts. (6.7%) for localized relapsed DLBCL after previous chemotherapy. A median total dose of RT was 30.6Gy (range, 16.0Gy-50.4Gy). After RT, 5 pts. (5.7%) of adjuvant therapy were progressive, 5 pts. (11.6%) of the pts. with low SUVmax at PET-CT, 25 pts. (65.8%) of primary refractory, and 11 pts. (91.7%) of relapsed DLBCL. Disease progressions outside of the radiation fields were recognized at 5 pts. (100.0%) of adjuvant therapy, 5 pts. (100.0%) of low SUV max cases, 12 pts. (48.0%) of primary refractory, and 10 pts. (90.9%) of localized relapsed DLBCL. There was no treatment related mortality during RT. At a median follow-up time of 33.3 months (range, 6.5-74.0), the 2 year progression free survival (PFS) after RT and overall survival (OS) rates are 74.4%, 76.7%, respectively. In Adjuvant group, PFS and OS were 94.5%, 93.1%, respectively. In low SUV max group, 70.1%, 83.7%, primary refractory group, 34.2%, 39.5%, and relapsed group, 8.3%, 50.0%, respectively.Conclusions: RT as adjuvant therapy and for low SUV max residual disease after chemotherapy resulted in a good prognosis. High rates of disease progression outside the RT field were outstanding and they might indicate the limitation of local treatment for DLBCL. Because RT triggers few severe adverse events, it is tolerable even for elderly people and patients with long history of chemotherapy. However, it may be desirable for primary refractory and relapsed DLBCL as localized disease after chemotherapy to treat with chemotherapy as a systematic therapy. DisclosuresMasahiro:Chugai Pharmaceutical co.,LTD: Consultancy. Nishimura:Chugai Pharmaceutical Co., LTD: Consultancy.