Higher Probability Of Response Research Articles

Pegylated interferon alpha‐2b (Peg‐IFN α‐2b) affects early virologic response dose‐dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg‐IFN α‐2b plus ribavirin

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN alpha-2b during the first 12 weeks was the independent factor for c-EVR (P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving > or = 1.2 microg/kg/week of Peg-IFN, and declined to 38% at 0.9-1.2 microg/kg/week, and 22% in patients given <0.9 microg/kg/week (P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 (P < 0.0001) and SVR (P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.

79 Ipilimumab-Related Colitis in Patients with Advanced Melanoma Receiving Ipilimumab Therapy: Histopathologic and Serologic Characterization

Background: Natural history observations in early onset IBD have prompted the increasing use of anti-TNFα therapy. Inter-individual variation, however, is seen in efficacy outcomes. These differences may be explained in part by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. Recent GWA studies in IBD have increased our understanding of the genetic susceptibility to IBD and provide insight regarding the various mechanisms of inflammation. We hypothesize that interindividual differences in therapeutic outcomes to anti-TNFαmay be associated with IBD susceptibility genes. Aim: Test associations of GWA identified IBD susceptibility loci (34 SNPs) with infliximab (IFX) responsiveness in pediatric IBD patients. Methods: Complete follow up and GWAS data was available on 63 children receiving IFX. Harvey Bradshaw index (HBI) was used to calculate disease activity. Outcomes were primary nonresponse: no change or increase in HBI at week 10; and secondary loss of response: drop in HBI by >3 points at week 10 (response) and then increase to or above baseline HBI week 14 or later. Chi square testing examined the association between 34 SNPs and IFX responsiveness. Time to loss of response was calculated using Kaplan Meier analysis. Results: Six SNPs (Table 1) were associated with primary non-response (p < 0.05). There were 5 different SNPs (Chromosome) associated with loss of response; rs11174631 (12q12); OR =10.6, p= 0.03; rs8049439 (16p11); OR = 3.8, p= 0.03, rs2456449 (8q24); OR= 4.8, p = 0.02, rs10044354 (5q15); OR = 3.8, p = 0.03, rs6908425 (6p22); OR = 4.1, p = 0.03. Of these 5 SNPs, 4 were also associated with the time to loss of response (median 9 months): rs11174631 (p= 0.03), rs2456449 (p = 0.03), rs10044354 (p = 0.04), rs6908425 (p = 0.02). Conclusion: These findings suggest that there may be different genetic predictors and perhaps biological explanations for primary non response vs. secondary loss of response. Replication studies are currently underway. Defining predictors of response to anti-TNFα will allow the identification of patients with a high probability of response before initiating therapy so to negate exposure to ineffective therapies and protect patients from treatment related serious adverse events. Primary Non Response

80 Increased Risk of Inflammatory Bowel Disease After Salmonella or Campylobacter Gastroenteritis: A Population-Based Cohort Study

Background: Natural history observations in early onset IBD have prompted the increasing use of anti-TNFα therapy. Inter-individual variation, however, is seen in efficacy outcomes. These differences may be explained in part by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. Recent GWA studies in IBD have increased our understanding of the genetic susceptibility to IBD and provide insight regarding the various mechanisms of inflammation. We hypothesize that interindividual differences in therapeutic outcomes to anti-TNFαmay be associated with IBD susceptibility genes. Aim: Test associations of GWA identified IBD susceptibility loci (34 SNPs) with infliximab (IFX) responsiveness in pediatric IBD patients. Methods: Complete follow up and GWAS data was available on 63 children receiving IFX. Harvey Bradshaw index (HBI) was used to calculate disease activity. Outcomes were primary nonresponse: no change or increase in HBI at week 10; and secondary loss of response: drop in HBI by >3 points at week 10 (response) and then increase to or above baseline HBI week 14 or later. Chi square testing examined the association between 34 SNPs and IFX responsiveness. Time to loss of response was calculated using Kaplan Meier analysis. Results: Six SNPs (Table 1) were associated with primary non-response (p < 0.05). There were 5 different SNPs (Chromosome) associated with loss of response; rs11174631 (12q12); OR =10.6, p= 0.03; rs8049439 (16p11); OR = 3.8, p= 0.03, rs2456449 (8q24); OR= 4.8, p = 0.02, rs10044354 (5q15); OR = 3.8, p = 0.03, rs6908425 (6p22); OR = 4.1, p = 0.03. Of these 5 SNPs, 4 were also associated with the time to loss of response (median 9 months): rs11174631 (p= 0.03), rs2456449 (p = 0.03), rs10044354 (p = 0.04), rs6908425 (p = 0.02). Conclusion: These findings suggest that there may be different genetic predictors and perhaps biological explanations for primary non response vs. secondary loss of response. Replication studies are currently underway. Defining predictors of response to anti-TNFα will allow the identification of patients with a high probability of response before initiating therapy so to negate exposure to ineffective therapies and protect patients from treatment related serious adverse events. Primary Non Response

Conservative treatment in patients with muscle-invasive bladder cancer by transurethral resection, neoadjuvant chemotherapy with gemcitabine and cisplatin, and accelerated radiotherapy with concomitant boost plus concurrent cisplatin – assessment of response and toxicity.

Summary Background Curative treatment options for invasive bladder cancer include radical cystectomy and therapeutic strategies with bladder preservation. Aim To evaluate the toxicity and clinical effectiveness of transurethral resection, neoadjuvant chemotherapy with gemcitabine and cisplatin, and accelerated radiotherapy with concomitant boost plus concurrent cisplatin in muscle invasive bladder cancer. Materials and Methods Between October 2005 and March 2008, 27 patients with histologically proven invasive carcinoma of the bladder (T2-4a,N0-1,M0) who were fit for combined radiochemotherapy and refused radical surgery were selected to bladder-sparing protocol. Results In this study, a group of twenty one patients (78%) received two cycles of chemotherapy, and six of them (22%) only one, because of treatment related toxicity. Complete response after finished conservative treatment: transurethral resection, neoadjuvant chemotherapy with gemcytabin and cisplatin, and accelerated hyperfractionated radiotherapy with concomitant boost plus concurrent cisplatin, occurred in 18 patients (67%), partial response in 2 (8%), stable disease in 7(25%). Toxicities for hematologic and nonhematologic parameters during neoadjuvant chemotherapy were acceptable. Conclusion Conservative treatment in patients with muscle-invasive bladder cancer provides a high probability of local response with acceptable toxicity in properly selected patients.

Esophagus and Gastric Cancer: How Surgeon’s Experience and Personal Genomics May Improve Locoregional Control and Survival

Large-scale studies provide strong evidence that high-volume hospitals or high-volume surgeons improve short-term outcomes for patients undergoing high-risk surgical resection for solid cancers [1]. Although high-quality evidence for the role of surgical resection quality is lacking, some data support the view that surgeon’s experience influences long-term survival of patients with resectable gastrointestinal tumors, including esophagus and gastric cancer [2]. In a recent issue of the World Journal of Surgery, Sundelof et al. [3] reported the impact of hospital or surgeon volume on both short-term and long-term outcomes of patients with esophageal and esophago-gastric junctional (EGJ) cancer. Because of the absence of randomized trials and the limitations of this study [4], we would like to comment particularly on surgeon’s volume on long-term outcomes of patients with gastroesophageal cancer. Patients with upper gastrointestinal cancer die from metastasis or metastatic recurrence after complete tumor removal (R0 resection). Although most patients die from distant metastases, appropriate local and nodal control also may have an important role in prognosis. How can local and nodal control influence overall longterm survival when nonmetastatic esophagus cancer, such as most solid tumors, is a systemic disease? The latest accumulating evidence suggests that recurrence-free and overall survival can be improved by appropriate locoregional control in two main ways: 1) local and/or nodal recurrence may be the first, isolated event without any sign of further distant recurrence, therefore, preventing local failures by appropriate surgery alone or plus chemoradiotherapy can lead to improved overall survival; and 2) the lack of residual disease after surgical resection may enhance the effectiveness of postoperative adjuvant treatment for solid cancers [4]. The article by Sundelof et al. [3] has some limitations. This is a retrospective study with a small number of patients (n = 232). These patients underwent surgical resection during a previous period (1994–1997) when the current standard treatment, which has been changed since, included neoadjuvant and postoperative chemoradiotherapy. Despite the limitations of this study [3], the latest data from high-quality, randomized trials reveal the important role of high-volume surgeons and high-volume hospitals in achieving locoregional control and improved overall survival. Prognosis of resectable esophagus and EGI cancer remains poor even if patients are treated in specialized institutions. These patients die from recurrence after an adequate R0 resection plus modern adjuvant treatment. This inability of systemic cytotoxic treatment to eliminate micrometastatic disease or circulating cancer cells is attributable to tumor resistance for most solid tumors [5]. The development of novel combinations of empirical chemotherapeutic agents and targeted drugs also will have clinical limitations if we are unable to tailor the correct drug combinations in patients with a high response probability. Robust markers to predict prognosis and response to various combinations of systemic treatment are not currently available. Novel models are now proposed using the latest technological advances with personal genomics [6], T. Liakakos Department of Surgery, Athens University Hospital, Athens, Greece

Potassium and Phosphorus in Muscat Rosada Grape Yield in Elqui Valley Soil

A B S T R A C T The effects of P and K on grapevines (Vitis vinifera L.) var. Muscat Rosada were evaluated four years, considering the same levels of N. The experiment was conducted at the Vicuna Experimental Station (30° S; 70°44´ W) of the Instituto de Investigaciones Agropecuarias (INIA). The soil is alluvial antropic miscellaneous (Entisols). Three fertilization treatments were established: 1) N 160 + P2O5 200 + K2O 300; 2) N 160 + P2O5 0 + K2O 300; and 3) N 160 + P2O5 200 + K2O 0. At the beginning of the experiment, grape vines received all the phosphate fertilizers, 200 kg ha -1 of P2O5 as triple superphosphate in Treatments 1 and 3. Nitrogen was applied as urea for four years. The applications were initiated when the vine buds measured 20 cm. The K was applied to the soils of Treatments 1 and 2, at a dosage of 200 kg ha -1 K2O, using potassium sulphate. Between berry set and 30 d before harvest, 100 kg ha -1 K2O were applied as potassium sulphate by fertigation. Significant effects of the P fertilization were observed by the second year, with increased cluster numbers per plant. K also increased grape fruit yield by the third year. This response was obtained with less than 5 mg kg -1 of P available in the soil and less than 145 mg kg -1 of exchangeable K in the soil. The initially low content of available K and P suggests a high probability of response to the application of both elements.

Clinical trial: individualized treatment duration for hepatitis C virus genotype 1 with peginterferon‐alpha 2a plus ribavirin

Individualized treatment regimens, taking into account the heterogeneity of patients with chronic hepatitis C, are needed to improve treatment outcomes. To investigate prospectively the period of undetectable viraemia required for a high rate of sustained virological response in patients with chronic hepatitis C genotype 1 and the relationship to early viral kinetics. Forty-five chronic hepatitis C genotype 1 patients were given peginterferon-alpha 2a plus ribavirin. Viraemia and hepatocyte HCV-RNA levels were quantified using a TaqMan assay. Beyond the first time point of undetectable viraemia (<20 IU/mL) between baseline and treatment week 12, 32 of 45 (71%) patients were randomized to additional 12 weeks (G12); 24 weeks (G24) or 36 weeks therapy (G36). The remaining 13 patients received 48 weeks' treatment (G48). The sustained virological response rates were: G12--five of 11 (45%); G2 --eight of 10 (80%); G36--eight of 11 (73%); G48--four of 13 (31%). The anti-viral efficacy (epsilon) and treatment-induced loss of infected hepatocytes (Mdelta), were significantly higher in patients with early viral clearance. In G12, patients with sustained virological response had lower baseline viraemia than those who relapsed. Early viraemia clearance is a better marker than baseline viral load and differentiates chronic hepatitis C genotype 1 with high or low probability of sustained virological response. In patients with viraemia clearance within 12 weeks of starting peg-interferon/ribavirin therapy, an additional period of undetectable viraemia of minimum 24 weeks is required for high sustained virological response.

A non-invasive fibrosis score predicts treatment outcome in chronic hepatitis C virus infection

Objective. The results of a previous study suggest that an index calculated according to the formula (normalized ASAT×PK-INR)×100/thrombocyte count (×109/L; GUCI) may reflect liver fibrosis in patients with chronic hepatitis C virus (HCV) infection. The aims of the present study were (i) to validate the association between the Göteborg University Cirrhosis Index (GUCI) score and liver fibrosis and (ii) to evaluate the utility of this index in predicting the outcome of antiviral treatment. Material and methods. A total of 269 patients with chronic HCV infection, stratified according to HCV genotype (1/4 versus 2/3) participated in a phase III trial using pegylated interferon α-2a and ribavirin (DITTO study). Retrospective analyses of the baseline GUCI scores and assessments of pretreatment liver biopsies using the Ishak protocol were performed. Cut-off GUCI scores were calculated to distinguish patients with a high or low probability of sustained viral response (SVR). Results. Striking associations between GUCI and Ishak fibrosis stages (stages 0–2 versus stages 3–4, p=0.0002, stages 3–4 versus stages 5–6, p=0.002) were observed. In patients with genotype 1 or 4, a GUCI score below 0.33 was associated with a rapid viral response to antiviral treatment and an SVR rate of 80%. Ninety-two percent of patients (92/101) with a SVR had a pretreatment GUCI score below 1.11. Conclusions. Our results suggest that the GUCI score appropriately reflects the stage of liver fibrosis in HCV-infected patients, and predicts initial viral kinetics as well as treatment outcome in patients infected with HCV genotype 1 or 4.

Polymorphisms in angiogenesis related genes predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)

10576 Background: The inhibition of angiogenesis is central to the mechanism of action of BV, a monoclonal antibody to vascular endothelial growth factor (VEGF). We evaluated functionally significant polymorphisms of genes involved in the angiogenesis/VEGF pathway as potential molecular predictors of clinical outcome in pts with mCRC who received BV as part of their frontline therapy. These genes included: VEGF, VEGF receptor 2 (KDR), neuropilin 1 (NRP 1), Interleukin (IL) 6 and 8, IL receptor 1 and 2 (CXCR 1, CXCR 2) adrenomedullin (AM), leptin, fibroblast growth factor receptor 4 (FGFR4), tissue factor (TF), matrix metalloproteinases (MMP 2,7,9), epidermal growth factor receptor (EGFR), aryl hydrocarbon receptor nuclear translocator (ARNT), and nuclear factor kappa b (NFkb). Methods: PCR-RFLP assays were performed on genomic DNA extracted from the blood of 30 pts with mCRC treated with first-line FOLFOX/BV or XELOX/BV at USC. Results: the cohort consisted of 21 males and 9 females with a median age of 56 years (range: 29–81). 20 pts received XELOX/BV as part of an on-going phase II study, 10 pts received FOLFOX/BV. Radiologic response was evaluable in 27/30 pts: 2/27 (7%) complete response (CR), 14/27 (52%) partial response (PR), and 10/27 (37%) stable disease (SD) and 1/28 (4%) progressive disease. At a median follow-up of 19.4 months, 16/30 pts progressed with a median progression free survival (PFS) of 11.8 months. Pts homozygous A/A at the leptin 5'UTR region had a higher probability of response than pts with the G/A or G/G genotypes (p=0.03, Fisher's exact test). Pts with one or more G allele (G/G or A/G) at locus -181 in the promoter region of MMP7 had a higher probability of response than pts with the AA genotype (p=0.014, Fisher's exact test). There were statistically significant associations between genomic polymorphisms of KDR, CXCR2, MMP7 and PFS (&lt;0.05, Log-rank test). Conclusions: This pilot study demonstrated, in a preliminary fashion, the potential predictive and prognostic value of several genomic polymorphisms in pts with mCRC treated with FOLFOX/BV or XELOX/BV. No significant financial relationships to disclose.

Epidermal growth factor receptor (EGFR) mRNA expression levels are strongly correlated between primary colorectal cancer and corresponding liver metastases

4106 Background: As it has been well known that epidermal growth factor receptor (EGFR) is strongly related to a tumor proliferation and a metastasis, new EGFR-inhibitory small molecules, such as gefitinib and erlotinib, and EGFR antibodies have been developed recently. It is reported that the high expression levels of EGFR mRNA are associated with high response probability and longer progression-free survival in gefitinib-treated lung cancer patients. Thus, since liver metastases are the main cause of death for most of colorectal cancer (CRC) patients, it is reasonable to expect that measurement of EGFR gene expression levels in liver metastases would provide the best prediction of therapy benefit, but in most cases, only biopsies of the patient’s primary tumor are readily available for analysis. Our aim was to determine how EGFR gene expression levels in primary CRC were related to those in liver metastases. Methods: Thirty-one pairs of primary CRC and corresponding liver metastases were analyzed. (18 males and 13 females: Median age 66 (range 45–85)). Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR (Taqman PCR). Results: No significant difference was seen between median mRNA expression levels of EGFR in primary cancer and those in corresponding liver metastases (Median value: 1.35 vs 1.24, p=0.99 , Wilcoxon signed rank test), although the median value of EGFR mRNA from normal liver tissue is significantly higher than those from normal colon mucosa (Median value: 5.06 vs 1.39, p&lt;0.0001). When matched tissue sets were compared on an individual basis, there was a significant correlation for EGFR mRNA expression between primary cancer and corresponding liver metastases (rs=0.78, p&lt;0.0001, Spearman rank correlation coefficient). Conclusions: A good prediction of EGFR mRNA levels in liver metastases can be obtained by measuring those of primary CRC. No significant financial relationships to disclose.

Immunosuppressive treatment strategies in low-risk MDS

<h2>Summary</h2> Ineffective haematopoiesis with peripheral cytopenias despite normo- or hypercellular bone marrow is the hallmark of the myelodysplastic syndromes especially in the low-risk subgroups. It is caused by increased secretion of inhibitory cytokines in the marrow through a yet unresolved pathophysiological mechanism. Immunoinhibitory or modulatory therapy aims at restoring haematopoiesis by reversing these inhibitory processes and includes antithymocyte globulin (ATG), ciclosporin A (CSA), direct TNF-inhibitors and lenalidomide. Although not yet approved for clinical use, ATG therapy improves mono-, bi- and trilineage cytopenias in around 35–40% of low-risk MDS patients usually after a single treatment course. Highest response rates are seen in younger patients, those with a shorter duration of the disease and low transfusion requirement, with hypocellular bone marrow or with thrombocytopenia. The presence of the HLA-DR15 (DR2) genotype is an additional parameter predicting a response. In contrast, differentiation defects with an increased blast cell percentage or sideroachrestic changes characterize the poor responders. A simple scoring system, using age, duration of transfusion dependency, and HLA-DR15 status, has been developed and allows identifying patients with a high, intermediate, or low probability of response to treatment with ATG. Other immunosuppressive agents which can also induce responses, e.g. CSA, have been combined with ATG, but have not yet been fully evaluated for their potential role in the treatment of MDS. Lenalidomide has a superior efficacy in the 5q-syndrome, but also some efficacy in the other low-risk MDS patients. Further clinical trials are needed to define the potential of immunosuppressive/modulatory treatment in MDS.

Drug Sensitivity by TRAC (DiSC) Assay as a Prognostic Factor for Patient Response in Untreated CLL: Results from the UK LRF CLL4 Trial.

Background. The UK LRF CLL4 trial opened in 1999: 777 previously untreated patients have been randomised between chlorambucil (Chl), fludarabine (Flu) and cyclophosphamide (Cy) plus Flu (FluCy).Methods. We measured Drug Sensitivity prior to initial therapy by TRAC (tumour response to anti-neoplastic compounds) assay, a development of the DiSC assay and divided patients (pts) into three groups: Drug resistant (DR, LC90 >= 10 ug/ml for Flu and mafosfamide (for Cy), >6.3ug/ml for Chl), Drug sensitive (DS, <0.87ug.ml Flu, <2.3ug/ml Chl, <3.3ug/ml mafosfamide) and Intermediate (DI, others).Results. Response rates by TRAC (Table 1) show a good correlation with clinical response. For example, 49% of all pts were DS and 90% of them responded to chemotherapy; whilst 9.5% were DR and only 13/42 (31%) responded. Of the 24 DR to Chl, 17/24 (71%) were DS or DI to Flu and 100% were DS or DI to FluCy. Of 14 pts DR to Flu, only 5 (36%) were DS or DI to FluCy.Table 1Response rates compared with Drug Sensitivity to drug(s) receivedDrug SensitivityChlFluFluCyOverallDS85.1 (94)90.7 (54)95.7 (70)89.9 (218)DI66.3 (92)79.2 (53)97.3 (37)76.4 (182)DR37.6 (24)21.4 (14)25.0 (4)31.0 (42)Total71.5 (210)77.7 (121)93.7 (111)78.7 (442)Data are: Response rate (%) (# pts)Biological markers with prognostic significance were also measured at trial entry (Oscier et al, ASH 2006). Whilst pts with mutated (mut) VH genes had above average response, p53 loss (>20%) was associated with in vivo drug resistance and very poor outcome. Thus, pts could be classified into three groups with Low, Standard or High risk of disease progression based on VH genes and FISH (Table 2).Table 2Comparison of Drug Sensitivity with Risk GroupRisk GroupDrug SensitivityLow (mut VH)Standard (unmut VH, VH 3–21, del11q)High (p53 loss)OverallDS90.7 (7590.1 (111)66.7 (3)89.9 (189)DI77.1 (48)75.2 (105)33.3 (6)74.2 (159)DR75.0 (4)30.0 (20)21.4 (14)31.6 (38)Overall85.0 (127)78.3 (236)30.4 (23)77.7 (386)While almost all patients without p53 loss respond to FluCy, 30% do not respond to Chl and only a minority of these have p53 loss. The potential importance of TRAC is its ability to identify drug resistant pts and to predict sensitivity to alternative treatments for these, as well as for pts with p53 loss. 47 of 386 pts (12%) were either DR by TRAC to treatment given or were High Risk with p53 loss: 45 (96%) were DS or DI to a variety of CLL regimens including Chl, Flu, FluCy, high-dose methylprednisolone, COP (Cy + vincristine + prednisolone), pentostatin and anthracyclines.Conclusions. TRAC assays are effective at identifying pts with a low or high probability of response. Furthermore, a TRAC result gives indications of which treatment regimes are more likely to work in the proportion of pts with p53 loss or who are resistant to standard first-line chemotherapy regimens. A second randomisation in the CLL4 trial is designed to establish whether, after relapse or non-response to initial therapy, treatment selection based on a TRAC assay improves response and survival.

Experience of a Brazilian Institution with Adult Acute Lymphoblastic Leukemia: Clinical, Laboratory and Prognosis in 102 Patients.

ALL is an aggressive bone marrow neoplasm, mainly associated with a poor outcome in adult patients. The aim of this study is to describe clinical, laboratory and prognostic factors in 102 patients treated in one institutional department from 1990 to 2005, retrospectively. Adult ALL subtype L3 (FAB) or B-IV (EGIL) was excluded. Statistical analysis was done by SPSS 10.0.The association of features and prognosis was assessed by Pearson's chi-square. OS and DFS curves were constructed by Kaplan-Meier method and the differences were analyzed by the log-rank test. Mean age was 30,6 (12 to 82) years and 55,9% was male. Clinical findings, at diagnosis, were fatigue (55,9%), splenomegaly (56,9%), hepatomegaly (54,6%), lymphadenopathy (52,6%), fever (38,8%), bone pain (28,6%), bleeding (27,5%) and headache (15,3%). Involvement of CNS was detected in 11(10,8%) patients and testicular involvement was observed in one patient. Cutaneous infiltration occurred in one patient immunophenotyping T-IV(group b). Kidney and pulmonary infiltration, documented by biopsy, was found in 2 and 1 patients respectively. At diagnosis; mean blood values were 8,5g/dl, 84.341/mm3 and 76.275/mm3 for hemoglobin, leukocytes and platelets respectively. 98,7% of the patients presented with lymphoblasts in peripheral blood. FAB classification was L1 and L2, 50% each. B and T-ALL was observed in 69,7% and 30,2% respectively. One case was identified as biphenotypic B and T leukemia. Karyotype analysis was performed in 40 cases, Ph chromosome was identified in 20% (8/40) of the cases. Others abnormalities were hyperdiploid karyotype (6/40); t(4;11) in 2 cases; t (1;19) and t(10;11) each one with 1 case. Patients were treated with different protocols: BFM 86 modified (BFM 86M) in 47,1% (48/102) of the patients, OPAL86 and OPAL87 protocols (Linker e cols) in 45,1% (46/102) and CHOP in 7,8% (8/102). Ten patients died in early induction phase and 70,6% (65/92) were in complete remission after induction treatment. Age less than 35 years (p=0.021), CNS not infiltrated (p= 0.022) and immunophenotyping B1 and B3 (p=0.018) were associated with a better induction response in a univariated analysis. The first two parameters were associated with a high probability of complete response (p=0.041 and 0.034, respectively) in a multivariate analysis. In a median follow up of 49 months, we have observed a four-years OS of 30,4% (median 19 months). Univariate analysis of OS showed that age less than 35 and mainly less than 18 years (p=0.01), absent bleeding and hepatomegaly at diagnosis (p=0.0022; p=0.029), early time to complete remission (p=0.0001) and treatment protocol BFM 86M (p=0.0034) were associated with better survival. In a multivariate analysis age >35y, presence of hepatomegaly or bleeding at diagnosis were associated with poor OS, and were used to created a prognosis score. Patients with none to one adverse factor have a significantly better survival than patients with more than one (p=0.0001). We have observed in our population a DFS of 27% in 4 years with a median DFS of 18,9 months. Only fever, at diagnosis, was an adverse factor related to DFS in univariate analysis (p=0.0057).

Avaliação do estado nutricional da soja

O objetivo deste trabalho foi comparar os diagnósticos do estado nutricional de um conjunto de 111 lavouras comerciais de soja, pelos métodos: Sistema Integrado de Diagnose e Recomendação (DRIS) e Diagnose da Composição Nutricional (CND), com uso do conceito de potencial de resposta à adubação. Nas lavouras analisadas, observou-se que Zn, P e Fe foram os nutrientes diagnosticados por ambos os métodos como os mais limitantes pela ausência, e Mg e Mn os mais limitantes por excesso. A freqüência de lavouras com diagnósticos concordantes, quanto ao potencial de resposta à adubação, foi maior para os nutrientes considerados de maior deficiência relativa (90,3%), em relação aos considerados de maior excesso relativo (81,9%). Quando se avaliaram os diagnósticos concordantes quanto ao estado nutricional, a freqüência variou de 85,9% para o P a 98,6% para o Mn. Os métodos DRIS e CND tendem a ser concordantes quanto ao diagnóstico nutricional; o agrupamento de classes de potencial de resposta à adubação pode resultar no agrupamento, em uma única classe de estado nutricional, os nutrientes com alta e baixa probabilidade de resposta à adubação.

Dermatofibrosarcoma protuberans: a surgical disease with a molecular savior

Dermatofibrosarcoma protuberans is a low-grade malignancy of the skin and subcutaneous tissues with low potential for the development of distant metastases. This tumor is characterized by infiltrative growth, and a chromosomal translocation involving the COL1A1 gene on chromosome 17 and the gene platelet-derived growth factor B gene on chromosome 22. This review will examine recent data confirming the central role of surgery in managing this disease and new findings for the application of molecularly targeted therapy in patients with unresectable disease. The largest published series of dermatofibrosarcoma protuberans cases has reported that surgery can lead to excellent local control in dermatofibrosarcoma protuberans in over 95% of cases. In patients with metastatic disease, or with locally advanced disease not suitable for surgical excision, inhibition of platelet-derived growth factor receptors with imatinib (Gleevec) can lead to striking clinical results, including complete responses in some patients. The identification of platelet-derived growth factor B as a near universal translocation partner in chromosomal rearrangements in dermatofibrosarcoma protuberans has led to the successful application of therapy targeted at platelet-derived growth factor receptors. Although wide surgical excision remains the standard of care, patients with locally advanced disease not suitable for wide surgical excision or with metastatic disease can be managed with the platelet-derived growth factor receptors inhibitor imatinib with high probability of response.

Biochemical approaches to the combination chemotherapy of colon cancer.

The employment of biochemical concepts to select drugs for use in the treatment of colorectal cancer is advocated. It is stressed that new drug mixtures, even those employing agents inactive alone, with unique mechanisms of action may be fashioned through biochemical design. Following delineation of activity in animal model systems, these drug combinations then become candidates for use in man. It is emphasized that 6-thioguanine is a particularly attractive agent for consideration as a component of new combinations of drugs to be used in patients with cancer. The desirability of this agent derives from (a) the known, albeit weak, activity of 6-thioguanine against colorectal neoplasms of man, thereby providing some inherent activity to be joined by additional materials; (b) a knowledge of several major biochemical and pharmacologic determinants of tissue susceptibility to its cytotoxic action, possibly allowing the ultimate selection of patients with a high probability of response; and (c) the availability of four different agents or classes of agents which synergistically interact with 6-thioguanine to inhibit the growth of malignant cells by diverse biochemical mechanisms.

Prevention of mother-to-child transmission of multi-drug resistant HIV-1 using maternal therapy with both enfuvirtide and tipranavir

The management of multi-drug resistant HIV is a complex challenge in daily practice. Of particular concern is the presence of these strains in pregnant females as drug resistance does not only limit therapeutic options for the mother but may also reduce the effectiveness of perinatal prophylaxis. In order to avoid mother-to-child transmission clinicians may feel compelled to prescribe recently approved drugs for which there is none or only limited experience in pregnancy. We present a case of a pregnant female with drug-resistant HIV who received a mega-HAART regimen including the recently approved drugs enfuvirtide and tipranavir. Only limited information is available on perinatal prescription of enfuvirtide and the use of tipranavir in pregnancy has not yet been reported. (excerpt)

A multi-gene algorithm as predictor of response to chemo-radiotherapy in head and neck cancer

10086 Background: Chemo-radiotherapy results in clinical cure for stage III/IV head and neck cancer in approximately 40% of cases, with significant treatment-associated morbidity and mortality. Molecular genetic factors predictive of treatment outcome would clearly be of value in selection of patients with highest probability of response. We have analysed the structure and epigenetic regulation of specific genes as possible predictors of outcome to chemo-radiotherapy. The genes analyzed were: p53 (single nucleotide polymorphism (SNP) and mutation), MDM2 (SNP), Chfr (methylation), CRABP1 (methylation). Methods: 84 patients with locally advanced head and neck cancer receiving cisplatin-based chemo-radiotherapy were studied. SNP genotypes were determined by direct sequencing of DNA from normal tissue. Acquired mutations in p53 and aberrant methylation in the CpG islands of specific genes were analyzed by direct sequencing and methylation-specific PCR. Results: There were 6 treatment-related deaths in 84 patients, all occurring in cases with germ-line haplotype p53 72 Arg/Arg, MDM2 309T/T. At the time of analysis, 39/84 (46%) patients had progressed or died, with median time to progression or death = 17.3 months. Complete response was more common in patients whose genetic/epigenetic profile was p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to the profile p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (91% vs 46%, log rank p = 0.002). Progression-free survival was significantly longer for patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated, compared to those with p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (% surviving progression-free at 2 years = 74% vs 36%, p = 0.001). Overall survival was significantly longer in patients with the profile p53 72 Arg/Arg wild type, MDM2 309 G/G, Chfr methylated, CRABP1 methylated compared to those with p53 72 Arg/Arg mutant, MDM2 309 T/T, Chfr unmethylated, CRABP1 unmethylated (% surviving at 2 years = 88% vs 40%, p = 0.0004). Conclusions: Genetic and epigenetic parameters influence the toxicity and clinical outcome of chemo-radiotherapy in head and neck cancer. No significant financial relationships to disclose.

Order of patient entry influences outcome for metastatic renal cell cancer after non‐myeloablative allogeneic stem cell transplantation

Allogeneic transplantation for renal cell carcinoma has shown encouraging preliminary results. We reviewed the published literature to evaluate the impact of patient selection. Most studies did not include information on prognostic factors. We used patient entry rank within individual studies as a novel surrogate for patient selection, motivated by our own experience of an apparent impact of entry rank. One hundred patients were identified from nine studies. Twenty-six per cent of patients demonstrated either a partial or complete response. Median overall survival was 12.3 months. Grade 2-4 acute graft-versus-host disease correlated with an increased likelihood of response (odds ratio: 5.4, 95% confidence interval: 1.6-18.1, P = 0.006) but not survival. Earlier patient entry rank on each trial was associated with a higher probability of response (P = 0.004) and superior survival (P = 0.004). Patient entry rank served as a powerful prognostic factor, suggesting bias in patient selection that evolved over the course of the study. Further studies are warranted to determine the influence of order of patient entry in other early clinical trial settings.

Immunosuppressive Treatment Is Associated with Durable Responses and a Survival Advantage in Younger Patients with int-1 Myelodysplastic Syndrome.

Immunosuppressive therapy (IST) can improve cytopenias in selected patients with myelodysplastic syndrome (MDS). Between 1998 and 2004, 129 patients with MDS [94 int-1, 13 int-2, 16 low and 6 high International Prognostic Scoring System (IPSS) stage] were given IST on investigational protocols: 116 received ATG 160mg/kg, 42 with additional cyclosporine (CsA); 13 received CsA alone for up to 6 months. Mean follow-up was 47 (range 0.7–120) months. Previously, we reported a score, using HLA-DR15 type, age and duration of red cell transfusion-dependence to segregate patients into high probability (HP), intermediate probability (IP), and low probability (LP) of hematological response to IST. Here we compare survival, response, and leukemic progression in HP and LP/IP NIH IST-treated patients and in non-IST controls enrolled in the International MDS Risk Analysis Workshop (IMRAW) (Blood 89:2079, 1997). Overall, 29% of NIH IST patients responded: HP patients (median ages for HP and the combined LP/IP] were 49 and 65 yr, respectively) were more likely to respond to IST than LP patients 38/55 (69%) vs 0/71 plus 0/3 IP; p<0.0001) (IP was included in LP group for analysis of survival), with better responses to ATG/CsA than with ATG alone (p=0.015). Neither abnormal cytogenetics nor bone marrow cellularity affected the response rate independent of IPSS int-1 or HP status. Seven of eight (87%) int-1 patients ≤ 60 with trisomy 8 as the sole abnormality and 16/34 with normal cytogenetics (47%) responded to one course of ATG; all 11 int-1 patients with 5q- were >60 years of age and none responded to IST. Marrow cellularity did not influence response to IST. Only two responders relapsed and required re-treatment with ATG; both responded to the second treatment. All but one patient with trisomy 8 increased the percentage of these cells in the marrow following therapy; the two responding monosomy 7 patients showed normal cytogenetics and FISH analysis following response to therapy. Age and IPSS stage were the major factors affecting survival in both treated and untreated patients. The actuarial survival of the 44 IST int-1 patients (median age 54) age ≤ 60 was superior to the untreated 87 int-1 IMRAW patients age ≤ 60 years (median age 48); the projected median survival was >16.4 years for the IST group and 5.2 years for the IMRAW group (p=0.0016), while there was no difference in survival between IST and IMRAW int-1 patients > 60 years of age (p=NS). Leukemic evolution was also decreased in the int-1 IST treated group ≤ 60 years of age compared to the comparable conservatively treated IMRAW group (projected time for 25% pts to develop AML was >16.4 years for IST patients vs 6.9 years for the IMRAW group) (p<0.001). These findings indicate that our IPSS int-1 patients ≤age 60 who received IST had improved survival compared to an untreated historical control group and that combined ATG/CsA gave superior responses compared to ATG alone.