Publisher Correction: CODA: Integrating multi-level context-oriented directed associations for analysis of drug effects.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Petri net-based prediction of therapeutic targets that recover abnormally phosphorylated proteins in muscle atrophy.

BACKGROUND: Muscle atrophy, an involuntary loss of muscle mass, is involved in various diseases and sometimes leads to mortality. However, therapeutics for muscle atrophy thus far have had limited effects. Here, we present a new approach for therapeutic target prediction using Petri net simulation of the status of phosphorylation, with a reasonable assumption that the recovery of abnormally phosphorylated proteins can be a treatment for muscle atrophy. RESULTS: The Petri net model was employed to simulate phosphorylation status in three states, i.e. reference, atrophic and each gene-inhibited state based on the myocyte-specific phosphorylation network. Here, we newly devised a phosphorylation specific Petri net that involves two types of transitions (phosphorylation or de-phosphorylation) and two types of places (activation with or without phosphorylation). Before predicting therapeutic targets, the simulation results in reference and atrophic states were validated by Western blotting experiments detecting five marker proteins, i.e. RELA, SMAD2, SMAD3, FOXO1 and FOXO3. Finally, we determined 37 potential therapeutic targets whose inhibition recovers the phosphorylation status from an atrophic state as indicated by the five validated marker proteins. In the evaluation, we confirmed that the 37 potential targets were enriched for muscle atrophy-related terms such as actin and muscle contraction processes, and they were also significantly overlapping with the genes associated with muscle atrophy reported in the Comparative Toxicogenomics Database (p-value < 0.05). Furthermore, we noticed that they included several proteins that could not be characterized by the shortest path analysis. The three potential targets, i.e. BMPR1B, ROCK, and LEPR, were manually validated with the literature. CONCLUSIONS: In this study, we suggest a new approach to predict potential therapeutic targets of muscle atrophy with an analysis of phosphorylation status simulated by Petri net. We generated a list of the potential therapeutic targets whose inhibition recovers abnormally phosphorylated proteins in an atrophic state. They were evaluated by various approaches, such as Western blotting, GO terms, literature, known muscle atrophy-related genes and shortest path analysis. We expect the new proposed strategy to provide an understanding of phosphorylation status in muscle atrophy and to provide assistance towards identifying new therapies.

Author Correction: CODA: Integrating multi-level context-oriented directed associations for analysis of drug effects.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

CODA: Integrating multi-level context-oriented directed associations for analysis of drug effects.

In silico network-based methods have shown promising results in the field of drug development. Yet, most of networks used in the previous research have not included context information even though biological associations actually do appear in the specific contexts. Here, we reconstruct an anatomical context-specific network by assigning contexts to biological associations using protein expression data and scientific literature. Furthermore, we employ the context-specific network for the analysis of drug effects with a proximity measure between drug targets and diseases. Distinct from previous context-specific networks, intercellular associations and phenomic level entities such as biological processes are included in our network to represent the human body. It is observed that performances in inferring drug-disease associations are increased by adding context information and phenomic level entities. In particular, hypertension, a disease related to multiple organs and associated with several phenomic level entities, is analyzed in detail to investigate how our network facilitates the inference of drug-disease associations. Our results indicate that the inclusion of context information, intercellular associations, and phenomic level entities can contribute towards a better prediction of drug-disease associations and provide detailed insight into understanding of how drugs affect diseases in the human body.

Comparable Allogeneic Hematopoietic Cell Transplantation Outcome of a Haplo-Identical Family Donor with an Alternative Donor in Adult Aplastic Anemia.

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA.

Biweekly dose-dense gemcitabine-oxaliplatin and dexamethasone for relapsed/refractory aggressive non-Hodgkin lymphoma: A multicenter, single-arm, phase II trial.

AIM: We performed a phase II study to evaluate the efficacy of combination chemotherapy consisting of gemcitabine, dexamethasone and oxaliplatin (GemDOx) as a biweekly regimen and salvage therapy in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS: Gemcitabine (1000 mg/m(2) ) and oxaliplatin (85 mg/m(2) ) were administered intravenously on days 1 and 15, and dexamethasone (40 mg) was administered orally on days 1-4. RESULTS: Twenty-nine patients were enrolled, and most patients had diffuse large B-cell lymphoma (n = 18). The median age of the patients and median prior number of chemotherapy cycles were 53 (range, 26-74) years and 1 (range, 1-4) cycle, respectively. Only 17 (58.6%) and 9 (31.0%) patients completed two or more and four or more cycles, respectively, and the median number of received cycles was two (range, 1-8). Overall response rates were 27.6% (complete response in 13.8%) among intent-to-treat patients and 47.1% (complete response in 23.5%) among patients who had received at least two GemDOx cycles. Median progression-free survival and median overall survival were 3.9 and 20.5 months, respectively. The most-frequent grade 3 or 4 toxicity was neutropenia (22.9%), and no grade 3 or 4 peripheral neurotoxicity was noted. CONCLUSION: GemDOx chemotherapy, therefore, showed modest activity against relapsed or refractory aggressive NHL, although toxicities were acceptable.

Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload.

BACKGROUND: Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality. STUDY DESIGN AND METHODS: This study was an open-label, single-arm, prospective clinical study to evaluate the efficacy and safety of deferasirox (DFX) in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). Patients with serum ferritin levels of at least 1000 ng/mL and ongoing transfusion requirements were enrolled. DFX was administered for up to 1 year. A total of 100 patients were enrolled. RESULTS: Serum ferritin levels decreased significantly following treatment (from 2000 to 1650 ng/mL, p = 0.004). The median absolute reduction in serum ferritin levels was -65 ng/mL in AA (p = 0.037), -647 ng/mL in lower-risk MDS (MDS-LR; p = 0.007), and -552 ng/mL in higher-risk MDS (MDS-HR)/AML (p = 0.482). Mean labile plasma iron (LPI) levels decreased from 0.24 µmol/L at baseline to 0.03 µmol/L at 1 year in all patients (p = 0.036). The mean LPI reduction in each group was -0.17 µmol/L in AA, -0.21 µmol/L in MDS-LR, and -0.30 µmol/L in MDS-HR/AML. Gastrointestinal disorders were commonly observed among groups (16.0%). DFX was temporarily skipped for adverse events in seven patients (7.0%) and was permanently discontinued in 11 patients (11.0%). CONCLUSION: DFX reduced serum ferritin and LPI levels in patients with transfusional iron overload. Despite the relatively high percentage of gastrointestinal side effects, DFX was tolerable in all subgroups.

Magnetic resonance imaging pattern of bone marrow involvement as a new predictive parameter of disease progression in newly diagnosed patients with multiple myeloma eligible for autologous stem cell transplantation.

We investigated the prognostic value of the magnetic resonance imaging (MRI) pattern of bone marrow involvement in patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). 126 patients with untreated MM indicated for ASCT underwent spine MRI and cytogenetic analysis at diagnosis. All patients received ASCT after induction therapy of VAD (vincristine, doxorubicin, dexamethasone; n = 55) or a thalidomide-based regimen (TCD; n = 71). Thalidomide maintenance therapy was performed in 68 patients. The MRI pattern was normal in 27, focal in 47, and diffuse/variegated in 52 patients. Patients with the diffuse/variegated pattern showed significantly higher stage (P = 0·038), higher ß-2 microglobulin level (P = 0·001) and severe anaemia (P = 0·015). However, the cytogenetics were not different among the MRI patterns (P = 0·890). Progression-free survival (PFS) was lower in the diffuse/variegated pattern (P = 0·002) than other patterns, but not overall survival (OS) (P = 0·058). Thalidomide maintenance therapy was correlated only with PFS (P = 0·001). High-risk cytogenetics were associated with both poorer PFS (P < 0·001) and OS (P = 0·003). In a multivariate analysis, the diffuse/variegated MRI pattern was an independent predictor of disease progression (Hazard Ratio, 1·922; 95% confidence interval, 1·185-3·118; P = 0·008). The diffuse/variegated MRI pattern is a novel prognostic factor for disease progression in MM patients eligible for ASCT.

Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine.

PURPOSE: We conducted a phase III randomized clinical trial to compare two myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) in patients with leukemia and myelodysplastic syndrome. PATIENTS AND METHODS: After randomization, 64 patients received busulfan (3.2 mg/kg per day × 4 days) plus cyclophosphamide (60 mg/kg per day × 2 days; BuCy), and 62 patients received busulfan (same dose and schedule) plus fludarabine (30 mg/m(2) per day × 5 days; BuFlu). RESULTS: The median age was 41 years (range, 17 to 59 years). Five patients in the BuFlu arm experienced graft failure (primary, n = 1; secondary, n = 4). At 4 weeks after HCT, the median percentage of recipient hematopoietic chimerism was significantly greater in the BuFlu arm (0% v 5.5%; P < .001), and complete donor chimerism was greater in the BuCy arm (97.2% v 44.4%; P < .001). Severe (grade 3 or higher) infection and gastrointestinal adverse events were significantly more common in the BuCy arm, but the frequencies of hepatic adverse events were similar in the two arms. Nonrelapse mortality was similar in the two arms, but the BuCy arm had better overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS; OS at 2 years, 67.4% v 41.4%, P = .014; RFS, 74.7% v 54.9%, P = .027; EFS, 60.7% v 36.0%, P = .014). CONCLUSION: Our results indicate that the BuFlu regimen is not a suitable replacement for the BuCy regimen in young adults who are eligible for myeloablative conditioning therapy for allogeneic HCT.

A combination of melphalan, prednisone, and 50 mg thalidomide treatment in non-transplant-candidate patients with newly diagnosed multiple myeloma.

BACKGROUND/AIMS: The clinical efficacy and safety of a three-drug combination of melphalan, prednisone, and thalidomide were assessed in patients with multiple myeloma who were not candidates for high-dose therapy as a first-line treatment. Because the side effects of thalidomide at a dose of ≥ 100 mg daily can be a barrier to effective treatment for these patients, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg, for non-transplant candidates. METHODS: Twenty-one patients were treated in 4-week cycles, receiving 4 mg/m(2) melphalan and 40 mg/m(2) prednisone on days 1-7 and 50 mg thalidomide daily. The primary efficacy outcome was the overall response rate. Aspirin (100 mg daily) was also provided as prophylactic treatment for thromboembolism. RESULTS: The overall response rate was 57.1%; a complete response was seen in 23.8% of patients, a partial response in 33.3%, and stable disease in 9.5%. After a median follow-up time of 16.1 months, the median time to progression was 11.4 months (95% confidence interval, 2.1 to 20.6); the median overall survival was not reached. Grades 3 and 4 adverse events included infection (10%), peripheral neuropathy (5%), diarrhea (5%), thrombosis (10%), and loss of consciousness (10%). Two patients discontinued treatment due to loss of consciousness and neuropathy. CONCLUSIONS: Low-dose thalidomide (50 mg) plus melphalan and prednisone is an effective combination drug therapy option for newly diagnosed myeloma patients who are ineligible for high-dose chemotherapy.

Clinical effect of reduced-intensity conditioning regimen containing antithymocyte globulin for hematopoietic cell transplantation from unrelated-donors.

The impact of reduced-intensity conditioning (RIC) on the outcomes of hematopoietic cell transplantation (HCT) from unrelated -donors (UD) remains to be determined. We therefore assessed 128 patients, aged 16 to 66 years, with acute leukemia (n = 105) or myelodysplastic syndrome (n = 23) in a UD-HCT trial using RIC with busulfan, fludarabine, and antithymocyte globulin. Patients were transplanted with unmanipulated bone marrow (BM, n = 41) or mobilized peripheral blood mononuclear cells (M-PB, n = 87) and received cyclosporine and methotrexate for graft-versus-host disease (GVHD) prophylaxis. After a median follow-up of 26.7 months (range, 5.9-70.7 months) in surviving patients, 19 patients had died without progression/recurrence of underlying disease, giving a cumulative incidence of transplantation-related mortality (TRM) of 17% (95% confidence interval, 11%-27%; 1-year TRM, 14%). Graft failure (n = 7) and infections (n = 5) were the most common causes of TRM. Only three patients died due to GVHD (acute, one; chronic, two). Graft failure, which occurred in eight patients, showed a significant correlation with graft source (BM, 6/41 vs. M-PB, 2/87; P = 0.009). Donor-patient HLA-disparity did not correlate with GVHD, 1-year TRM, and graft failure. RIC containing antithymocyte globulin led to decreased GVHD-associated, as well as overall, TRM after UD-HCT.

Continuous infusion of intermediate-dose cytarabine and fludarabine with idarubicin for patients younger than 60 years with resistant acute myeloid leukemia: a prospective, multicenter phase II study.

We assessed continuous infusion (CI) of fludarabine and cytarabine (FLAG) plus idarubicin for patients under 60-years old with resistant acute myeloid leukemia (AML). Induction chemotherapy consisted of idarubicin (12 mg/m(2) iv infusion over 30 min on Days 1-3), plus fludarabine (30 mg/m2/day) and cytarabine (1,000 mg/m(2)/day) on Days 1-5 as a 24-hr CI. G-CSF was added on Days 1-5. The 29 patients enrolled were of median age 40 years (range, 18-57 years); of these, 8 (27.6%) had primary refractory disease, 19 (65.5%) were in early relapse, and 1 each (3.4%) was in multiple relapse and relapse after SCT. In response to induction, 8 patients (27.6%) achieved CR, 2 (6.9%) achieved CRp, and 19 (65.5%) failed treatment; of the latter, 14 had aplasia, three had an indeterminate course, and two showed resistance. Seven patients remain alive, while two were lost to follow-up. Nineteen patients died, 14 of infection, one of toxicity during consolidation, three of relapse after SCT, and two of persistent disease. These findings indicate that although CI of FLAG plus idarubicin was effective for eradicating blasts, it carried a high risk of toxicity. Reduced doses are recommended for CI of FLAG plus idarubicin.

Clinical overview of extrapulmonary small cell carcinoma.

The objective of this study was to review the natural history of extrapulmonary small cell carcinoma (EPSCC) with specific emphasis on clinical features, response to treatment and survival. The records of all patients (n=34) with EPSCC treated at Yeungnam University Medical Center and Catholic University of Daegu Medical Center between 1998 and 2005 were retrieved and reviewed. The primary sites of tumor were the esophagus and thymus in 6 patients (17.6%) each, pancreas and stomach in 5 patients each (14.7%); other sites included were the cervix, abdominal lymph nodes, abdominal wall, bladder, colon, maxillary sinus, nasal cavity, ovary, parotid gland and liver. Twenty three patients out of 34 had limited disease. The median survival of all patients was 14 months. Independent prognostic factors included stage and primary tumor location. The prognosis for the patients with extensive disease and in the gastrointestinal group was unfavorable. EPSCC is a non homogeneous disease entity. As a result of its frequent recurrence, multimodal therapy has a better outcome even in cases of limited disease. Combination chemotherapy plays a central role for treatment of extensive disease in EPSCC. Further multicenter studies are now needed to determine more details regarding disease sub-class and optimal treatment modality.

The efficacy of docetaxel and cisplatin combination chemotherapy for the treatment of advanced gastric cancer after failing to 5-fluorouracil based chemotherapy.

PURPOSE: This study was conducted to confirm the efficacy and toxicity of docetaxel and cisplatin combination chemotherapy (DP) in patients with advanced gastric cancer. MATERIALS AND METHODS: Patients with measurable gastric adenocarcinoma received intravenous docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with premedication on day 1, which was repeated every 3 weeks. All patients received DP as a second-line treatment after failing to 5-FU based chemotherapy. RESULTS: 34 patients were enrolled in this study between January 1998 and August 2003. A total of 112 cycles (median 3 cycles) were administered. Responses were evaluable in 30 patients. The objective response rate was 16.7% (95% CI: 3.5 approximately 30.3), with a stable disease in 56.7% (95% CI: 40.0 approximately 74.4) and a progressive disease in 26.7% (95% CI: 10.9 approximately 42.5) of patients, with a median follow up duration of 20 months for all the patients, The median duration of response, time to progression and overall survival were 2.1 months (95% CI: 0.4 approximately 3.9), 4.2 months (95% CI: 2.3 approximately 6.1) and 6.8 months (95% CI: 1.3 approximately 12.3), respectively, with a 1-year survival rate of 32%. The toxicity was evaluated in 30 patients, with neutropenia being most common. Renal impairment was seen in two patients with grade 3 creatinine elevation and liver enzyme elevation in four with grades 3 and 4. CONCLUSION: Although DP was an active combination regimen, with a tumor control rate of about 73% and with moderate tolerance, adjustment of the administration schedule, with further evaluation of other combination chemotherapies of docetaxel with new agents, other than cisplatin, seem warranted.