Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions (AU)

Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

Relationship between pediatric blood and marrow transplant center volume and day +100 mortality: Pediatric Blood and Marrow Transplant Consortium experience.

The number of patients receiving a BMT is currently being used as a factor in the accreditation process in determining whether a center can provide a high-quality BMT. Such criteria particularly impact pediatric BMT centers as most of them perform a relatively small number of BMTs. To determine whether patient volume is a valid marker of pediatric BMT center's capabilities, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) evaluated data from its registry to define the relationship between a pediatric transplant center's patient volume and day +100 mortality. The analyses evaluated 2575 transplants from 60 centers reporting to the PBMTC between the years 2002 and 2004. The volume-outcome relationship was evaluated while adjusting for 46 independent data categories divided between nine variables that were known- or suspected-mortality risk factors. We found no association between transplant center volume and day +100 mortality in several analyses. A calculated intraclass correlation coefficient also indicated that differences in individual transplant center volume contributed to only 1% of the variance in day +100 mortality within the PBMTC. The results of this study suggest that factors other than transplant center volume contribute to variation in day +100 mortality among pediatric patients.

Merging of the National Cancer Institute-funded cooperative oncology group data with an administrative data source to develop a more effective platform for clinical trial analysis and comparative effectiveness research: a report from the Children's Oncology Group.

PURPOSE: The National Cancer Institute-funded cooperative oncology group trials have improved overall survival for children with cancer from 10% to 85% and have set standards of care for adults with malignancies. Despite these successes, cooperative oncology groups currently face substantial challenges. We are working to develop methods to improve the efficiency and effectiveness of these trials. Specifically, we merged data from the Children's Oncology Group (COG) and the Pediatric Health Information Systems (PHIS) to improve toxicity monitoring, to estimate treatment-associated resource utilization and costs, and to address important clinical epidemiology questions. METHODS: COG and PHIS data on patients enrolled on a phase III COG trial for de novo acute myeloid leukemia at 43 PHIS hospitals were merged using a probabilistic algorithm. Resource utilization summary statistics were then tabulated for the first chemotherapy course based on PHIS data. RESULTS: Of 416 patients enrolled on the phase III COG trial at PHIS centers, 392 (94%) were successfully matched. Of these, 378 (96%) had inpatient PHIS data available beginning at the date of study enrollment. For these, daily blood product usage and anti-infective exposures were tabulated and standardized costs were described. CONCLUSIONS: These data demonstrate that patients enrolled in a cooperative group oncology trial can be successfully identified in an administrative data set and that supportive care resource utilization can be described. Further work is required to optimize the merging algorithm, map resource utilization metrics to the National Cancer Institute Common Toxicity Criteria for monitoring toxicity, to perform comparative effectiveness studies, and to estimate the costs associated with protocol therapy.

Bowel obstruction after treatment of intra-abdominal tumors.

BACKGROUND: Tumors of the solid viscera are one of the most common types of pediatric malignancies. Due to the intra-abdominal location of many of these neoplasms, laparotomy and/or bowel resection are often necessary, predisposing patients to postoperative intestinal obstruction. Additionally, chemotherapy and radiation therapy may lead to acute and chronic bowel injury, also potentially predisposing these patients to postoperative bowel obstruction. We reviewed our data over an eleven-year period to identify the incidence of obstruction as well as factors associated with its development. METHODS: A retrospective data analysis of all patients diagnosed with intra-abdominal Wilms' tumor, rhabdomyosarcoma, neuroblastoma, and Hodgkin's and non-Hodgkin's lymphoma in a single institution from 1997 to 2007 was conducted. Data collected included demographic factors, operations, incidence of small bowel obstruction (SBO) and the use of adjuvant or neoadjuvant chemoradiation therapy. Patients who developed SBO were compared to those who did not develop obstruction. Data comparisons were analyzed statistically using Fisher's exact test, 2-tailed Student's t-Test, or chi-square proportional analysis with significance reported for p<0.05. RESULTS: A total of 291 patients were identified during the study period. Mean age at diagnosis was 8.1+/-5.8 years. Males accounted for 57% of all patients. Tumor distribution was as follows: Wilms' tumor: 56 (19%); non-Hodgkin's lymphoma: 71 (24%); Hodgkin's lymphoma: 64 (22%); rhabdomyosarcoma: 32 (11%); and neuroblastoma: 68 (24%). There were a total of 12 bowel obstructions in 11 patients (3.7%). Mean follow-up for all patients was 3.6+/-2.7 years. Children with bowel obstruction were more likely to be male (4.5:1, p=0.061) and younger (4.2 years versus 8.1 years; p=0.087). Wilms' tumor accounted for 45% of patients with bowel obstruction, but made up only 19% of the study population. The incidence of bowel obstruction in patients with Wilms' tumor was 8.9% compared to an overall incidence of 3.8% (p=0.043). CONCLUSION: Bowel obstruction is relatively uncommon after intra-abdominal malignancies in children. Wilms' tumor, rhabdomyosarcoma and Burkitt's lymphoma appear to be associated with the highest risk of bowel obstruction.

Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Hematopoietic stem cell transplantation (HSCT) with a conditioning regimen of busulfan, cyclophosphamide, and etoposide for children with acute myelogenous leukemia (AML): a phase I study of the Pediatric Blood and Marrow Transplant Consortium.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important treatment modality for children with AML. The optimal conditioning regimen is unknown. The aim of this study was to determine the appropriate dosing of etoposide in combination with busulfan and cyclophosphamide in this setting. PROCEDURE: Twenty patients with a diagnosis of AML in first or second remission, or myelodysplasia scheduled for bone marrow transplantation, were included in this study. Patients received busulfan 640 mg/m(2) in 16 doses, cyclophosphamide 120 to 150 mg/kg in two doses, and etoposide from 40-60 mg/kg as a single dose. Extensive toxicity data was collected. RESULTS: Nineteen patients were evaluable for toxicity. Mucositis was seen in all patients. Four patients developed bacteremia and one patient died from overwhelming sepsis on day +3. Four patients developed moderate to severe skin toxicity. The major dose-limiting +3 toxicity was hepatic toxicity, which occurred in 14 of 19 patients. Eight patients developed clinical veno-occlusive disease, including three patients at dose level 4, two of whom had life-threatening disease. This hepatic toxicity defined the MTD of 640 mg/m(2) busulfan, 120 mg/kg of cyclophosphamide, and 60 mg/kg of etoposide. Overall, 9 of 20 patients enrolled in the study survive in remission, 8/14 allogeneic (median follow-up 44 months), and one of six autologous patients (follow-up, 54 months). CONCLUSIONS: We conclude that the combination of busulfan, cyclophosphamide, and etoposide at the doses defined above has activity in the treatment of children with high-risk AML/MDS undergoing allogeneic HSCT. Whether it offers an advantage over other conditioning regimens will require a randomized trial with a larger cohort of patients.

[Iatrogenic bladder lithiasis in the Burch technique. An infrequent complication]. / Litiasis vesical yatrogénica en la técnica de Burch. Una complicación infrecuente.

OBJECTIVE: To describe an uncommon case of iatrogenic bladder lithiasis in a female patient who underwent colposuspension according to the Burch technique. METHODS/RESULTS: A female patient who had undergone colposuspension for urinary stress incontinence presented with irritative bladder symptoms and dyspareunia two years later. Patient evaluation revealed stone formation on the nonresorbable suture. Stone removal was achieved endoscopically using local anesthesia and without compromising continence. CONCLUSION: Removal of the calculus that had formed on the suture was achieved by endoscopy without compromising continence.

Alpha hemolytic streptococcal infection during intensive treatment for acute myeloid leukemia: a report from the Children's cancer group study CCG-2891.

PURPOSE: Past reports indicate that alpha hemolytic streptococcal (AHS) organisms are a common cause of infection among acute myeloid leukemia (AML) patients. This study was intended to ascertain the population incidence and rate (infections per 100 patient-days of treatment) of AHS and to identify associated risk factors. PATIENTS AND METHODS: Patients (n = 874 with 151,350 days of risk) enrolled on the Children's Cancer Group (CCG) protocol for newly diagnosed AML, CCG-2891, which randomly assigned intensity of induction and intensification, were prospectively evaluated for infectious complications. RESULTS: AHS occurred in 21% of patients, was primarily blood borne (86%), made up 21% of bacteremic infections, and had a recurrent incidence of 31% during subsequent therapy. AHS was more often life-threatening (59%) than other infections (41%) (P = .001). AHS rates increased with age less than 10 years (odds ratio [OR], 2.0; P = .007), intensively timed induction (OR, 1.8 to 1.9; P = .02), and high-dose cytarabine intensification (OR, 3.7; P<.0001). Among all courses, the greatest incidence (19%) and rate (0.41) were associated with the use of high-dose cytarabine. Gastrointestinal toxicity correlated significantly with AHS bacteremia (P<.01). Infection with AHS resulted in increased hospital days (P =.0001). Only among bone marrow transplant patients were overall survival (OR, 2.8; P = .0001) and disease-free survival (OR, 2.1; P = .008) decreased after AHS bacteremia. CONCLUSION: This study, the first to prospectively examine AHS incidence among uniformly treated patients in multiple institutions, established that as the intensity of AML therapy has increased, so has the rate of AHS. Young children, those with previous AHS bacteremias, and those receiving high-dose cytarabine are at particularly high risk of AHS bacteremia.

Use of DNA polymorphisms to monitor engraftment after allogeneic bone marrow transplantation.

Bone marrow transplantation (BMT) has been established as a life-saving procedure in hematologic malignancies and bone marrow failure syndromes, and it may be valuable in other types of neoplastic disease. DNA polymorphisms are used to monitor engraftment after transplantation from a related or unrelated donor. DNA polymorphisms are not useful after autologous BMT or if the donor is an identical twin. The most valuable polymorphism for this purpose is caused by variation in certain repeated sequences that are known as variable number of tandem repeats (VNTR). The VNTRs are valuable because they each have several alleles increasing the probability of finding one that is useful in a given case. This method can be used to sensitively detect small amounts of residual recipient hematopoiesis. To accomplish this the laboratory must first find a polymorphic allele that is unique in the recipient. Detection of the unique allele in peripheral blood or bone marrow after BMT is tantamount to finding recipient hematopoiesis. The presence of both donor and recipient hematopoiesis can result in a state of stable mixed chimerism and not necessarily presage a relapse after BMT for leukemia; however, the presence of residual recipient cells in some cases may indicate an increased probability of relapse, particularly in chronic myelogenous leukemia.

Adenocarcinoma of minor salivary gland origin with skeletal metastasis in a child.

Primary epithelial neoplasms of the salivary gland in children are uncommon but are well recognized and occur principally in the major salivary glands. The purpose of this report is to document our experience with an adenocarcinoma of the buccal submucosa (one of several sites of minor salivary gland tissue) that metastasized to multiple bones as the initial sites of distant disease after a local recurrence. The clinical history, imaging studies, and microscopic sections including immunoperoxidase studies were evaluated from the primary tumor, local recurrence, and a metastatic lesion from the femur. The histopathologic features and immunohistochemical phenotype of the adenocarcinoma in the buccal submucosa supported its salivary gland origin. This case of adenocarcinoma of the intraoral buccal tissues independent of the parotid gland in a 12-year-old female is an unusual clinical presentation of a salivary gland neoplasm in childhood, and its ability to metastasize to distant skeletal sites is also remarkable in terms of a primary salivary gland carcinoma regardless of age at diagnosis.

Oral care with vancomycin paste for reduction in incidence of alpha-hemolytic streptococcal sepsis.

PURPOSE: alpha-Hemolytic streptococcal (AHS) sepsis is increasing in oncology patients receiving myelosuppressive chemotherapy. In response to a high rate of AHS sepsis in this population at our institution, an oral care protocol was instituted, including vancomycin 0.5% in flavored methylcellulose (vanc paste) applied orally t.i.d. at the oncologists' discretion. PATIENTS AND METHODS: A retrospective cohort study of 239 neutropenic episodes among 42 children receiving myelosuppressive chemotherapy between 1988 and 1991 compared the incidence of septicemia based on the prophylactic use of vanc paste. RESULTS: A total of 236 consecutive neutropenic episodes were evaluable, 121 with vanc paste and 115 without. AHS sepsis occurred in one child using vanc paste and in six children not using vanc paste (p = 0.06). Excluding staph-only positive blood cultures, which would not be reduced with a topical oral antibiotic drug, there were 6 and 13 positive blood cultures in the vanc-paste and nonvanc-paste patients, respectively (p = 0.09). There was no increase in incidence of gram-negative bacteremia among vanc-paste recipients. Vancomycin resistance was not encountered. CONCLUSION: This analysis suggests that vanc paste effectively reduces AHS sepsis, does not increase gram-negative bacteremia, and is not associated with vancomycin resistance. A multicentered, placebo-controlled, double-blind study is currently planned.

Unrelated-donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children.

PURPOSE: Bone marrow transplantation (BMT) for Philadelphia chromosome-positive (Ph1) chronic myelogenous leukemia (CML) results in a 55% to 64% disease-free survival (DFS) rate in 20% to 30% of cases with a matched-sibling donor (MSD). Studies that include primarily adults with CML, using unrelated-donor (URD) BMT, have expanded this option to those without an MSD. We review and compare the efficacy of URD and MSD BMT in children with Ph1 CML. PATIENTS AND METHODS: Eleven children with URD BMTs were reviewed and compared with 11 children with MSD BMTs for Ph1 CML. Among the URD BMT recipients, there were three with fully matched marrows and 10 with advanced CML. The median time from diagnosis to transplant was 2.6 years. Among the MSD BMT recipients, 11 had fully matched marrows and five had advanced CML. The median time from diagnosis to BMT was 0.7 years. All received non-T-depleted marrows after cyclophosphamide and fractionated total-body irradiation. RESULTS: Both groups had similar engraftment times. Late graft failure occurred in two URD patients. Graft-versus-host disease (GVHD), > or = grade II, was similar in both groups (77% for URD BMT, 45% for MSD BMT), although more severe acute disease and more persistent chronic disease was seen in the URD group. The Kaplan-Meier estimate of DFS was 45% +/- 15% (SE) and 78% +/- 14% (SE) in the URD and MSD groups, respectively, at 3 years. All had Karnofsky scores of more than 70%, except one URD patient debilitated from GVHD. CONCLUSION: CML is eventually fatal to all patients without BMT. The high survival rate seen among children who receive a URD BMT, despite several adverse factors, opens this important therapeutic option to those without an MSD.

Disseminated infection with Fusarium in recipients of bone marrow transplants.

Clinical data from 10 episodes of disseminated infection with Fusarium among eight recipients of bone marrow transplants and from 31 cases reported previously in the literature were analyzed in an effort to characterize the natural history of this rare infection and its response to therapy. The characteristic signs of fusarial infection--disseminated skin nodules, fungemia, and multiple-organ involvement--are results of its propensity for early spread. From a review of the literature and our own experience, it appears that recovery of phagocytic mechanisms (the primary immunologic defenses against Fusarium) in the form of rising neutrophil counts is mandatory for clinical resolution. Even after a graft begins to function adequately, Fusarium may not be completely eradicated, as evidenced by the high incidence of recurrence among patients with subsequent neutropenic episodes. Fusarium is highly resistant to conventional antifungal drugs in vitro, but its progression may be slowed by intensive antifungal therapy until the recovery of adequate neutrophil levels.