RESILIENT part 1: a phase 2 dose-exploration and dose-expansion study of second-line liposomal irinotecan in adults with small cell lung cancer.

BACKGROUND: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. METHODS: This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. CONCLUSION: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. LAY SUMMARY: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4ß7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1. RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.

BACKGROUND: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer. METHODS: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected. RESULTS: The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups. CONCLUSIONS: Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).

Economic Impact of Routine Cavity Margins Versus Standard Partial Mastectomy in Breast Cancer Patients: Results of a Randomized Controlled Trial.

OBJECTIVE: The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer. BACKGROUND: Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear. METHODS: Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0-III breast cancer were randomized to undergo either standard PM ("no shave", n = 116) or have additional CSM taken ("shave", n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery-related care through subsequent 90 days. RESULTS: The 2 groups were well-matched in terms of baseline characteristics. Those in the "shave" group had a longer operative time at the initial surgery (median 76 vs 66 min, P < 0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P < 0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P < 0.01) were greater for the initial surgery in patients in the "shave" group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the "shave" and "no shave" groups. CONCLUSIONS: Overall costs were not significantly different between the "shave" and "no shave" groups due to significantly fewer reoperative surgeries in the former.

Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

OBJECTIVE: We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. BACKGROUND: The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. METHODS: From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. RESULTS: Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. CONCLUSIONS: Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets.

In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA(+) T cells and Tim-3(+) NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8(+) T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422.

Ethnic disparities in renal cell carcinoma: An analysis of Hispanic patients in a single-payer healthcare system.

OBJECTIVE: To investigate differences between Hispanics and non-Hispanic whites diagnosed with and treated for renal cell carcinoma in an equal access healthcare system. METHODS: We carried out a retrospective cohort study within the Kaiser Permanente healthcare system using records from renal cell carcinoma cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall and disease-specific survival was calculated, and a Cox proportion hazard model estimated the association of ethnicity and survival. RESULTS: A total of 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 years vs 65.3 years). Clear cell renal cell carcinoma was more prevalent, whereas papillary renal cell carcinoma was less common among Hispanics. Hispanics had a lower American Joint Committee on Cancer stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities, such as chronic kidney disease and diabetes, but were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age and Hispanic ethnicity were independent predictors of worse cancer-specific outcome. CONCLUSIONS: Within an equal access healthcare system, Hispanics seem to be diagnosed at younger ages, to have greater comorbidities and to present more frequently with clear cell renal cell carcinoma compared with non-Hispanic white patients. Despite lower stage and greater receipt of surgery, Hispanic ethnicity seems to be an independent predictor of mortality. Further work is necessary to confirm these findings.

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.

Density and Polarization States of Tumor-Associated Macrophages in Human Cutaneous Squamous Cell Carcinomas Arising in Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients (SOTRs) are 100 times more likely to develop cutaneous squamous cell carcinoma (SCC) with greater metastatic propensity compared with the general population, likely due to chronic immunosuppression and adverse drug effects on keratinocytes. Tumor-associated macrophages (TAMs) play critical roles in malignancies, either aiding in eradication of malignant cells or promoting tumor growth. OBJECTIVE: The authors examined whether TAM density and polarization states differ between SOTRs and nontransplant individuals. MATERIALS AND METHODS: The authors obtained normal skin, SCC in situ (SCCis), and SCC from SOTRs and nontransplant patients (N = 45) and stained with macrophage marker CD68, M1 marker CD40, and M2 marker arginase-1. RESULTS: The authors report a significantly higher density of TAMs in both SCCis and SCC. The intratumoral macrophage infiltration in SCCis from SOTR was significantly decreased compared with nontransplant patients. Tumor-associated macrophages in SCCis and SCC displayed both M1 and M2 polarization, and M2 activation levels were significantly lower in SCC from SOTR. CONCLUSION: Tumor-associated macrophages are present in early carcinogenesis and may play a critical role in the transition from SCCis to SCC, before invasion of the basement membrane by tumor cells. The intratumoral macrophage density in early stages of tumor development is significantly affected in SOTR.

Early clinical experience with digital breast tomosynthesis for screening mammography.

PURPOSE: To examine recall rates from screening mammography and the mammographic findings that caused recall in women who underwent digital breast tomosynthesis with conventional mammography (referred to as two-dimensional [ 2D two-dimensional ] with three-dimensional [ 3D three-dimensional ] imaging [ 2D two-dimensional + 3D three-dimensional ]) and in women who underwent conventional mammography alone (referred to as 2D two-dimensional ). MATERIALS AND METHODS: This was an institutional review board-approved, HIPAA-compliant study with waivers of informed consent. A retrospective review of 2D two-dimensional + 3D three-dimensional and 2D two-dimensional screening mammograms from August 1, 2011, to December 31, 2012, was performed. Recall rates and abnormalities that caused recall were compared by controlling for differences in patient age, breast density, and risk factors. Cancer detection rate was assessed from this time period and from 1 year before the introduction of tomosynthesis for a historic control. RESULTS: This study included 17 955 screening mammograms; of the total, there were 8591 (47.8%) 2D two-dimensional + 3D three-dimensional screening examinations and 9364 (52.2%) 2D two-dimensional examinations. The recall rate was 7.8% (671 of 8592) for 2D two-dimensional + 3D three-dimensional and 12.3% (1154 of 9364) for 2D two-dimensional (P < .0001); the rate of recall was 36.6% lower in the 2D two-dimensional + 3D three-dimensional group than in the 2D two-dimensional group. Recall rates for the 2D two-dimensional + 3D three-dimensional group were significantly lower for patients with asymmetries, ( 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 3.1% [267 of 8591] vs 7.4% [689 of 9364], respectively; P < .0001) and calcifications ( 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 2.4% [205 of 8591] vs 3.2% [297 of 9364], respectively; P = .0014). For patients with masses and architectural distortion, the difference in recall rates was not significant (masses: 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 2.5% [215 of 8591] vs 2.5% [237 of 9364], respectively; P = .90; architectural distortion: 2D two-dimensional + 3D three-dimensional vs 2D two-dimensional , 0.68% [58 of 8591] vs 0.69% [65 of 9364]; P = .88). Cancer detection was highest in the 2D two-dimensional + 3D three-dimensional group at 5.9 cancers per 1000 examinations, with 5.7 cancers per 1000 examinations in the concurrent 2D two-dimensional group, and 4.4 cancers per 1000 examinations in the historic control. CONCLUSION: Use of tomosynthesis ( 2D two-dimensional + 3D three-dimensional ) compared with conventional mammography ( 2D two-dimensional ) is associated with a lower recall rate of screening mammography, most often for asymmetries.

Anthracycline dose intensification in acute myeloid leukemia.

BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903.

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)-defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Tumor histology during induction therapy in patients with high-risk neuroblastoma.

BACKGROUND: In high-risk neuroblastoma patients, response to induction chemotherapy is emerging as an important determinant of overall survival. We sought to determine whether histological changes in the primary tumor following induction therapy could be used as a marker of response. PROCEDURE: Second-look primary tumor specimens from 43 patients were reviewed according to specific morphological features. RESULTS: In the majority, induction therapy resulted in a shift from an intermediate/high to low mitosis-karyorrhexis index (MKI) (P = 0.0009) and from undifferentiated/poorly differentiated to differentiating tumors (P < 0.0001). Following induction therapy, persistence of intermediate/high tumor MKI and ≥90% persistent neuroblastic cells were predictive of a poor outcome (P = 0.001 and 0.03, respectively). Less than 10% tumor necrosis was associated with a trend towards lower survival. CONCLUSIONS: High proliferative activity in the primary tumor following induction therapy portends a poor outcome in patients with high-risk neuroblastoma. If confirmed in a larger cohort, tumor histology at second-look surgery could be used to define a subset of very high risk patients who would benefit from alternative therapies prior to myeloablative dose-intensive transplant.

WT1 mutations in T-ALL.

The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL.

Long-term clinical outcomes following treatment of childhood craniopharyngioma.

PURPOSE: To review our institution's experience with treatment of craniopharyngioma in children, and to report long-term treatment outcomes stratified by treatment era to assess whether modern treatment techniques result in improvements in local control and survival. MATERIALS AND METHODS: We retrospectively reviewed the records of 100 children who underwent surgery for craniopharygioma at Children's Hospital Boston (CHB) from August 1976 to March 2003. Of these, 79 children (median age 8.5 years) had initial treatment at CHB and sufficient follow-up data to be included in this analysis. We report their treatment course, recurrence rates, and treatment-related morbidity. We compared the results in two different treatment eras based on changes in surgical approach at CHB. RESULTS: Thirty-six patients underwent initial treatment with surgery alone; 63% treated prior to 1988 recurred and 36% treated after 1988 recurred. Recurrence rates following combined modality therapy (CMT) with limited surgery followed by radiation were 21 and 5% in the pre- and post-1988 eras, respectively. Accounting for treatment era, patients treated with surgery alone were 7.7 times as likely to recur as those treated with CMT (95%CI: 2.0, 28.7). In the Cox regression model, there was no significant difference in local control or overall survival based on treatment era; initial treatment remained the only statistically significant variable (P = 0.02). CONCLUSIONS: Advancements in treatment techniques have improved local control in children diagnosed with craniopharyngioma. The excellent survival rates necessitate long-term patient follow-up to identify and manage any treatment-related effects, including second tumors, vascular abnormalities, and endocrinopathies.

Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors. Glioblastoma is an uncommon, malignant tumor of children that is even less frequently observed in children with NF1. PROCEDURE: We performed a retrospective review of patients with NF1 and glioblastoma to determine specific clinical and pathologic indicators of overall prognosis. RESULTS: Five patients were identified from the CHB/DFCI database for whom pathologic and imaging studies were available. All pathologic specimens demonstrated vascular proliferation and necrosis. All samples stained positively for p53. Chromogenic in situ hybridization (CISH) for epidermal growth factor receptor (EGFR) copy numbers was increased, PTEN copy numbers were normal and the promoter of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene was unmethylated in the one patient evaluated. In the same time period, there were 56 patients without NF1 diagnosed with glioblastoma who were treated at our institution. Although the small sample size precludes formal statistical analysis, the 2-year survival of patients with NF1 is 60% with median overall survival of 9.25 years compared to non-NF1 patients with a 2-year survival of 25% and median overall survival 1.08 years. CONCLUSIONS: This study provides preliminary evidence that children with NF1 may be at risk for glioblastoma, but that these patients have an increased survival compared to children without NF1. Additional molecular studies will be required to determine if the pathogenesis of these tumors differs from glioblastoma in children without NF1.

Up-Regulation of alpha4beta7 integrin on peripheral T cell subsets correlates with the development of acute intestinal graft-versus-host disease following allogeneic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major complication after hematopoietic stem cell transplantation (HSCT). The pathophysiology of aGVHD involves priming of naïve donor T cells in host secondary lymphoid tissue, followed by migration of effector T cells to target organs. Mediators of lymphocyte trafficking are believed to play a significant role in this migration. In this retrospective case-controlled study, we analyzed the expression of alpha4beta7 integrin and CCR9, 2 surface T cell molecules specific for intestinal trafficking, from blood samples collected previously from 59 patients after HSCT (20 without aGVHD, 20 with skin aGVHD, and 19 with intestinal aGVHD). All samples had been obtained before the onset of aGVHD symptoms (with 1 sample collected on the day of symptom onset). Analysis by flow cytometry demonstrated that alpha4beta7 integrin was significantly increased on both naïve and memory T cells in patients who subsequently developed intestinal aGVHD, with the most significant differences observed in memory subsets. Immunohistochemical staining on rectal biopsy specimens from patients with intestinal aGVHD showed that expression of alpha4beta7 integrin was concentrated on mononuclear cells in blood vessels within the intestinal mucosa. These results suggest that alpha4beta7 integrin likely is involved in lymphocyte trafficking in intestinal aGVHD and may have potential clinical use as a correlative biomarker or as a target for the treatment and prophylaxis of intestinal aGVHD after HSCT.

Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only.

BACKGROUND: Surgical resection is often the only treatment necessary for pediatric low-grade gliomas (LGGs) and is thought to define a population with an excellent long-term prognosis. The goal of this study was to describe the multidimensional late-effects of pediatric LGG survivors treated exclusively with surgery. METHODS: A retrospective chart review of "surgery-only" LGG survivors followed at Dana-Farber/Children's Hospital Cancer Care was undertaken. Patients had to be diagnosed with an LGG before the age of 22 years, treated with "surgery-only" and be at least 2 years from diagnosis. RESULTS: Sixty survivors were eligible with a median age at the time of review of 16.3 years and the median time since diagnosis of 8.4 years. Tumor locations were predominantly posterior fossa (47%) or cortical (33%). Eighty-five percent of patients had at least one ongoing late-effect, and 28% had three or more. The most common late-effects consisted of motor dysfunction (43%), visual problems (32%), anxiety (19%), social difficulties (19%), seizure disorders (17%), depression (15%), poor coordination/ataxia (14%), behavioral problems (13%), and endocrinopathies (10%). Nine patients had a history of suicidal ideation; two with suicide attempts. The mean full-scale IQ was normal, however, the number of survivors scoring one standard deviation below the mean was twice the expected number. Special education services were utilized by more than half of the survivors. CONCLUSIONS: "Surgery-only" LGG survivors may be more affected by their tumor and its resection than previously appreciated. A prospective study is needed to address this survivor population.

Analysis of candidate genes and hypertension in African American adults.

OBJECTIVE: We investigated the associations between hypertension status and the genotypes of four single nucleotide polymorphism (SNP) sites in four hypertension-related genes (Angiotensinogen [AGT], Angiotensin I Converting Enzyme [ACE], Angiotensinogen II receptor, subtype 1 [AGTR1], and Alpha 1-Antichymotrypsin [ACT or SERPINA3]), in an African American sample. METHODS: DNA from 628 participants of the Carolina African American Twin Study of Aging project, a population-based study of African American adult twins, was genotyped using SNPs shown to be associated with hypertension in other studies. RESULTS: The ACE SNP (ACE4 or A-240T) was associated with hypertension (P = .047 in a generalized estimating equations alternating logistics regression model that included age, body mass index, sex, and education. The analysis indicated a protective effect of the TT genotype (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.03-2.48, P = .04) and of the AT genotype (OR 1.91, 95% CI 1.01-3.62, P = .047) compared with the AA genotype. DISCUSSION: These results extend previous findings of associations of various polymorphisms of ACE to hypertension and support the association of hypertension to the A allele of ACE4. The potential for this polymorphism to alter expression by its position in the gene's promoter region suggests that future studies of altered ACE protein activity are warranted.