Expression of Wilms tumor gene in high risk neuroblastoma: complementary marker to tyrosine hydroxylase for detection of minimal residual disease.

BACKGROUND: Neuroblastoma (NB) is an enigmatic tumor that often presents with metastatic disease at diagnosis and it is this aggressive propensity which places it among the deadliest pediatric tumors despite intensive multimodal therapy including hematopoietic stem cell transplantation (HSCT). We have previously demonstrated that Wilms tumor 1 gene (WT1) is a surrogate marker of proliferation in leukemia. To determine the potential association between WT1 and a known marker of NB, tyrosine hydroxylase (TH) in this high risk group of patients. METHODS: A total of 141 random samples from 34 patients were obtained, at diagnosis (n=27), during therapy (n=95), in clinical remission (n=13), and at the time of relapse (n=6). Quantitative RT-PCR was used for the evaluation of the level of gene expression using specific primers. RESULTS: Although similar gene expressions were demonstrated in both controls when evaluating both genes, significant difference was found at each clinical time point. Furthermore, when comparing patient samples from diagnosis to clinical remission and diagnosis to clinical relapse, individual gene expression varied. WT1 demonstrated significance (P=0.0002) and insignificance (P=0.06) whereas TH remained non-significant (P=0.2, P=0.09) respectively. CONCLUSIONS: WT1 gene is indicative of cellular proliferation in NB and for this reason it can be adjuvant to TH for the detection minimal residual disease (MRD).

Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease.

IMPORTANCE: Diurnal fluctuations of motor and nonmotor symptoms and a high prevalence of sleep-wake disturbances in Parkinson disease (PD) suggest a role of the circadian system in the modulation of these symptoms. However, surprisingly little is known regarding circadian function in PD and whether circadian dysfunction is involved in the development of sleep-wake disturbances in PD. OBJECTIVE: To determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness, and disease metrics. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study from January 1, 2009, through December 31, 2012, of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. Both groups underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions at the Parkinson's Disease and Movement Disorders Center of Northwestern University. INTERVENTIONS: Twenty-four hour monitoring of serum melatonin secretion. MAIN OUTCOMES AND MEASURES: Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale), and circadian markers of the melatonin rhythm, including the amplitude, area under the curve (AUC), and phase of the 24-hour rhythm. RESULTS: Patients with PD had blunted circadian rhythms of melatonin secretion compared with controls; the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD patients (P < .001). Markers of the circadian phase were not significantly different between the 2 groups. Compared with PD patients without excessive daytime sleepiness, patients with excessive daytime sleepiness (Epworth Sleepiness Scale score ≥10) had a significantly lower amplitude of the melatonin rhythm and 24-hour melatonin AUC (P = .001). Disease duration, Unified Parkinson's Disease Rating Scale scores, levodopa equivalent dose, and global Pittsburgh Sleep Quality Index score in the PD group were not significantly related to measures of the melatonin circadian rhythm. CONCLUSIONS AND RELEVANCE: Circadian dysfunction may underlie excessive sleepiness in PD. The nature of this association needs to be explored further in longitudinal studies. Approaches aimed to strengthen circadian function, such as timed exposure to bright light and exercise, might serve as complementary therapies for the nonmotor manifestations of PD.

An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low- and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era.

Expression of estrogen-related gene markers in breast cancer tissue predicts aromatase inhibitor responsiveness.

Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.

Relation of mucous membrane alterations to oral intake during the first year after treatment for head and neck cancer.

BACKGROUND: Acute oral mucositis is associated with pain and impaired swallowing. Little information is available on the effects of chronic mucositis on swallowing. METHODS: Sixty patients treated for cancer of the head and neck were examined during the first year after their cancer treatment. Oral mucosa was rated with the Oral Mucositis Assessment Scale. Stimulated whole-mouth saliva, oral pain rating, percent of oral intake, and 2 subscales of the Performance Status Scale for Head and Neck (PSS-HN) cancer were also collected. RESULTS: Mucositis scores and pain ratings decreased over time while functional measures of eating improved over time. Reduction in chronic mucositis was correlated with improved oral intake and diet. CONCLUSION: Lack of association with pain was attributed to the absence of ulcerations. Continued impairment of oral intake during the first year posttreatment may be related to oral mucosal changes and other factors.

Comparison of electrodesiccation and potassium-titanyl-phosphate laser for treatment of dermatosis papulosa nigra.

BACKGROUND: There is a lack of randomized split-face studies investigating treatments for dermatosis papulosa nigra (DPN) in dark skin. OBJECTIVE: To compare the efficacy, safety, and tolerability of potassium-titanyl-phosphate (KTP) laser with efficacy, safety, and tolerability of electrodesiccation in the treatment of DPN in subjects with Fitzpatrick skin phototypes IV to VI. METHODS: Fourteen subjects with Fitzpatrick skin phototypes IV to VI were randomized to receive two KTP laser treatments 4 weeks apart to half of the face. The contralateral half received two electrodesiccation treatments 4 weeks apart. Response was evaluated by photography reviewed by blinded dermatologists at 4 weeks after the second treatment. A treatment quality questionnaire about side effects and cosmetic outcome was also administered. RESULTS: Difference in improvement of DPN between the KTP side and the electrodesiccation side per each rater (p=.99, p=.54) and per raters combined (p=.50) did not reach statistical significance. There was no treatment difference for subjective effectiveness (p=.06) or subjective confidence improvement (p=.99), although there was a significant treatment difference for subjective discomfort (p=.002) in favor of KTP. Both treatments were well tolerated without significant adverse effects. CONCLUSIONS: Although treatment of DPN with KTP laser and electrodesiccation are comparable in efficacy, KTP laser is preferable for patient comfort.

Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma.

PURPOSE: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB). PATIENTS AND METHODS: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated. RESULTS: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% +/- 11% v 80% +/- 18%, respectively; P =.13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% +/- 10% v 83% +/- 15%, respectively; P =.06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of >/= 3 compared to those with scores of less than 3 (0% v 58% +/- 11%; P =.002). There was no correlation between bone scan scores and outcome following induction therapy. CONCLUSION: MIBG scores >/= 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.

Results of the Lynn Sage Second-Opinion Program for local therapy in patients with breast carcinoma. Changes in management and determinants of where care is delivered.

BACKGROUND: The treatment options of breast conservation therapy (BCT) and immediate reconstruction for patients with carcinoma of the breast have not been adopted widely. The objectives of this study were to determine how often a second opinion on the local therapy of breast carcinoma changed patient management and to identify factors predictive of remaining at the second-opinion site for therapy. METHODS: Two hundred thirty-one patients with intraductal carcinoma or Stage I and II breast carcinoma were reviewed retrospectively. At the time of the second opinion, patients completed a questionnaire regarding their initial surgical opinion and the reason for seeking consultation. RESULTS: Only 46% of patients had a complete discussion of treatment options prior to the second opinion. The second opinion changed management in 54 patients (20.3%). The most common finding was eligibility for BCT in patients who were offered only mastectomy. Definitive local therapy occurred at the second-opinion site in 65.8% of patients. The only predictors of remaining at the second-opinion site were insurance type (P = 0.008) and the patient's perception that options were not discussed at the initial opinion (P < 0.001). CONCLUSIONS: Second opinions provide useful information to patients and may change the management of their disease. They result in significant patient capture for an institution.