Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors
Cholinergic neurons in the medial habenula (MHb) modulate anxiety during nicotine withdrawal although the molecular neuroadaptation(s) within the MHb that induce affective behaviors during nicotine cessation is largely unknown. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their behavioral role as autoreceptors in these neurons has not been described. To test the hypothesis that nAChR signaling in MHb cholinergic neurons could modulate anxiety, we expressed novel "gain of function" nAChR subunits selectively in MHb cholinergic neurons of adult mice. Mice expressing these mutant nAChRs exhibited increased anxiety-like behavior that was alleviated by blockade with a nAChR antagonist. To test the hypothesis that anxiety induced by nicotine withdrawal may be mediated by increased MHb nicotinic receptor signaling, we infused nAChR subtype selective antagonists into the MHb of nicotine naive and withdrawn mice. While antagonists had little effect on nicotine naive mice, blocking alpha4beta2 or alpha6beta2, but not alpha3beta4 nAChRs in the MHb alleviated anxiety in mice undergoing nicotine withdrawal. Consistent with behavioral results, there was increased functional expression of nAChRs containing the alpha6 subunit in MHb neurons that also expressed the alpha4 subunit. Together, these data indicate that MHb cholinergic neurons regulate nicotine withdrawal-induced anxiety via increased signaling through nicotinic receptors containing the alpha6 subunit and point toward nAChRs in MHb cholinergic neurons as molecular targets for smoking cessation therapeutics.
Social interactions typically involve movements of the body that become synchronized over time and both intentional and spontaneous interactional synchrony have been found to be an essential part of successful human interaction. However, our understanding of the importance of temporal dimensions of social motor synchrony in social dysfunction is limited. Here, we used a pendulum coordination paradigm to assess dynamic, process-oriented measures of social motor synchrony in adolescents with and without autism spectrum disorder (ASD). Our data indicate that adolescents with ASD demonstrate less synchronization in both spontaneous and intentional interpersonal coordination. Coupled oscillator modeling suggests that ASD participants assembled a synchronization dynamic with a weaker coupling strength, which corresponds to a lower sensitivity and decreased attention to the movements of the other person, but do not demonstrate evidence of a delay in information transmission. The implication of these findings for isolating an ASD-specific social synchronization deficit that could serve as an objective, bio-behavioral marker is discussed.
The Clubhouse Model has been in existence for over sixty-five years; however, a review that synthesizes the literature on the model is needed. The current study makes use of the existing research to conduct a systematic review of articles providing a comprehensive understanding of what is known about the Clubhouse Model, to identify the best evidence available, as well as areas that would benefit from further study. Findings are summarized and evidence is classified by outcome domains. Fifty-two articles met the selection criteria of Randomized Clinical Trials (RCT's), quasi-experimental studies, or observational studies for domains of employment (N = 29); quality of life/satisfaction (N = 10); reductions in psychiatric hospitalization(s) (N = 10); social relationships (N = 10); education (N = 3); and health promotion activities (N = 2). RCT results support the efficacy of the Clubhouse Model in promoting employment, reducing hospitalization(s), and improving quality of life. Quasi-experimental and observational studies offer support in education and social domains. The findings from this review indicate that Clubhouses are a promising practice but additional studies using rigorous methods that report the strength of the outcomes are needed to evaluate Clubhouse programs with fidelity to the Clubhouse Model.
Clusters of alpha satellite on human chromosome 21 are dispersed far onto the short arm and lack ancient layers
Human alpha satellite (AS) sequence domains that currently function as centromeres are typically flanked by layers of evolutionarily older AS that presumably represent the remnants of earlier primate centromeres. Studies on several human chromosomes reveal that these older AS arrays are arranged in an age gradient, with the oldest arrays farthest from the functional centromere and arrays progressively closer to the centromere being progressively younger. The organization of AS on human chromosome 21 (HC21) has not been well-characterized. We have used newly available HC21 sequence data and an HC21p YAC map to determine the size, organization, and location of the AS arrays, and compared them to AS arrays found on other chromosomes. We find that the majority of the HC21 AS sequences are present on the p-arm of the chromosome and are organized into at least five distinct isolated clusters which are distributed over a larger distance from the functional centromere than that typically seen for AS on other chromosomes. Using both phylogenetic and L1 element age estimations, we found that all of the HC21 AS clusters outside the functional centromere are of a similar relatively recent evolutionary origin. HC21 contains none of the ancient AS layers associated with early primate evolution which is present on other chromosomes, possibly due to the fact that the p-arm of HC21 and the other acrocentric chromosomes underwent substantial reorganization about 20 million years ago.
Clubhouses are recovery centers that help persons with serious mental illness obtain and maintain community-based employment, education, housing, social integration, and other services. Key informants from U.S. clubhouses were interviewed to create a conceptual framework for clubhouse sustainability. Survival analyses tested this model for 261 clubhouses. Clubhouses stayed open significantly longer if they had received full accreditation, had more administrative autonomy, and received funding from multiple rather than sole sources. Cox regression analyses showed that freestanding clubhouses which were accredited endured the longest. Budget size, clubhouse size, and access to managed care did not contribute significantly to sustainability.
Awake whole-brain functional connectivity alterations in the adolescent spontaneously hypertensive rat feature visual streams and striatal networks
Brain mechanisms underpinning attention deficit/hyperactivity disorder (ADHD) are incompletely understood. The adolescent spontaneously hypertensive rat (SHR) is a widely studied preclinical model that expresses several of the key behavioral features associated with ADHD. Yet, little is known about large-scale functional connectivity patterns in the SHR, and their potential similarity to those of humans with ADHD. Using an approach comparable to human studies, magnetic resonance imaging in the awake animal was performed to identify whole-brain intrinsic neural connectivity patterns. An independent components analysis of resting-state functional connectivity demonstrated many common components between the SHR and both Wistar Kyoto and Sprague-Dawley control strains, but there was a divergence in other networks. In the SHR, three functional networks involving the striatum had only weak correlations with networks in the two control strains. Conversely, networks involving the visual cortex that was present in both control strains had only weak correlations with networks in the SHR. The implication is that the patterns of brain activity differ between the SHR and the other strains, suggesting that brain connectivity patterns in this animal model of ADHD may provide insights into the neural basis of ADHD. Brain connectivity patterns might also serve to identify brain circuits that could be targeted for the manipulation and evaluation of potential therapeutic options.
OBJECTIVE: The primary purpose was to develop, field test, and validate a computerized-adaptive test (CAT) for posttraumatic stress disorder (PTSD) to enhance PTSD assessment and decrease the burden of symptom monitoring.
METHODS: Data sources included self-report and interviewer-administered diagnostic interviews. The sample included 1,288 veterans. In phase 1, 89 items from a previously developed PTSD item pool were administered to a national sample of 1,085 veterans. A multidimensional graded-response item response theory model was used to calibrate items for incorporation into a CAT for PTSD (P-CAT). In phase 2, in a separate sample of 203 veterans, the P-CAT was validated against three other self-report measures (PTSD Checklist, Civilian Version; Mississippi Scale for Combat-Related PTSD; and Primary Care PTSD Screen) and the PTSD module of the Structured Clinical Interview for DSM-IV.
RESULTS: A bifactor model with one general PTSD factor and four subfactors consistent with DSM-5 (reexperiencing, avoidance, negative mood-cognitions, and arousal), yielded good fit. The P-CAT discriminated veterans with PTSD from those with other mental health conditions and those with no mental health conditions (Cohen's d effect sizes > .90). The P-CAT also discriminated those with and without a PTSD diagnosis and those who screened positive versus negative for PTSD. Concurrent validity was supported by high correlations (r=.85-.89) with the validation measures.
CONCLUSIONS: The P-CAT appears to be a promising tool for efficient and accurate assessment of PTSD symptomatology. Further testing is needed to evaluate its responsiveness to change. With increasing availability of computers and other technologies, CAT may be a viable and efficient assessment method.
Developing a multi-institutional PACS archive and designing processes to manage the shift from a film to a digital-based archive
The Quality Assurance Review Center (QARC) works to improve the standards of care in treating cancer by improving the quality of clinical trials medicine. QARC operates as a data management and review center providing quality assurance services for multiple external groups including cooperative groups and pharmaceutical companies. As the medical world migrates from analog film to digital files, QARC has developed an innovative and unique digital imaging management system to accommodate this trend. As QARC acquires electronic data from institutions across six continents, the system is continually developed to accommodate Digital Imaging and Communications in Medicine (DICOM) imaging originating from a wide variety of Picture Archival and Communications System (PACS) manufacturers, thus creating one of the largest and most diverse multi-institutional imaging archives in the cancer research community.
Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer
BACKGROUND: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.
PATIENTS AND METHODS: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb.
RESULTS: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or or=2 versus patients with or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or
CONCLUSIONS: There is no evidence that induction chemotherapy is beneficial in either prognostic group.
PURPOSE: The need for international collaboration in cancer clinical trials has grown stronger as we have made progress both in cancer treatment and screening. We sought to identify those efforts already underway which facilitate such collaboration, as well as barriers to greater collaboration.
METHODS: We reviewed the collective experiences of many cooperative groups, governmental organizations, nongovernmental organizations, and academic investigators in their work to build international collaboration in cancer clinical trials across multiple disease sites.
RESULTS: More than a decade of work has led to effective global harmonization for many of the elements critical to cancer clinical trials. Many barriers remain, but effective international collaboration in academic cancer treatment trials should become the norm, rather than the exception.
CONCLUSION: Our ability to strengthen international collaborations will result in maximization of our resources and patients, permitting us to change practice by establishing more effective therapeutic strategies. Regulatory, logistical, and financial hurdles, however, often hamper the conduct of joint trials. We must work together as a global community to overcome these barriers so that we may continue to improve cancer treatment for patients around the world.
Treatment results for patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984-1997: a report from the Children's Oncology Group
PURPOSE: To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997.
METHODS: Chart review and standard statistical procedures.
PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized.
RESULTS: Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, < or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors > 5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients.
CONCLUSION: Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.
Recommendations for research priorities in breast cancer by the coalition of cancer cooperative groups scientific leadership council: imaging and local therapy
Imaging and local therapy are important modalities for detection and management of localized breast cancer. Improvements in screening and local therapy have contributed to reduced breast cancer-associated morbidity and mortality. The Coalition of Cancer Cooperative Groups (CCCG) convened the Scientific Leadership Council (SLC) in breast cancer, an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for breast imaging and locoregional therapy, and also identified six trials judged to be of high priority. Current high priority trials included trials determining: (1) the role of accelerated partial breast versus whole-breast radiation (B39), (2) the feasibility, safety, and local and systemic control of small localized breast cancers treated with tumor ablation (Z1072), (3) the role of removal of the primary cancer in selected patients with metastatic disease (E2108), and (4) the clinical and biological effects of pre-operative anti-HER2-directed and ER-directed therapies in localized or locally advanced breast cancer (B41, Z1031, Z1041). Ongoing and future trials will further refine optimal locoregional management, and additional research is required to develop improved screening methods and identify high risk populations most likely to benefit from targeted screening.
Impact of tumor viability at second-look procedures performed before completing treatment on the Intergroup Rhabdomyosarcoma Study Group protocol IRS-IV, 1991-1997: a report from the children's oncology group
PURPOSES: The aims of the study were to compare results of clinical/radiographic studies before second-look procedures (SLP) with SLP specimens from patients with gross residual sarcoma at diagnosis and to relate tumor viability to outcome.
PATIENTS: Seventy-three patients underwent SLP before completing chemotherapy, with (n = 59) or without (n = 14) radiotherapy. Tumor sites were bladder/prostate (n = 27), head/orbit/parameningeal (n = 22), extremity/trunk (n = 14), and retroperitoneum/pelvis (n = 10).
RESULTS: Of 14 patients, 1 (7%) with clinical/radiographic complete response (CR) had viable tumor. Of 59 patients, 35 (59%) without CR had viable tumor. Five-year failure-free survival (FFS) rates were 81% in 37 patients without viable tumor and 53% in 36 patients with viable tumor (Cox proportional hazards adjusted P = .05). Five-year FFS rates were 67% in 15 patients with clear margins and 43% in 21 patients with tumor-involved margins (n = 18) or viable gross tumor (n = 3) (Cox proportional hazards adjusted P = .04). Five-year survival was 78% to 79% among 73 patients with and 333 patients without SLP during treatment.
CONCLUSIONS: Second-look procedures can show whether viable tumor is present and may be beneficial in selected patients with rhabdomyosarcoma. Disappearance of tumor (CR) usually correlated with no viable tumor at SLP. However, 41% of patients without CR had no viable tumor. Those without viable tumor had increased FFS but not survival compared to those with viable tumor.
Thirty- and ninety-day outcomes after sublobar resection with and without brachytherapy for non-small cell lung cancer: results from a multicenter phase III study
OBJECTIVE: Sublobar resection (SR) is commonly used for patients considered high risk for lobectomy. Nonoperative therapies are increasingly being reported for patients with similar risk because of perceived lower morbidity. We report 30- and 90-day adverse events (AEs) from American College of Surgeons Oncology Group Z4032, a multicenter phase III study for high-risk patients with stage I non-small cell lung cancer.
METHODS: Data from 222 evaluable patients randomized to SR (n = 114) or SR with brachytherapy (n = 108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0, at 30 and 90 days after surgery. Risk factors (age, percent baseline carbon monoxide diffusion in the lung [DLCO%], percent forced expiratory volume in 1 second [FEV1%], upper lobe vs lower lobe resections, performance status, surgery approach, video-assisted thoracic surgery vs open and extent, and wedge vs segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of grade 3 or higher (G3+) AEs. Respiratory AEs were also specifically analyzed.
RESULTS: Median age, FEV1%, and DLCO% were similar in the 2 treatment groups. There was no difference in the location of resection (upper vs lower lobe) or the use of segmental or wedge resections. There were no differences between the groups with respect to "respiratory" G3+ AEs (30 days: 14.9% vs 19.4%, P = .35; 0-90 days: 19.3% vs 25%, P = .31) and "any" G3+ AEs (30 days: 25.4% vs 30.6%, P = .37; 0-90 days: 29.8% vs 37%, P = .25). Further analysis combined the 2 groups. Mortality occurred in 3 patients (1.4%) by 30 days and in 6 patients (2.7%) by 90 days. Four of the 6 deaths were thought to be due to surgery. When considered as continuous variables, FEV1% was associated with "any" G3+ AE at days 0 to 30 (P = .03; odds ratio [OR] = 0.98) and days 0 to 90 (P = .05; OR = 0.98), and DLCO% was associated with "respiratory" G3+ AE at days 0 to 30 (P = .03; OR = 0.97) and days 0 to 90 (P = .05; OR = 0.98). Segmental resection was associated with a higher incidence of any G3+ AE compared with wedge resection at days 0 to 30 (40.3% vs 22.7%; OR = 2.56; P < .01) and days 0 to 90 (41.5% vs 29.7%; OR = 1.96; P = .04). The median FEV1% was 50%, and the median DLCO% was 46%. By using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of "respiratory" and "any" G3+ AE for days 0 to 30 and 0 to 90.
CONCLUSIONS: In a multicenter setting, SR with brachytherapy was not associated with increased morbidity compared with SR alone. SR/SR with brachytherapy can be performed safely in high-risk patients with non-small cell lung cancer with low 30- and 90-day mortality and acceptable morbidity. Segmental resection was associated with increased "any" G3+ AE, and DLCO% less than 46% was associated with "any" G3+ AE and "respiratory" G3+ AE at both 30 and 90 days.
S0356: a phase II clinical and prospective molecular trial with oxaliplatin, fluorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma
PURPOSE: Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival.
PATIENTS AND METHODS: Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair.
RESULTS: Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS.
CONCLUSION: Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.
The impact of adjuvant brachytherapy with sublobar resection on pulmonary function and dyspnea in high-risk patients with operable disease: preliminary results from the American College of Surgeons Oncology Group Z4032 trial
BACKGROUND: Z4032 was a randomized study conducted by the American College of Surgeons Oncology Group comparing sublobar resection alone versus sublobar resection with brachytherapy for high-risk operable patients with non-small cell lung cancer (NSCLC). This evaluates early impact of adjuvant brachytherapy on pulmonary function tests, dyspnea, and perioperative (30-day) respiratory complications in this impaired patient population.
METHODS: Eligible patients with stage I NSCLC tumors 3 cm or smaller were randomly allocated to undergo sublobar resection with (SRB group) or without (SR group) brachytherapy. Outcomes measured included the percentage predicted forced expiratory volume in 1 second (FEV1%), percentage predicted carbon monoxide diffusion capacity (DLCO%), and dyspnea score per the University of California San Diego Shortness of Breath Questionnaire. Pulmonary morbidity was assessed per the Common Terminology Criteria for Adverse Events version 3.0. Outcomes were measured at baseline and 3 months. A 10% change in pulmonary function test or 10-point change in dyspnea score was deemed clinically meaningful.
RESULTS: Z4032 permanently closed to patient accrual in January 2010 at 224 patients. At 3-month follow-up, pulmonary function data are currently available for 148 (74 SR and 74 SRB) patients described in this report. There were no differences in baseline characteristics between arms. In the SR arm, 9 patients (12%) reported grade 3 respiratory adverse events, compared with 12 (16%) in the SRB arm (P = .49). There was no significant change in percentage change in DLCO% or dyspnea score from baseline to 3 months within either arm. In the case of FEV1%, percentage change from baseline to 3 months was significant within the SR arm (P = .03), with patients reporting improvement in FEV1% at month 3. Multivariable regression analysis (adjusted for baseline values) showed no significant impact of treatment arm, tumor location (upper vs other lobe), or surgical approach (video-assisted thoracoscopic surgery vs thoracotomy) on 3-month FEV1%, DLCO%, and dyspnea score. There was no significant difference in incidence of clinically meaningful (10% pulmonary function or 10-point dyspnea score change) change between arms. Twenty-two percent of patients with lower-lobe tumors and 9% with upper-lobe tumors demonstrated 10% decline in FEV1% (odds ratio, 2.79; 95 confidence interval, 1.07-7.25; P = .04).
CONCLUSIONS: Adjuvant intraoperative brachytherapy in conjunction with sublobar resection did not significantly worsen pulmonary function or dyspnea at 3 months in a high-risk population with NSCLC, nor was it associated with increased perioperative pulmonary adverse events. Lower-lobe resection was the only factor significantly associated with clinically meaningful decline in FEV1%.
Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group
PURPOSE: Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control.
METHODS AND MATERIALS: All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as > 10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation.
RESULTS: Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children.
CONCLUSION: Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma.
Radiation therapy quality in CCG/POG intergroup 9961: implications for craniospinal irradiation and the posterior fossa boost in future medulloblastoma trials
PURPOSE: Associations of radiation therapy (RT) deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose craniospinal irradiation and chemotherapy. The aim of this study is to evaluate the quality of RT on Children's Cancer Group/Pediatric Oncology Group 9961 and analyze associations of RT deviations with outcome.
MATERIALS AND METHODS: Major volume deviations were assessed based on the distance from specified anatomical region to field edge. We investigated associations of RT deviations with progression-free survival (PFS), overall survival (OS), and explored associations with demographics and clinical variables.
RESULTS: Of the 308 patients who were evaluable for volume deviations, 101 patients (33%) did not have any. Of the remaining 207 patients, 50% had only minor deviations, 29% had only major deviations, and 21% had both minor and major deviations. Of the patients with major deviations, 73% had a single major deviation. The most common major deviation was in the cribriform plate region, followed by the posterior fossa (PF); PF deviations resulted from treating less than whole PF. There were no significant differences in PFS or OS between patients with deviations and those without. There was no evidence of associations of deviations with patient age.
CONCLUSIONS: Approximately one-third of patients had major volume deviations. There was no evidence of a significant association between these and outcome. This lack of correlation likely reflects the current high quality of RT delivered in Children's Oncology Group institutions, our strict definition of volume deviations, and the relatively few instances of multiple major deviations in individual patients. In is noteworthy that the types of PF volume deviations observed in this study were not adversely associated with outcome. As we move forward, quality assurance will continue to play an important role to ensure that deviations on study do not influence study outcome.
Hansen Disease (leprosy) is an infectious disease that targets macrophages and Schwann cells, caused by the acid fast intracellular organism, Mycobacterium leprae. Clinically, it presents with a spectrum of findings that may include hypopigmented macules, erythematous plaques and nodules, and thickened or tender peripheral nerves. The most feared complication is mutilating damage to facial structures or digits resulting from loss of sensation in affected skin. In non-endemic areas, the diagnosis of leprosy is frequently delayed because it may mimic other more common skin conditions. We present a case of borderline/lepromatous leprosy in an otherwise healthy young Brazilian man that was initially diagnosed as tinea versicolor, but did not respond to appropriate treatment. This case highlights the importance of having a high index of suspicion for leprosy in patients from endemic areas who present with lesions that could be consistent with this disease.
The clinical features of pediatric psoriasis warrant further attention. A national study was conducted to determine the prevalence of scalp and nail involvement and a history of guttate psoriasis at onset according to age, sex, and disease severity. One hundred eighty-one children ages 5 to 17 years with plaque psoriasis were enrolled in a multicenter, cross-sectional study. Subjects and guardians were asked about a history of scalp and nail involvement and whether the initial presentation was guttate. Peak psoriasis severity was assessed and defined historically as mild psoriasis (MP) or severe psoriasis (SP) according to the Physician's Global Assessment and body surface area measures. One hundred forty-three (79.0%) subjects reported a history of scalp involvement, and 71 (39.2%) described a history of nail involvement. Boys were less likely than girls to report a history of scalp involvement (odds ratio [OR] = 0.40, 95% confidence interval [CI] = 0.19-0.84) but more likely to have had nail involvement (OR = 3.01, 95% CI = 1.62-5.60). Scalp and nail involvement was not related to psoriasis severity. In contrast, subjects with SP (35.9%) more often reported a history of guttate lesions than did those with MP (21.8%) (p = .02). Antecedent streptococcal infection was more common in children with guttate than those with plaque psoriasis at onset (p = .02) but did not correlate with severity. Sex-related differences in scalp and nail involvement suggest koebnerization. Preceding streptococcal infection predicts guttate morphology but not severity, and initial guttate morphology is associated with eventual greater severity of disease. More aggressive monitoring and management should be considered for guttate psoriasis, given its later association with more severe disease.