Sleep Treatment Education Program for Young Adult Cancer Survivors (STEP-YA): Protocol for an Efficacy Trial.

BACKGROUND: Young adult cancer survivors (YACS) are at elevated risk for chronic insomnia, even years after completing treatment. In addition to potential health consequences, insomnia can interrupt social, educational, and vocational development just as they are trying to "make up" for time lost to cancer. Cognitive behavioral therapy for insomnia (CBTI) is recommended as first-line treatment for insomnia but remains largely unavailable to YACS due to several barriers (ie, shortage of trained providers, geographic limitations, financial limitations). Traditional CBTI has not been adapted to meet YACS' unique developmental and circadian challenges. To improve availability of effective behavioral insomnia treatment for this population, we developed the Sleep Treatment Education Program for Young Adult Cancer Survivors (STEP-YA), a low-intensity educational intervention delivered virtually online. OBJECTIVE: In this phase 2 "proof of concept" trial, primary aims are to test the efficacy of STEP-YA to improve insomnia symptoms and mood in YACS and assess the utility of individualized coaching to improve treatment effects. A secondary aim will explore participant variables associated with clinically significant response to STEP-YA. METHODS: This 2-arm randomized prospective trial will enroll 74 off-treatment YACS aged 20 years to 39 years with clinically significant insomnia. Each participant completes the STEP-YA intervention in a 1-on-1 synchronous online session led by a trained interventionist following a structured outline. The 90-minute intervention presents educational information on the development of insomnia after cancer and offers specific suggestions for improving insomnia symptoms. During the session, participants review the suggestions and develop a personalized sleep action plan for implementing them. After the session, participants are randomized to either the coaching condition, in which they receive 2 telephone coaching sessions, or the no-coaching condition, which offers no subsequent coaching. The Insomnia Severity Index (ISI) and the Profile of Mood States: Short Form (POMS-SF) are assessed at baseline and 4 and 8 weeks postintervention. RESULTS: Enrollment began in November 2022, with 28 participants currently enrolled. We anticipate recruitment will be completed in 2024. The primary endpoint is a change in ISI score from baseline to 8 weeks postintervention. The secondary endpoint is change in mood symptoms (POMS-SF) from baseline to 8 weeks postintervention. Change scores will be treated as continuous variables. Primary analyses will use ANOVA methods. A within-subjects analysis will examine if the STEP-YA intervention is associated with significant changes in insomnia and mood over time. A 2-way ANOVA will be used to evaluate the utility of coaching sessions to improve treatment effects. CONCLUSIONS: Chronic insomnia has significant negative effects on YACS' medical, educational, and psychological functioning. STEP-YA aims to address their needs; study results will determine if the intervention warrants future effectiveness and dissemination studies and if individualized coaching is necessary for adequate treatment response. TRIAL REGISTRATION: ClinicalTrials.gov NCT05358951: https://clinicaltrials.gov/study/NCT05358951. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52315.

Evaluating SunSmart: a brief educational intervention promoting sun protection in young adult cancer survivors.

PURPOSE: Young adult cancer survivors (YACS) are at risk for secondary skin cancers but relevant interventions have not been validated in this population. To address this, we designed and tested SunSmart, a set of two educational videos designed to promote sun protection (SP). One provides SP education (Information) and the second combines SP education with content on negative appearance consequences of sun exposure (Information + Appearance). METHODS: One hundred ninety-three YACS (aged 18-35) were randomized to one of three groups: (1) Information, (2) Information + Appearance, or (3) control (sleep hygiene video). Participants completed measures on SP behaviors at baseline and follow-up. One-way ANCOVAs examined the intervention effect on follow-up SP behaviors controlling for baseline behaviors. RESULTS: The intervention did not significantly affect SP behaviors. However, secondary analyses limited to participants with the lowest baseline SP adherence found that the Information + Appearance group had significantly lower intentional sun exposure than the control group (p = 0.02) at follow-up. CONCLUSIONS: Contrary to hypotheses, the SunSmart intervention did not significantly improve sun protection in YACS, even when it presented information on negative appearance consequences of sun exposure. However, secondary analyses suggest SunSmart may be more effective in YACS with the lowest SP adherence. Future research is required to improve intervention efficacy with YACS (e.g., increased focus on secondary cancer risks). IMPLICATIONS FOR CANCER SURVIVORS: Despite their increased risk of secondary skin cancer, YACS in the current study reported significant sun exposure and inadequate SP. The need for development and validation of effective interventions to address these concerns remains.

Evaluating posttraumatic stress in young adult cancer survivors: Implications of revised DSM-5 traumatic event criteria.

OBJECTIVE: The Diagnostic and Statistical Manual for Psychiatric Diagnoses (DSM-5) significantly narrowed conditions under which life-threatening illnesses meet qualifying traumatic event (QTE) criteria for posttraumatic stress disorder (PTSD). To investigate the impact of this change on identification of PTSD in young adult cancer survivors (YACS), we compared prevalence of QTE exposure using DSM-5 and earlier DSM-IV criteria. METHODS: The Structured Clinical Interview for the DSM-5 (SCID-5) was customized for study goals and administered to a convenience sample of 250 YACS ages 18-40 followed at a single cancer center. RESULTS: The SCID-5 was well-tolerated by participants and estimated duration was brief (33 min; range 12-75). Only 35 interviews (14%) presented complex scoring questions. 168 participants (67.2%) identified cancer as their "most stressful or traumatic experience." Applying DSM-IV criteria, 227 YACS (90.8%) reported any QTEs; prevalence was significantly reduced following more restrictive DSM-5 QTE criteria, with only 124 YACS (49.6%) reporting ≥1 QTE (z = -9.68, p < 0.001). CONCLUSIONS: The SCID-5 can be successfully adapted to assess QTEs in YACS following both DSM-IV and DSM-5 criteria. DSM-5 criteria significantly limit prevalence of QTE exposures compared with DSM-IV. As the majority of YACS identify cancer as their most stressful life event, it is critically important to investigate its impact on their psychological functioning. Until more is known about how PTSD symptoms may arise after cancer, clinicians and researchers should adapt PTSD assessments to systematically evaluate the role of cancer as a traumatic event that may lead to PTSD symptoms in YACS.

Validation of the Three-Item Insomnia Severity Index Short Form in Young Adult Cancer Survivors: Comparison with a Structured Diagnostic Interview.

Chronic insomnia affects ∼25% of young adult cancer survivors (YACS) but is often overlooked in routine follow-up. A recently introduced three-item version of the Insomnia Severity Index (ISI-3) was compared with a diagnostic interview (SCID-5) in 250 YACS (ages 18-40) to evaluate its validity in this population. The ISI-3 had good discrimination compared with the SCID-5 (area under the receiver operating characteristic curve = 0.88). Although no ISI-3 cutoff met study criteria for both sensitivity (≥0.85) and specificity (≥0.75), an ISI-3 cutoff of ≥4 had high sensitivity (94%) and moderate specificity (70%), and is recommended as the first step in a two-step screening procedure.

Validation of the Insomnia Severity Index (ISI) for identifying insomnia in young adult cancer survivors: comparison with a structured clinical diagnostic interview of the DSM-5 (SCID-5).

OBJECTIVES: Insomnia is a common problem affecting young adult cancer survivors (YACS) even years after treatment, yet it often goes unidentified and untreated. The Insomnia Severity Index is a widely-used insomnia measure, but has not been studied as an insomnia screener for YACS. The goal of this study was to validate the ISI in YACS by determining its utility in identifying YACS with insomnia disorder diagnosed with the Structured Clinical Interview for the DSM-5 (SCID-5). METHODS: 250 YACS completed the ISI and SCID-5 Insomnia Module. Area under the curve (AUC) was calculated to reflect the ISI's discrimination between YACS with and without SCID-5 insomnia disorder. An ISI cut-off score with sensitivity ≥0.85 and specificity ≥0.75 was deemed acceptable. RESULTS: Of 250 participants, 52 met criteria for SCID-5 insomnia disorder diagnosis. The ISI had excellent discrimination, with an AUC = 0.91. A cut-off score ≥8 met study clinical screening criteria with sensitivity of 0.85 and specificity of 0.77. A cut-off score ≥7 with a higher sensitivity (0.96) but lower specificity (0.70) was noted as a potential alternative. Cut-off scores ≥12 and ≥ 14 were recommended for applications prioritizing overall accuracy. CONCLUSIONS: Results support validity of the ISI for identifying YACS with insomnia disorder. For clinical screening, data support the use of an ISI cut-off score ≥8 in YACS, and additional cut-off scores were found for research purposes or higher sensitivity. Results of this study and prior studies of the ISI offer important reminders that cut-off scores derived from different populations are not generalizable.

Pediatric hematology and oncology fellow education in sexual and reproductive health: A survey of fellowship program directors in the United States.

PURPOSE: Pediatric oncology clinicians identify a need for increased sexual and reproductive health (SRH) education with adolescent and young adult (AYA) cancer patients. By surveying pediatric oncology fellowship directors, this study clarifies the state of current fellowship education about SRH for the AYA patient. METHODS: A survey was sent to all pediatric oncology fellowship program directors (PDs) in the United States consisting of 13 questions pertaining to three primary SRH domains: sexual health, fertility, and safe sex practices. Descriptive statistics and χ2 were used in data analyses. RESULTS: Sixty-three PDs responded to the survey (91% response rate). Of these, 88% reported having formal instruction regarding fertility, 41% reported curriculum regarding contraception and 30% reported some education regarding sexual health. The curriculum "being too full" was identified as a barrier to education on fertility (29%), sexual health (40%), and safe sex practices (38%). Not being a required or expected part of the program was more likely to be endorsed as a barrier for sexual health (26%) and safe sex practices (30%) compared with fertility (8%) (P < 0.005). Lack of experts to teach was a more frequently endorsed barrier to education on sexual health (47%) compared with either fertility (23%) or safe sex practices (25%) (P < 0.005). CONCLUSIONS: This study identifies important gaps in oncology fellow education about SRH. Future research must explore optimal education strategies that are feasible and acceptable by PDs and fellow learners, and effective in optimizing AYA SRH care.

Developing efficient and effective behavioral treatment for insomnia in cancer survivors: Results of a stepped care trial.

BACKGROUND: Insomnia is common among cancer survivors. Although behavioral treatments for insomnia are effective, access is limited. Stepped care delivery models may provide insomnia treatment that is more efficient and accessible to cancer survivors. METHODS: Fifty-one survivors (mean age, 55 years) with elevated Insomnia Severity Index (ISI) scores (≥12) first participated in Sleep Training Education Program (STEP)-1: a single, sleep education session. Those reporting elevated ISI scores 1 month later were offered STEP-2: a 3-session, group cognitive behavioral treatment for insomnia that has been demonstrated to be efficacious. Participants were considered treatment responders if their ISI score improved by ≥6 points and were considered as having remitted if their posttreatment ISI score was <12. Mood was assessed with the Profile of Mood States-Short Form (POMS-SF). RESULTS: Following STEP-1, ISI scores improved (17.1 to 11.2; P < .001), with 45% responding and 41% remitted. Insomnia remission after STEP-1 was associated with lower insomnia severity and shorter duration of sleep problems at baseline. Of the 30 (59%) survivors with unremitted insomnia after STEP-1, 14 (47%) participated in STEP-2. Following STEP-2, ISI scores improved (16.9 to 8.8; P < .001), with 79% responding and 71% remitted. STEP-2 participation was associated with interest in sleep treatment at baseline, but not demographic/health-related variables. Mood improved significantly following both STEP-1 and STEP-2 (P < .001). CONCLUSION: A stepped care approach to treating insomnia among cancer survivors has the potential to improve treatment accessibility. A sizable proportion of survivors can benefit from 2 different low-intensity approaches that could be delivered by nonsleep specialists. For individuals who require more intensive care, assessing treatment interest can identify those who are likely to engage.

Regional practice norms for the care of childhood cancer survivors at risk for cardiomyopathy: A Delphi study.

BACKGROUND: Treatment-associated cardiomyopathy is a leading cause of morbidity and mortality for childhood cancer survivors (CCS). As evidence is not available to guide the management of CCS at risk for cardiomyopathy, we aim to describe the collective opinion of regional experts for the care of these patients using a consensus-based Delphi methodology. PROCEDURE: Nineteen physicians from the New England region who care for CCS treated with cardiotoxic therapy (anthracyclines, thoracic radiation) participated in a Delphi panel querying their management approach, using three rounds of anonymous questionnaires formatted as five clinical scenarios. Consensus ≥ 89% agreement. RESULTS: The response rate was 100% for the first round and 95% for subsequent rounds. Panelists reached consensus on screening asymptomatic CCS with serial echocardiograms (94%) and electrocardiograms (89%), with some disagreement on frequency during pregnancy (83%). All panelists agreed with exercise promotion, with no restrictions on weight training. Consensus was reached on indications for referrals; cardiology for asymptomatic left ventricular dysfunction (ALVD) (100%) and maternal-fetal medicine for pregnancy (94%). In the scenario of ALVD, there was disagreement on the benefit of additional cardiac testing (50% cardiologists recommended cardiac MRI), and although all panelists endorsed treating with angiotension-converting enzyme (ACE) inhibitors, most adult cardiologists (75%) also recommended therapy with beta blockers, compared with none of the pediatric cardiologists or primary-care physicians. CONCLUSIONS: Despite a lack of evidence to guide the management of CCS at risk for cardiomyopathy, a panel of regional physicians reached consensus on managing most clinical scenarios. A controversial area requiring further study is the medical management of ALVD.

Finding sexual health aids after cancer: are cancer centers supporting survivors' needs?

PURPOSE: Sexual dysfunction is one of the most prevalent and distressing treatment-related side effects for both male and female cancer survivors. Survivorship care guidelines recommend therapeutic sexual aids to help improve sexual problems. However, little is known about the availability of sexual aids and resources at cancer centers. METHODS: Twenty-five comprehensive cancer centers affiliated with both the National Cancer Institute and the National Comprehensive Care Network were surveyed using the "mystery shopper" method to determine whether various types of sexual aids were available at the centers. Staffs from cancer center staff retail stores and patient boutiques were queried in separate telephone calls regarding the availability of these aids for and women. RESULTS: Of the 25 centers contacted, 23 (92%) responded about aids for men, and 22 (88%) responded about aids for women. Eighty-seven percent of the centers reported having no sexual aids available for men, and 72% of centers reported having no aids available for women. The most common advice given to mystery shoppers was a suggestion to use the internet. Only one center had numerous aids/resources for both men and women. CONCLUSIONS: The large majority of cancer centers reported having no sexual aids or other sexual health resources available for men or women. IMPLICATIONS FOR CANCER SURVIVORS: Results underscore the widespread lack of resources to promote sexual health rehabilitation at major cancer centers, both for male and female survivors.

A qualitative study of sexual and reproductive health communication with adolescent and young adult oncology patients.

BACKGROUND: Adolescent and young adult patients with cancer (AYAs) identify sexual and reproductive health (SRH) as an important but often neglected aspect of their comprehensive cancer care. The purpose of this study was to explore AYA perceptions and experiences of SRH communication with oncology clinicians. METHODS: Twenty-three AYA patients and survivors ages 15-25 years from a large academic oncology center participated in semistructured qualitative interviews investigating their experiences discussing SRH issues, including specific topics discussed, conversation barriers and facilitators, suggestions for clinicians on how to improve conversations, and education and resource needs. Interviews were audio recorded, transcribed, and coded using a thematic analysis approach. RESULTS: Interviews with AYAs revealed two primary themes-a need for oncology clinicians to discuss SRH and critical gaps in current SRH communication practices. AYAs reported a need for improved SRH communication for the purposes of general education, addressing specific SRH issues experienced, and understanding the long-term impact of cancer and treatment on SRH. The current communication gaps are exacerbated by patient discomfort initiating conversations and the presence of family members. AYAs shared six key recommendations for clinicians on how to improve SRH communication. CONCLUSIONS: AYAs identify a role for oncology clinicians in discussing SRH as a primary aspect of comprehensive health care during cancer treatment and in survivorship; however, multiple gaps and barriers interfere with such discussions. Future efforts must focus on clinician education and training in SRH as well as education and intervention opportunities for AYAs to optimize the care provided.

Open-label placebo reduces fatigue in cancer survivors: a randomized trial.

PURPOSE: Cancer-related fatigue (CRF) is a common and challenging late effect for many cancer survivors. Clinical trials demonstrate robust placebo effects on CRF in blinded trials. Recently, open-label placebo (OLP) has been shown to improve a variety of symptoms in other populations. We conducted a randomized controlled trial to investigate the effect of OLP on CRF in cancer survivors, and to explore biologic and psychological correlates of placebo efficacy. METHODS: Forty cancer survivors (92.5% female; mean age 47.3 years) were randomized to OLP or no treatment control. OLP participants were prescribed two placebo tablets twice daily, for 3 weeks. All participants completed assessments at Baseline, Day 8, and Day 22. The primary endpoint was change in CRF (FACIT-F), and secondary outcomes included exercise frequency, mood, and quality of life. We examined whether personality characteristics or a genetic variation important in dopamine catabolism (catechol-O-methyltransferase; COMT) affected the placebo response. RESULTS: The OLP group reported significantly improved CRF at both Day 8 (p = 0.005) and Day 22 (p = .02), while the control group did not (ps > .05). CRF improvement differed by COMT genotype, but was not associated with personality characteristics. Marginal improvements were noted in the placebo group for some secondary outcomes (exercise frequency and quality of life), but not in the control group. CONCLUSIONS: Results demonstrate that even when administered openly, placebos improve CRF in cancer survivors and dopaminergic systems may be associated with this response. This novel research has meaningful implications for the use of OLP in symptom management for cancer survivors.

The management of childhood cancer survivors at risk for stroke: A Delphi survey of regional experts.

BACKGROUND: Evidence is not available to guide management of childhood cancer survivors (CCS) at risk for radiation-associated cerebral vascular disease (CVD) and stroke. We propose to use a consensus-based methodology to describe the collective opinion of regional experts for the care of these patients and identify areas of controversy. PROCEDURE: Thirty physicians from the New England region who care for CCS participated in a Delphi panel querying their management approach (imaging, laboratory tests, medications, counseling, referrals) to a CCS treated with cranial radiation formatted as five clinical scenarios (asymptomatic, small- and large-vessel CVD, transient ischemia, stroke) in three rounds of anonymous questionnaires. Consensus defined as ≥90% agreement. RESULTS: Response rate was 100% for all three rounds. Panelists reached consensus on laboratory tests to assess stroke risk factors, stroke risk and prevention counseling, brain imaging to monitor survivors with known CVD, and acute care for stroke symptoms. Only 67% panelists agreed with MRI screening asymptomatic survivors with no history of CVD, 87% endorsed aspirin as stroke prevention for large-vessel CVD and 57% for small-vessel CVD. There was no consensus on specialty referrals. Overall, panelists practicing at large institutions and neurology subspecialists were more likely to advocate for screening, interventions, and referrals. CONCLUSIONS: Despite lack of evidence to guide stroke prevention in CCS treated with cranial radiation, a panel of regional physicians reached consensus on managing most clinical scenarios. Controversial areas requiring further study are surveillance imaging for asymptomatic survivors, aspirin for stroke prevention, and indications for specialty referral.

Improvement in sexual function after ovarian cancer: Effects of sexual therapy and rehabilitation after treatment for ovarian cancer.

BACKGROUND: Sexual dysfunction is a distressing long-term effect after gynecological cancer and affects the majority of survivors for years after the completion of therapy. Despite its prevalence, treatment-related sexual dysfunction is underrecognized and undertreated for survivors. Thus, the aim of this study was to develop and test a brief psychoeducational intervention for managing sexual dysfunction for women who have undergone treatment for ovarian cancer (OC). METHODS: Forty-six OC survivors with documented, treatment-related sexual dysfunction received a single half-day group intervention that included sexual health education and rehabilitation training, relaxation and cognitive behavioral therapy skills to address sexual symptoms, and a single tailored booster telephone call 4 weeks after the group. Assessment measures were completed at the baseline (baseline 1), after an 8-week no-treatment run-in period (baseline 2), and then again 2 and 6 months after the intervention. The Female Sexual Function Index (FSFI) was used to assess sexual functioning, and the Brief Symptom Inventory 18 (BSI-18) was used to capture psychological distress. RESULTS: Between baseline 1 and baseline 2, there were no significant changes in the study measures, and this indicated no natural improvement during the run-in period. In contrast, the total FSFI scores improved significantly from baseline 1 to the 2- (n = 45; P < .0005) and 6-month time points (n = 42; P < .05). The BSI-18 scores were also significantly improved at the 2- (P < .005) and 6-month time points (P < .01) in comparison with baseline 1. CONCLUSIONS: This brief behavioral intervention led to significant improvements in overall sexual functioning and psychological distress that were maintained at the 6-month follow-up. The results demonstrate the feasibility of this brief, low-intensity behavioral intervention and support the development of a larger randomized controlled trial. Cancer 2018;124:176-82. © 2017 American Cancer Society.

Evaluation and treatment of insomnia in adult cancer survivorship programs.

PURPOSE: Insomnia is commonly experienced by cancer survivors. Chronic insomnia is associated with significant physical and psychosocial consequences if not properly treated. Both the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN) recommend the evaluation of sleep disturbances and evidence-based treatment of insomnia during routine survivorship care. To better understand current clinical practices, we conducted a survey of major cancer centers across the United States (US). METHODS: Adult survivorship programs at the 25 US cancer centers that are both NCI-designated comprehensive cancer centers and NCCN member institutions were surveyed about the evaluation and treatment of insomnia in their hospital. RESULTS: All institutions responded to the survey. Thirteen centers (56 %) reported screening <25 % of survivors for sleep disorders, and few clinicians providing survivorship care were well-prepared to conduct a proper sleep evaluation. Insomnia was most commonly treated with sleep hygiene, or pharmacotherapy, rather than cognitive-behavioral therapy. No program reported that >50 % of their survivors were receiving optimal insomnia-related care. A variety of methods to improve insomnia care were endorsed by respondents. CONCLUSIONS: There is a clear need to improve the evaluation and treatment of insomnia for cancer survivors at institutions across the country. Cancer centers deemed a number of modalities relevant for improving provider confidence in addressing sleep challenges. IMPLICATIONS FOR CANCER SURVIVORS: To improve the quality of insomnia care for survivors, systematic interventions to increase standardized screening for sleep disorders, providing additional sleep medicine training for survivorship clinicians, and optimizing the role of sleep medicine specialists in the oncology setting should be considered.

Evaluating a handbook for parents of children with food allergy: a randomized clinical trial.

BACKGROUND: Educational materials are needed to support parent management of and coping with childhood food allergy. OBJECTIVES: To evaluate whether a food allergy handbook can improve parental knowledge, confidence, and quality of life associated with the management of food allergy. METHODS: Participants included 153 parents of children diagnosed as having food allergy within the past 12 months who were recruited from hospital-based allergy clinics and food allergy organizations. Parents were randomly assigned to receive the food allergy handbook either after a baseline survey (handbook group) or at the conclusion of study participation (control group). Outcomes were assessed using online surveys at baseline, 2-week follow-up, and 2-month follow-up. RESULTS: Compared with parents in the control group, parents in the handbook group had significantly greater improvement in knowledge at the 2-week (mean difference, 2.92; 95% confidence interval [CI], 2.20-3.64; P < .001) and 2-month (mean difference, 2.46; 95% CI, 1.68-3.25; P < .001) follow-ups, significantly greater improvement in confidence at the 2-week (mean difference, 0.24; 95% CI, 0.09-0.39; P = .002) and 2-month (mean difference, 0.47; 95% CI, 0.30-0.63; P < .001) follow-ups, and significantly greater improvement in quality of life at the 2-month follow-up (mean difference, -0.48; 95% CI, -0.79 to -0.16; P = .004). Parents reported satisfaction with the content the handbook, with mean ratings of individual sections ranging from 2.7 to 3.2 on a 0- to 4-point scale and modal ratings of 3 (very useful). CONCLUSIONS: The food allergy handbook evaluated in this study is an effective parent resource to supplement physician management of food allergy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01914978.

Cell cycle arrest and apoptosis induced by O-acetyl-GD2-specific monoclonal antibody 8B6 inhibits tumor growth in vitro and in vivo.

O-Acetyl-GD2 ganglioside is suitable antigen for tumor immunotherapy with specific therapeutic antibody. Here, we investigate the anti-tumor activity of O-acetyl-GD2-specific monoclonal antibody 8B6 on O-acetyl-GD2-positive tumor cells. The results indicated that mAb 8B6 induced growth inhibition of O-acetyl-GD2-expressing tumor cell lines in vitro with features of cell cycle arrest and apoptosis. Monoclonal antibody 8B6 treatment was also very effective in suppression of tumor growth in mice by reducing the proliferation index and increasing the apoptotic index. Such a study represents a useful framework to optimize immunotherapy with O-acetyl-GD2-specific antibody in combination with chemotherapeutic agents.

Tonal contrasts and initial consonants: a case study of tamang, a 'missing link' in tonogenesis.

Tamang (Bodic division of Tibeto-Burman) is spoken at the edge of the East Asian 'tone-prone' zone, next to the almost tone-free Indian linguistic area, and is, chronologically, at the late end of the tone multiplication wave which has swept through East Asia in the course of the last two millennia. It can be regarded as a 'missing link' in tonogenesis: following the loss of voicing contrasts on syllable-initial consonants, Tamang has four tonal categories instead of its earlier two-tone system; the present state of the prosodic system is typologically transitional, in that these four tonal categories are realised by several cues which include fundamental frequency (F(0)), phonation type, and allophonic variation in the realisation of consonants. Acoustic and electroglottographic recordings of 131 words in two carrier sentences by 5 speakers were conducted (total number of target syllables analysed: n = 1,651). They allow for a description in terms of F(0), glottal open quotient, duration, and realisation of consonants. The results confirm the diversity of cues to the four tonal categories, and show evidence of laxness on tones 3 and 4, i.e. on the two tones which originate diachronically in voiced initials. The discussion hinges on the phonological definition of tone.

Final consonants and glottalization: new perspectives from Hanoi Vietnamese.

The evolution from final obstruents to final glottal stop and then to rhyme glottalization (i.e. from /at/ to /a?/, then to /a'/) is a well-established general trend in the history of the Sino-Tibetan language family and beyond. It has further been shown by laryngoscopy that in three languages which retain the nonreleased syllable-final obstruents /p/, /t/ and /k/ (Standard Thai, and two Chinese dialects), these obstruents are often accompanied by a glottal stop. The present research raises the issue whether there is another typological possibility: can nonreleased final obstruents be accompanied consistently by modal phonation, without glottal stop? Analysis of electroglottographic recordings of 126 syllables in two carrier sentences spoken by 4 speakers shows that, in Hanoi Vietnamese, the final obstruents /p/, /t/ and /k/ are not accompanied by glottalization, and that the open quotient increases in the course of the syllable rhyme. Obstruent-final rhymes (which may carry either of two tones: D1 or D2) are compared with nasal-final rhymes which, under one of the tones (tone B2), are confirmed to be glottalized. Our finding is that tones D1 and D2 (i.e. obstruent-final rhymes) are both produced in modal voice, which shows that the typological paradigm of observed realizations of syllable-final obstruents must be enlarged. The discussion puts forward the hypothesis that the unusual association of segments and voice quality found in Hanoi Vietnamese is a strategy to maintain the opposition between B2-tone and D2-tone rhymes.