Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225 mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6 months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

A chronic eyelid lesion in a child: multi-disciplinary approach to diagnosis, treatment and management of a highly atypical histiocytic lesion.

Malignant histiocytic neoplasm with histiocytic sarcoma phenotype is a rare malignant neoplasm, distinguished by malignant cells with phenotypic characteristics of mature tissue histiocytes. Histiocytic sarcoma typically presents as a primary malignancy, although can also present as a secondary malignancy, and is rarely seen in the pediatric population. Due to the rarity of this condition, diagnosis of histiocytic sarcoma is difficult and considered a diagnosis of exclusion. We describe a unique case of a chronic upper eyelid lesion with biopsy findings of a highly atypical histiocytic neoplasm initially concerning for histiocytic sarcoma; however, after integration of clinical findings, non-progressive and quiescent molecular profile, concluded to be an atypical juvenile xanthogranuloma in a child treated with excision and observation alone. This report highlights the importance of an integrated team approach to diagnosis of unusual histiocytic neoplasms.

Mesenchymal chondrosarcoma of the chest wall in an adolescent patient: A case report and brief review of the literature.

BACKGROUND: Mesenchymal chondrosarcoma is a rare and aggressive bone tumor with few reports of primary tumor in the chest wall. CASE: We report a case of a 17-year-old male presenting with back pain and a posterior mediastinal mass. Imaging demonstrated what was thought to be a benign chondral tumor. The patient underwent resection which confirmed extraskeletal mesenchymal chondrosarcoma. The patient declined proposed adjuvant chemotherapy and underwent multiple resections for rapid local reoccurrence. He ultimately elected for hospice care. CONCLUSION: The case highlights the importance of close disease monitoring and exploration of treatment options, given lack of established guidelines and consistent tumor features.

Efficacy of a Stress Management Intervention for Mothers of Children with Cancer.

OBJECTIVE: Mothers of children with cancer confront life stress that can impact their psychological and physical health and, in turn, the health of the family. Recommendations advocate preemptive stress-management interventions; however, few studies have investigated their efficacy. Here, we report results of a parallel randomized pilot trial examining health benefits of a stress management intervention designed to teach coping skills. METHODS: One hundred twenty mothers (age 36 ± 8 years) of children newly diagnosed with cancer were randomized to a 12-session stress management intervention (n = 60) or usual care (n = 60). Sessions took place in the inpatient or outpatient setting of a children's hospital. Primary outcome variables included psychological function and physical health assessed preintervention and postintervention and at 6-month follow-up (∼12 months postdiagnosis). RESULTS: Enrollment, retention, and satisfaction data supported feasibility and acceptability. Latent change score models showed the intervention reduced perceived stress (d = -0.37, p = 0.03), anxiety symptoms (ds = -0.38 and -0.56, ps < .03) and, a nonsignificant effect for depressive symptoms (d = -0.29, p = .11) across the 6 months following diagnosis. Intervention participants also endorsed fewer depressive symptoms than controls ∼12 months after diagnosis. The intervention improved stress management skills, which associated with the psychological benefits of participation. There were no intervention-related changes in perceived health or markers of inflammation. CONCLUSION: Intervention-related improvements in stress management skills may result in better psychological health in the face of caring for a child with cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02022449.

Sedation practices in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: The 5-year survival for pediatric acute lymphoblastic leukemia (ALL) is greater than 90%. One late effect of pediatric ALL associated with numerous long-term difficulties is neurocognitive deficits. The experience at our institution, as well as conversations with oncologists at other institutions, suggests an increase in the use of sedation during lumbar punctures (LPs) for treatment of pediatric ALL. Among the most common Children's Oncology Group (COG) ALL protocols, approximately 30 LPs are performed over 2-3 years. Studies in animals reveal that sedation drugs may harm the developing brain. Gaps in knowledge exist regarding their use in children, particularly repeated exposures. The purpose of this study is to summarize sedation practices for LPs related to the treatment of ALL at COG institutions. METHODS: Responsible Individuals (RIs) of the Cancer Control Committee of COG were invited to complete an internet-based survey about sedation practices at their institutions. RESULTS: Surveys were sent to 103 RIs with a 62% response rate (N = 64). A combined 2018 new patients with ALL were seen each year (mean = 31.5, range = 3-110) at the participating institutions. The majority (96%) of children with ALL received sedation for LPs. While there was considerable variability across institutions in the type of sedation given, the most common was propofol alone (n = 36, 56%). CONCLUSIONS: A substantial number of children with ALL receive sedation for LPs; however, there is variation in the medication used. Better understanding of sedation practices in children with ALL may inform future research to investigate which methods are the safest, with an emphasis on long-term neurocognitive late effects.

Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

BACKGROUND: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. FINDINGS: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung. INTERPRETATION: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. FUNDING: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

Cognitive and Occupational Function in Survivors of Adolescent Cancer.

PURPOSE: Adolescents with cancer have unique developmental considerations. These include brain development, particularly in the frontal lobe, and a focus on completing education and entering the workforce. Cancer and treatment at this stage may prove to uniquely affect survivors' experience of cognitive and occupational function. METHODS: An exploratory, cross-sectional, descriptive comparative study was employed to describe cognitive and occupational function in adult survivors of adolescent cancer (diagnosed between the ages of 15 and 21 years) and explore differences in age- and gender-matched controls. RESULTS: In total, 23 survivors and 14 controls participated in the study. While significant differences were not found between the groups on measures of cognitive and occupational function, several small and medium effect sizes were found suggesting that survivors may have greater difficulty than controls. Two small effect sizes were found in measures of neuropsychological performance (the Digit Vigilance test [d = 0.396] and Stroop test [d = 0.226]). Small and medium effect sizes ranging from 0.269 to 0.605 were found for aspects of perceived and total cognitive function. A small effect size was also found in work output (d = 0.367). CONCLUSIONS: While we did not find significant differences in cognitive or occupational function between survivors and controls, the effect sizes observed point to the need for future research. Future work using a larger sample size and longitudinal design are needed to further explore cognitive and occupational function in this vulnerable and understudied population and assist in the understanding of patterns of change over time.

Shared Care of Childhood Cancer Survivors: A Telemedicine Feasibility Study.

PURPOSE: With an increasing number of childhood cancer survivors (CCSs), determining the best model of survivorship transition care is becoming a growing priority. Shared care between pediatric oncology and adult primary care is often necessary, making survivorship a time of transition, but effective standard models are lacking. We sought to provide a more integrated approach to transition using telemedicine. METHODS: Recruited primary care provider/CCS dyads were instructed to log-in to a password-protected virtual meeting room using telemedicine equipment at the time or a regularly scheduled office visit. Dyads were joined by a pediatric survivorship clinic team member who conducted the telemedicine portion of the transition visit, which consisted of the review of an individualized treatment summary and care plan. Postquestionnaires were developed to evaluate key points such as fund of knowledge, satisfaction with the visit, and effectiveness of this electronic tool. RESULTS: There were 19 transition visits conducted, 13 of which used the telemedicine equipment as planned. Those that did not use the equipment were primarily unable to due to technical difficulties. Postquestionnaires were overall positive, confirming increased knowledge, comfort and abilities, and patient satisfaction in survivorship care. Negative comments were primarily related to equipment difficulties. CONCLUSIONS: A gap still remains in helping CCSs transition from oncology to primary care and this pilot study offered insights into how we might better bridge that gap through the use of telemedicine. Further research is needed to refine the transition process for CCSs, including evaluation and testing models for standard of care.

Partnering to optimize care of childhood cancer survivors.

Familiarizing yourself with the survivorship care plan can help ensure that survivors receive proper follow-up care. Collaboration among providers is also key.

JAK2+ Essential Thrombocythemia in a Young Girl With Budd-Chiari Syndrome: Diagnostic and Therapeutic Considerations When Adult Disease Strikes the Young.

A 12-year-old female with Budd-Chiari syndrome underwent liver transplant and subsequent splenectomy. Her platelet count began to rise postoperatively after previous normal values. JAK2V617F-positive essential thrombocythemia (ET) was diagnosed. This case demonstrates that the diagnosis of ET should be considered in the face of normal platelet counts and included on the differential diagnosis for pediatric patients. With this population in mind, we review the current literature on long-term use of platelet-lowering agents. We conclude that it is reasonable to use anagrelide as a first-line treatment for ET diagnosed according to the World Health Organization (WHO) system. In cases where WHO criteria do not result in a definitive diagnosis or when a patient experiences thrombotic events despite anagrelide therapy, hydroxyurea may be utilized as a first-line agent or as an adjunct. Further study in this area is warranted.

A pilot trial of a stress management intervention for primary caregivers of children newly diagnosed with cancer: preliminary evidence that perceived social support moderates the psychosocial benefit of intervention.

OBJECTIVES: (1) To examine the acceptability and feasibility of a stress management intervention for caregivers of children recently diagnosed with cancer. (2) To explore whether caregivers with lower baseline perceived social support derive greater benefit from the intervention than those with higher perceived support. METHODS: 45 primary caregivers were randomly assigned to intervention or standard care. Of these, 37 completed measures of social support, depression, anxiety, and perceived stress at both pre-intervention (T1; mean = 24 days post-diagnosis) and post-intervention time points (T2; mean = 165 days post-diagnosis). RESULTS: Enrollment, retention, and satisfaction data support feasibility and acceptability of the intervention. There was no overall significant impact of participation in the intervention on levels of distress at T2. However, T1 social support moderated intervention response, with caregivers who perceived lower T1 support showing greater psychological benefit from the intervention. CONCLUSIONS: Primary caregivers with lower levels of perceived social support may benefit from preemptive stress management intervention.

Hospitalization rates among survivors of childhood cancer in the Childhood Cancer Survivor Study cohort.

BACKGROUND: Chronic health conditions are common among long-term childhood cancer survivors, but hospitalization rates have not been reported. The objective of this study was to determine overall and cause-specific hospitalization rates among survivors of childhood cancer and compare rates to the U.S. population. PROCEDURE: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of 5+ year survivors of childhood malignancies treated at 26 participating centers. Self-reported hospitalizations from 10,366 survivors (diagnosed 1970-1986) were compared to U.S. population rates using age- and sex-stratified standardized incidence ratios (SIRs). Reasons for hospitalization were evaluated and associations between demographic, cancer and treatment-related risk factors with hospitalization were investigated. RESULTS: Survivors were, on average, 20.9 years from cancer diagnosis (SD: 4.6, range: 13-32) and 28.6 years of age (SD: 7.7, range: 13-51). Survivor hospitalization rates were 1.6 times the U.S. population (95% CI: 1.6; 1.7). Increased hospitalization rates were noted irrespective of gender, age at follow-up and cancer diagnosis, with highest SIRs noted among male (SIR = 2.6, 95% CI: 2.2; 3.0) and female (SIR = 2.7, 95% CI: 2.4; 3.1) survivors aged 45-54. Female gender, an existing chronic health condition and/or a second neoplasm, and prior treatment with radiation were associated with an increased risk of non-obstetrical hospitalization. CONCLUSIONS: Survivors of childhood cancer demonstrate substantially higher hospitalization rates. Additional research is needed to further quantify the healthcare utilization and economic impact of treatment-related complications as this population ages.

Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year WT survivors in the Childhood Cancer Survivor Study (CCSS). PROCEDURE: The CCSS, a multi-institutional retrospective cohort study, assessed WT survivors (N = 1,256), diagnosed 1970-1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (N = 4,023). RESULTS: The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HR) were 2.0, 95% confidence interval (CI) 1.8-2.3 for grades 1-4 and 4.7, 95%CI 3.6-6.1 for grades 3 and 4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (prevalence ratio [PR] 1.7; 95%CI 1.2-2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI 1.9-4.0%) and of mortality was 6.1% (95%CI 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin-HR 6.6; 95%CI 1.6-28.3; doxorubicin ≤ 250 mg/m(2) -HR 13.0; 95%CI 1.9-89.7; doxorubicin >250 mg/m(2) -HR 18.3; 95%CI 3.8-88.2), SMN (standardized incidence ratio [SIR] 9.0; 95%CI 3.9-17.7 with and 4.9; 95%CI 1.8-10.6 without doxorubicin) and death. CONCLUSION: Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.

Social outcomes in the Childhood Cancer Survivor Study cohort.

Difficulties with negotiating and achieving desired social outcomes in life may be exacerbated by the experience of childhood cancer, including adverse effects from therapies used to achieve a cure. This review of previous publications from the Childhood Cancer Survivor Study (CCSS) and other relevant literature provides insight into the prevalence of, and risk factors for, poor educational attainment, less than optimal employment status, and interpersonal relationship issues among long-term survivors of childhood cancer. The impacts of emotional health and physical disability on social outcomes are also examined. Study results suggest that childhood cancer survivors generally have similar high school graduation rates, but are more likely to require special education services than sibling comparison groups. Survivors are slightly less likely than expected to attend college, and are more likely to be unemployed and not married as young adults. Cancers and treatments that result in impairment to the CNS, particularly brain tumors, or that impact sensory functioning, such as hearing loss, are associated with greater risk for undesirable social outcomes, as are emotional health problems and physical disability. This review of relevant data from CCSS and other studies provides information on risk factors for social problems into adulthood. A greater understanding of the long-term social impacts from the diagnosis and treatment of childhood cancer is critically important for developing targeted interventions to prevent or ameliorate adverse psychosocial effects.

Romantic relationships of emerging adult survivors of childhood cancer.

OBJECTIVE: To assess whether childhood cancer survivors experience difficulties in their romantic relationships during emerging adulthood (18-25 years) and to identify who may be at risk for long-term social sequelae. METHODS: Emerging adult survivors of childhood cancer (n=60) and controls without a history of chronic illness (n=60) completed an online assessment of their romantic relationships, including perceived relationship satisfaction. Severity of initial treatment was rated by healthcare providers for participants with cancer. RESULTS: Although survivors of childhood cancer do not differ from demographically similar controls in satisfaction with, conflict in, and duration of romantic relationships, they reported fewer romantic relationships and greater distress at relationship end. Within the survivor group, higher trait anxiety, older age at diagnosis, and more severe treatment intensity increased risk for relationship difficulties, including lower relationship satisfaction and more distress at break-up. CONCLUSIONS: Findings appear to support the overall social resilience of survivors of childhood cancer. Certain subsets of survivors, however, may be at greater risk for difficulties in their close relationships as adults and therefore may be appropriate targets for intervention. Healthcare providers should routinely assess developmentally salient issues like love/romance that are important markers of identity development and ultimately impact long-term quality of life for survivors.

Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: a Children's Oncology Group Phase I Consortium Study.

PURPOSE: We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. PATIENTS AND METHODS: Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. RESULTS: Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. CONCLUSION: The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide.

Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group.

OBJECTIVES: Among a cohort of long-term neuroblastoma survivors, our aims were to (1) assess the association between treatment intensity and parent-reported hearing loss in the child, (2) evaluate the strength of the association between hearing loss and parent-reported academic and psychosocial difficulties in the child, and (3) examine the association between parent-reported academic and psychosocial difficulties in the child and the child's self-reported quality of life. PATIENTS AND METHODS: Through a mailed survey that included the Pediatric Quality of Life Inventory 4.0 and an outcomes questionnaire for parents, we evaluated 137 children (aged 8-17 years) who were previously enrolled in 1 of 2 Children's Cancer Group neuroblastoma clinical studies. RESULTS: Childhood survivors of neuroblastoma who had prevalent hearing loss, as reported by their parents, had at least twice the risk of an identified problem with reading skills, math skills, and/or attention and a similarly higher risk of a general learning disability and/or special educational needs than did neuroblastoma survivors without hearing loss. Consistent with this finding, hearing loss was associated with a 10-point-lower mean score in the school-functioning scale of the Pediatric Quality of Life Inventory 4.0. We also observed a clear pattern of poorer self-reported quality-of-life scores among children with parent-reported academic and psychosocial problems compared with those without such problems, particularly with school functioning, even after controlling for reported hearing loss. CONCLUSIONS: We found evidence that long-term neuroblastoma survivors, especially those with hearing loss, are at elevated risk for academic learning problems and psychosocial difficulties. We also found strong concordance between parent-reported learning problems in the child and indications of distress in the child's self-reported quality of life.

Radiotherapy for symptomatic metastases to bone in children.

Thirty-seven children less than age 19 years were treated from 1985 through 1998 with radiotherapy for symptomatic metastases to bone. The most common primary tumors were neuroblastoma (18), Ewing's sarcoma (5), and osteosarcoma (5). The interval from diagnosis of the primary tumor to treatment of the first symptomatic metastases involving bone ranged from 0 to 163 months (median 19). Thirty-seven children were treated with 150 courses of radiotherapy. Forty-three courses consisted of a single dose of 300 to 1,000 cGy. One hundred thirteen courses of radiotherapy consisted of five or fewer treatment fractions. Sixteen osseous sites were treated with two courses of radiotherapy and two sites were treated with three. The most commonly irradiated symptomatic bone sites were skull, spine, and hip/femurs. Survival from the first course of radiotherapy administered for metastases to bone varied from 1 to 52 months, with 11 patients (29.7%) surviving 12 or more months and only 3 patients (8.1%) surviving more than 2 years. The majority of children seemed to derive palliation from the radiotherapy based on assessment by family and medical personnel as well as by self-report in older patients. Children with symptomatic metastases to bone have an extremely poor prognosis, and short courses of radiotherapy are suggested as palliation. Repeat courses of radiotherapy can be given for persistent or recurrent symptoms.