Robert E Goldsby’s research while affiliated with University of California, San Francisco and other places

INTRODUCTION Advances in the treatment of children and adolescents with cancer have resulted in an increased percentage of pediatric cancer survivors (PCSs). However, PCSs are at increased risk of bone health issues from prolonged therapy with corticosteroids, higher cumulative corticosteroid dose, hematopoietic stem cell transplant (HCT), total body irradiation and cranial/craniospinal radiation which can decrease bone mineral density (BMD). Low BMD in PCS is associated with osteoporosis and osteopenia in adult life. The Children's Oncology Group's (COG) long-term follow-up (LTFU) guidelines (Version 6.0) recommend a baseline evaluation of BMD by DXA (Dual-energy X-ray absorptiometry) for PCS who received corticosteroids or HCT at entry into LTFU clinic (2 to 5 years after completion of therapy). Based on Z-scores the guidelines may recommend evaluation for endocrine defects and/or consultation with a bone health specialist with a repeat DXA after 2 years and thereafter as clinically indicated. Although there have been reports of fracture risk in pediatric cancer patients during or shortly after therapy, the fracture risk in PCS with low BMD for chronologic age based on Z-scores has not been established. The aim of this study is to review the extent of the clinical application of bone mineral density study guidelines across six California pediatric oncology cancer survivorship programs and determine the variation in practices based on low BMD. METHODS We performed a multicenter, retrospective chart review of PCSs from January 1, 2015, to Dec 31, 2019, at six children's hospitals in California affiliated with the University of California. Each participating site collected its own data from their institutional electronic medical records to analyze the utilization patterns of DXA scans in screening for low BMD in PCS. The study was approved by the Institutional Review Board of each hospital. Patients included were between 0-25 years of age at the time of cancer diagnosis, who had a DXA scan performed as part of off-therapy care and were followed at the LTFU clinic at the participating sites. Demographic, clinical and treatment data were collected, along with the DXA scan results (whole body, lumbar spine or femoral neck adjusted for age and gender) and the actions taken based on DXA scan results such as referrals to other subspecialties or pharmacotherapy. The number of new diagnoses in 2018 was included to estimate the relative sizes of the programs. RESULTS A total of 529 PCS patients met inclusion criteria at the six participating hospitals over the period of 5 years. The percentage of patients who were referred to other specialties based on DXA scan results varied from 0% to 46% at the different hospitals. The number of patients who were started on bisphosphonates across all the hospitals varied from 0% to 10%. The most common diagnosis overall in PCS who had DXA scans was acute lymphoblastic leukemia. CONCLUSION The study findings demonstrate that the current guidelines are neither universally nor uniformly applied. Practices regarding ordering DXA scans and ordering referrals based on the results varied in the different participating hospitals across California. We suggest updating the guidelines to be more targeted to more effectively direct resources to those most likely to benefit from screening and referral. Further research is necessary to determine the prevalence of treatment-related bone health issues and the most effective strategies for minimizing risk of osteopenia and osteoporosis during adulthood in PCS.

Renal cancer, although still rare among individuals under 45 years of age, is on the rise in the general population. The risk and timing of subsequent renal cancer in survivors of childhood cancer is not well established. Using the SEER registry, we reported the incidence of subsequent malignant renal neoplasms after treatment for primary malignancy diagnosed under 20 years of age. We evaluated clinical characteristics, standardized incidence ratio (SIR), and Kaplan-Meier survival estimates. Fifty-three survivors developed subsequent renal cancer (54 total cases). Of these, 54.7% were female, 88.7% were white, and 13.2% were Hispanic. Mean ages at primary malignancy and subsequent renal cancer were 10.1 and 31.1 years, respectively. Forty-seven cases were second cancers, 6 were third, and 1 was fourth. For survivors of childhood cancer, the overall SIR for renal cancer was 4.52 (95% CI: 3.39-5.89). The 5-year overall survival rate after development of subsequent renal cancer was 73% (95% CI: 58%-83%). Renal cancer occurs 4.5 times more frequently in childhood cancer survivors than in the general population, necessitating long-term care considerations.

Background: Malignant renal neoplasms are rare before the age of 45. Age, gender, and certain genetic and modifiable risk factors can influence the development these cancers. However, the risk in survivors of childhood cancer is not well established. Methods : Using the SEER registry, we identified survivors of childhood cancer who developed a renal cancer as a subsequent malignant neoplasm (SMN). Original childhood cancer was diagnosed under 20 years of age. We evaluated the clinical characteristics of the survivors of childhood cancer who developed SMNs of the kidney. We calculated standardized incidence ratios and performed Kaplan-Meier estimates to assess survival after SMN of the kidney. Results: We found 53 survivors developed a SMN of the kidney (one patient had 2 subsequent kidney cancers). Of the 54 subsequent kidney cancers, 47 occurred as a second cancer (43 carcinomas, 3 Wilms, and 1 Ewing sarcoma), 6 renal carcinomas occurred as a third cancer and 1 renal carcinoma occurred as a fourth cancer. Of the 53 cancer survivors with SMN of the kidney, 29 were female (54.7%), 47 were white (88.7%) and 7 were Hispanic (13.2%). The most common primary cancers were Hodgkins lymphoma (n=9) and neuroblastoma (n=7). Primary malignancy occurred at a mean age of 10.1 years and SMNs occurred at a mean age of 31.1 years. The overall SIR of developing a subsequent renal cancer was 4.52 (p<0.05; 95%CI 3.39-5.89). The 5-year overall survival after development of a SMN of the kidney was 73% (95%CI: 58%-83%). Conclusions: Subsequent malignant cancers of the kidney are rare but occur ~4.5 times more frequently in survivors of childhood cancer compared to the general population. This increased risk should be considered when providing long-term care for survivors of childhood cancer.

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? Methods: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. Results: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. Conclusion: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. Level of evidence: Level III, therapeutic study.

Introduction: Malignancies of the mobile spine carry high morbidity and mortality. This study sought to examine factors associated with receipt of "standard" treatment and survival for patients with primary mobile spine tumors in the California Cancer Registry (CCR). Methods: The CCR (1988 to 2016) data were obtained for patients with primary tumors of the mobile spine and at least 1-year follow-up. Sacrum/pelvis tumors were excluded. Age at diagnosis, sex, race, neighborhood socioeconomic status, insurance, Charlson Comorbidity Index, histologic diagnosis, stage at diagnosis, and treatment at a National Cancer Institute-designated Cancer Center (NCICC) were collected. Multivariate analyses were done to identify factors associated with all-cause mortality and receipt of "standard" treatment. Results: Four hundred eighty-four patients (64% White, 56% low neighborhood socioeconomic status, and 36% privately insured) were included. Chordoma (37%) was the most common diagnosis. Only 16% had metastatic disease at presentation. Only 29% received treatment at an NCICC. Lower age, Charlson Comorbidity Index, less extensive stage of disease, and private insurance were associated with lower all-cause mortality (all P < 0.05). Medicaid/public insurance (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.13 to 2.41) and Medicare (HR, 1.80; 95% CI, 1.25 to 2.59) were associated with higher mortality compared with private insurance. Patients who received no known treatment (HR, 2.41; CI, 1.51 to 3.84) or treatment other than the "standard" (HR, 1.45; CI, 1.11 to 1.91) had higher mortality compared with those who received the standard protocols. A critical predictor of receiving the standard treatment protocol was being treated at an NCICC. If patients did not receive care at such institutions, they received optimal treatment only 40% of the time (HR, 0.5; P = 0.004). Conclusions: Receipt of defined "standard treatment" protocols was associated with care received at an NCICC and lower all-cause mortality in patients with primary osseous malignancies of the mobile spine. Patients with public insurance are vulnerable to worse outcomes, regardless of age, disease burden, or receipt of standard treatment. Level of evidence: III.

BACKGROUND CONTEXT Malignant neoplasms of the mobile spine are associated with high morbidity and mortality. While treatment paradigms have evolved, factors associated with receipt of appropriate treatment and survival are not well defined. PURPOSE The goal of this study is to examine factors predictive of survival or receipt of the standard treatment paradigm for primary tumors of the mobile spine from 1988-2016 in the California Cancer Registry (CCR). STUDY DESIGN/SETTING The CCR was reviewed from the years 1988 to 2016 for patients who received treatment for a primary tumor of the mobile spine. PATIENT SAMPLE Patients of all ages with Ewing sarcoma, osteosarcoma, chondrosarcoma, or chordoma primarily located in the vertebral column and at least one year of registry follow-up were included. Sacrum/pelvis tumors were excluded. OUTCOME MEASURES Survival at the end of the study was the primary outcome of interest. A secondary outcome was receipt of the standard treatment paradigm by histology. METHODS Collected data included age, sex, race (white vs non-white), neighborhood socioeconomic status (nSES, low vs high), insurance status, Charlson Comorbidity Index (CCI), histologic diagnosis, tumor stage at presentation, and treatment at a National Cancer Institute designated Cancer Center (NCICC). Univariate and multivariate analyses were performed to identify predictors of survival and receipt of standard treatment for each histologic type. RESULTS Four hundred eighty-four patients met inclusion criteria. The cohort was mixed: >20 years old (80%), “white” (64%); “low nSES” (56%); private insurance (36%), Medicaid/public insurance (16%), Medicare (15%), uninsured/self-pay (6.4%). Chordoma (37%) was most common, while osteosarcoma was least common (16%). Ewing sarcoma and chondrosarcoma each accounted for 24% of the cohort. Locally advanced disease (40%) and localized disease (34%) were most common. Metastatic disease was uncommon (16%). The minority (29%) received treatment at a NCICC. Mortality was 58%. There were significant differences in receipt of “standard” treatment based on histology: chondrosarcoma (47%), chordoma (28%), Ewing's sarcoma (24%), osteosarcoma (21%) (p<0.0001). Patients with private insurance were most likely to receive “standard” treatment. Race and nSES were not associated with receipt of “standard” treatment for each histology, but being seen at an NCICC was (p = 0.0006). In regard to survival, age>20, higher CCI, Medicare/Medicaid insurance, more extensive stage of disease, and receiving no known treatment (compared to the “standard” treatment) were associated with lower odds of survival (all p<0.05). CONCLUSIONS Over a 28-year timeframe, the majority of patients with a primary osseous sarcoma of the mobile spine in the California Cancer Registry neither received “standard” treatment nor were cared for at an NCI cancer center. Mortality within 1 year was 58%. That survival was jeopardized by having public insurance and more extensive stage of disease and that survival was improved by receipt of “standard” treatment suggest that efforts should aim to improve access to designated cancer institutes and “standard” treatment paradigms to improve outcomes and survival for patients with malignant tumors of the mobile spine. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Background: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied. Materials and methods: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure. Results: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m2; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure. Conclusions: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study.

Background Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, but occurs infrequently in infants (<1 year). Historically, infants with RMS have worse overall survival compared to other pediatric age groups. Aim This study aims to assess the clinical features and treatment factors associated with survival comparing infants to children aged 1–9 years diagnosed with RMS. Methods Children aged <10 years diagnosed with RMS between 2000 and 2016 were identified using the SEER database. Descriptive statistics were used to assess demographic, clinical, and treatment characteristics of infants and children with RMS. Kaplan–Meier estimates and Cox proportional hazards regression were performed to assess for factors associated with survival. Results Age <1 year was independently associated with an increased risk of mortality. Compared to children aged 1–9 years, fewer infants received standard of care therapy, that is, chemotherapy combined with local control (surgery and/or radiation; 86.8 vs. 75.7%; p = .009). In comparing the frequency of specific treatment modalities (used alone or in combination with other modalities), infants were less likely to receive radiation therapy (34.0 vs. 66.4%; p < .001) and more likely to receive surgery (68.9 vs. 57.5%; p = .02) than children aged 1–9 years. Across age groups, chemotherapy combined with local control was significantly associated with reduced mortality. Alveolar histology, metastatic disease, and Hispanic ethnicity were negatively associated with survival. Conclusions Age of <1 year was an independent risk factor for increased mortality from RMS compared to ages 1–9 years. Fewer infants were treated with chemotherapy combined with local control, the therapy associated with best survival in all age groups. Other factors contributing to differences in survival should be further explored.

The impact of wearing a mask on face‐touching behavior is unknown. We conducted a survey of pediatric hematology/oncology staff to assess the perception of how masks would affect face‐touching behavior and a brief observational study of providers during conferences in a children's hospital to quantify how masks affect face‐touching behavior. Most felt that the mask would either increase (37.4%) or decrease (36.6%) their face‐touching behavior. During a total of 330 person‐minutes of observation, median face‐touching rate was 5.4 face touches/hour (FT/h) while wearing a mask and 20 FT/h without a mask. Masks may reduce face‐touching behavior amongst health care professionals.