bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and risk factors of bisphosphonate associated osteonecrosis of the jaws
Authors: Stumpe M. , Chandra R. , Yunus F. , Samant S.
Published: March 2020

9074

Background: Intravenous bisphosphonate therapy has been used for treatment of various benign and malignant bone diseases, including bony metastasis. Recent single case reports have described osteonecrosis (ON) of the mandible or maxilla as a previously unknown complication of this therapy. Methods: Records of 638 patients treated with intravenous pamidronate or zoledronic acid were reviewed to determine the incidence of jaw ON. Number of infusions, dosing interval, dosage administered, and duration of treatment were analyzed to determine risk factors for the development of this complication. Results: Mean age of the study group was 67 years and 61% were female. The most common primary malignancies included prostate, lung, breast, and multiple myeloma. The overall incidence of osteonecrosis was 6/638 (0.94%). Patients treated with pamidronate (n=336), zoledronic acid (n=169), and both agents (n=133) had an incidence of ON of 1.2%, 0%, and 1.5% respectively (p=NS). No significant relationship was observed between the incidence of ON and demographic parameters, primary tumor, cumulative drug dose, or dosing interval. However, patients who developed ON had a significantly greater mean number of infusions (20.7 versus 10.7, p=0.016) and significantly greater mean hours of infusion time (42.7 versus 17.7, p=0.0036) than those who did not develop the complication. Underlying dental disease appears to be associated with ON. Conclusions: This review represents the largest single series to date of patients treated with IV bisphosphonate therapy. The findings suggest positive correlation between the development of ON and drug exposure as measured by number of infusions and total infusion hours. However, this data must be interpreted with caution as the overall incidence of the complication was low (<1%), precluding rigorous statistical analysis. Dental comorbidity should be addressed prior to initiation of bisphosphonate therapy.

No significant financial relationships to disclose.
Disrupted sleep the night before breast cancer surgery is associated with increased post-surgical pain
Authors: Wright C. E. , Montgomery G. H. , Goldfarb A. , Pace B. , Silverstein J. H. , Weltz C. , Bovbjerg D. H.
Published: March 2020

9078

Background: Despite the best clinical care, pain following breast cancer surgery is a virtually universal patient experience that can have pervasive negative consequences. Given the sometimes prolonged impact of such pain, and the large variability across patients, additional research on modifiable presurgery risk factors is needed. Recent experimental studies have found that disruption of even a single night's sleep is sufficient to increase pain sensitivity the next day in healthy volunteers. The possible negative effects of poor sleep prior to cancer surgery have not been investigated despite the likelihood that sleep may be particularly disrupted at that time. We hypothesized that sleep disruption the night before outpatient breast cancer surgery would predict increased postsurgery pain. Methods: Pain was measured in 24 female lumpectomy patients using the Brief Pain Inventory 7 days postsurgery. Sleep disruption (% of time awake in the sleep period) was measured using an actigraph device for 10 nights, commencing 3 days before surgery. Statistical analyses included correlation and multiple regression. Results: Sleep disruption was significantly greater the night before surgery than 3 nights before surgery (p=.047). Heightened sleep disruption the night before surgery predicted increased pain intensity and pain interference with daily life (r=-.44, p=.034; r=-.49, p=.015), This relationship remained significant for pain interference even after controlling for age, race, surgery duration, presurgery mood, postoperative sleep disturbance and pain medication (B=-.12, C.I. -.23 to -.02, p=.027). Conclusions: This study is the first to document adverse effects of prior sleep disruption on pain sensitivity in a clinical oncology context. Future research should explore mechanisms responsible for these effects and examine the impact of interventions to improve sleep prior to surgery.

No significant financial relationships to disclose.
Recognized and unrecognized hyperglycemia in cancer inpatients
Authors: Kapoor S. , Cui J. , Busaidy N. , Lavis V. , Shah P.
Published: March 2020

9079

Background: Diabetes mellitus (DM) is a recognized co-morbidity with cancers. Prevalence of DM in cancer inpatients and occurrence of acute hyperglycemic crises in cancer patients have not been reported. Methods: Chart, laboratory, and pharmacy data were evaluated retrospectively over 3 months in 2006 and cases of acute hyperglycemic crises were evaluated from 2001–2004 in a big cancer hospital. Results: Of the 2,636 unique patient admissions identified through lab and pharmacy data over a 3 month period in 2006, 1,735 (65%) met the epidemiological (fasting glucose (FG)>=126 mg/dL and/ or receiving DM therapy (Rx)) and 1,306 (50%) met the clinical criteria for a diagnosis of DM (FG>=126 mg/dL and/ or any glucose>=200 mg/dL on two different days, and/ or receiving DM Rx). Of the 463 treated patients 224 (48%) were on one therapy (excluding 38 (8.2%) on short acting insulin only); 13.4% were on combination/ long acting insulin therapy; 16% were on insulin + oral antidiabetics (OADs), and 18% were on combination OADs. On these respective therapies during hospitalization 68%, 49%, and 31% had severe hyperglycemia (glucose >300 mg/dL); and 19%, 14%, and 0% had glucose >400 mg/dL. Eighty eight with a glucose >300 mg/dL and 13 with glucose >400 mg/dL remained untreated during hospitalization. In the case study severe hyperglycemia (>300 mg/dL) predated by 54±18 (Mean±SEM) days (7 known DM on Rx) in 12 out of 22 patients admitted with acute hyperglycemic crises to cancer hospital emergency services over 4 years (14 diabetic ketoacidosis, 8 hyperglycemic hyperosmolar state). Subsequent to the hyperglycemic crises 17/22 died in 14±4 months (median survival: 12 months). In patients not known to be DM 23±6 days elapsed between starting known diabetogenic drugs and testing plasma glucose (10±4 days in known DM). Conclusions: A large number of cancer patients with diabetes remain unrecognized, untreated or inadequately treated even during hospitalizations. Our data reinforces the need for testing, recognizing and appropriately managing diabetes with an aim to prevent acute hyperglycemic complications in cancer patients.

No significant financial relationships to disclose.
Work situation and work-related difficulties in stomach cancer survivors compared with the general population
Authors: Lee K. , Lee M. , Bae J. , Kim S. , Kim Y. , Ryn K. , Lee J. , Noh J. , Sohn T. , Hong S. , Yun Y.
Published: March 2020

9084

Background: We aimed to investigate the work situation and work-related difficulties among stomach cancer survivors compared with the general population. Methods: We enrolled 426 stomach cancer survivors diagnosed 2001 to 2003 from two hospitals and 994 members without a history of cancer selected randomly from a representative sample of Korea adults. We identified work situation and work-related difficulties in two groups using multivariate logistic regression. Results: An employment rate of stomach cancer survivors decreased from 66.2% to 53.1% at average 28 months after their diagnosis and it was lower than that of general population (63.5%). The primary reason for not-working in survivors were that they were easily fatigued (31.2%) and had limitations in physical functioning (13.0%). Examining work-related difficulties, 50.6% of survivors who were working at the time of survey reported that they were easily fatigued and 37.5% of survivors reported that their capacity of work decreased whereas only 22.4%, 10.6% of general population reported. Survivors had housework- related difficulties because they were easily fatigued (74.4%) and emotionally distressful (12.2%) whereas 58.0% and 4.0% of general population reported. Older age (adjusted odds ratio [aOR]=18.12; 95% confidence interval [CI]=6.59 to 49.81), female (aOR=5.30; 95% CI=7.37 to 31.31), low income (aOR=1.87; 95% CI=1.04 to 3.33), poor physical functioning (aOR=0.97; 95% CI=0.95 to 0.98) and total gastrectomy (aOR=2.40; 95% CI=1.26 to 4.60) were more likely to increase the likelihood of not working in stomach cancer survivors. Conclusions: Stomach cancer and its treatment had a negative impact on employment rate as previous studies with other type of cancer. Our study found that stomach cancer survivors had an experience not only work-related but also housework-related difficulties. This information on stomach survivors’ might be help to make a better plan for the intervention of stomach cancer survivors’ return to work.

No significant financial relationships to disclose.
Automated home-based symptom monitoring coupled with centralized telecare management in a statewide trial involving rural and urban community-based oncology practices
Authors: Theobald D. E. , Kroenke K. , Iseminger K. A. , Sanders R. , Norton K. , McCalley S. , Harvey P. , Butler D. , Dugan W. M. , Bechar N.
Published: March 2020

9089

Background: Pain and depression are two of the most prevalent and treatable cancer-related symptoms, each present in at least 20–30% of oncology patients. Therefore, we are conducting the NCI-funded Indiana Cancer Pain and Depression (INCPAD) study, a randomized clinical trial conducted in a statewide network of 13 community-based cancer clinics located in both rural and urban oncology practices. Methods: Patients are screened at the local clinics followed by telephone-based enrollment and informed consent, depression and pain care management, and serial research outcome assessments over a 12-month period. Patients randomized to the intervention complete automated home-based symptom monitoring by interactive voice-recorded phone calls or by internet on a tapering schedule (twice a week tapering to monthly), allowing a single nurse care manager to centrally monitor treatment of patients asynchronously and efficiently. Results: Of the first 1,612 patients screened for the trial, 820 (51%) screened positive for depression and/or pain. Of these screen-positive patients, 760 (93%) were successfully contacted by telephone, of whom 203 were ineligible (most often because of symptoms that did not reach severity thresholds), 299 refused, and 163 were enrolled. Reasons that patients refused included lack of interest in trial participation (n=176), the belief their symptoms were not cancer-related (n=35), too sick (n = 30), too busy (n = 21), or other reasons (n = 36). Conclusions: INCPAD demonstrates the feasibility of enrolling cancer patients from multiple geographically-dispersed practices and providing centralized symptom care management. The fact that two-thirds of eligible patients still refuse to participate in a relatively “low burden” trial focused on alleviating bothersome symptoms and conducted almost exclusively by telephone highlights the need for additional strategies to facilitate enrollment in cancer trials. In particular, specific approaches to overcome low enthusiasm for trial participation need to be developed.

No significant financial relationships to disclose.
Inpatient chemotherapy and risk for venous thromboembolism
Authors: Sousou T. , Khorana A.
Published: March 2020

9092

Background: Chemotherapy is a known risk factor for venous thromboembolism (VTE) but contemporary rates and risk factors for chemotherapy-associated VTE are not well described. Furthermore, it is linked to increased hospital length of stay and has negative impact on patient quality of life (QOL). Methods: We used discharge codes to identify all patients admitted to the University of Rochester Medical Center in Rochester, NY from January, 2000 through December, 2005 for chemotherapy and conducted a retrospective chart review to identify those that developed VTE. Inclusion criteria consisted of patients with a malignancy, age greater than eighteen years and no prior history of VTE. VTE was defined as any deep venous thrombosis (DVT) or pulmonary embolism (PE) occurring within 4 weeks of receiving inpatient chemotherapy. Results: A total of 659 patients were admitted for inpatient chemotherapy during the study period. Fifty-four patients developed a DVT and 14 patients developed a PE for a total VTE rate of 9.6%. Median time to developing VTE was 12 days (range, 1 to 28 days). Common sites of cancer among patients who developed VTE included lymphoma (36%) followed by leukemia (28%), multiple myeloma (13%) and gastrointestinal malignancies (8%) among others. Fifteen patients (23%) had stage IV disease. Twelve patients (18%) had a pre-chemotherapy platelet count greater than 350,000/mm3, a known risk factor for chemotherapy-associated VTE. Conclusions: VTE is common in patients receiving chemotherapy, including those with hematologic malignancies and can have significant impacts on patient QOL. The risk for VTE extends beyond the period of inpatient hospitalization. Increased efforts to improve compliance with thromboprophylaxis are warranted to reduce the burden of VTE among cancer patients receiving inpatient chemotherapy.

No significant financial relationships to disclose.
Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity
Authors: Pace A. , Carpano S. , Galiè E. , Savarese A. , Della Giulia M. , Aschelter A. , Silvani A. , Di Lauro L. , Jandolo B. , Cognetti F.
Published: March 2020

9114

Background: Peripheral neurotoxicity is a well recognized effect of cisplatin chemotherapy that can result in severe disability and represents a major dose-limiting factor. Several phase II studies have recently investigated the role of vitamin E as neuroprotectant in the prevention of cisplatin induced peripheral neurotoxicity and ototoxicity. Methods: An Italian randomized, placebo controlled, double blind multicentric study is ongoing to confirm the role of vitamin E supplementation in the prevention of neurotoxicity and ototoxicity induced by cisplatin Patients candidates to cisplatin chemotherapy were randomised to either vitamin E supplementation (a-tocopherol 400 mg/day) or to placebo. Patients were evaluated with neurological and neurophysiological examination before and after treatment. Neurotoxicity was measured using the comprehensive clinical and neurophysiological Total Neuropathy Score (TNS). Ototoxicity was evaluated with audiometric test and acoustic evoked potential before and after treatment. Results: 81 patients have been enrolled in 3 italian oncologic centers. An interim analysis on the first 50 patients was carried out. 25 patients (11 in the vit E group and 14 in the placebo group) received a cumulative dose higher than 300 mg/mq and were evaluable for neurotoxicity. Statistical analysis showed a significant difference (p < 0.05) in median neurotoxicity score observed in vit E group (TNS=1) respect to the placebo group (TNS=5). Conclusions: This is the first randomised, placebo controlled, double blind trial exploring the efficacy of vitamin E in the neuroprotection of cisplatin neurotoxicity. The results of this study confirm the neuroprotective effect of vitamin E supplementation against cisplatin-induced neurotoxicity.

No significant financial relationships to disclose.
Effect of chemotherapy on exercise capacity in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Kasymjanova G. , Kreisman H. , Pepe C. , Lajeunesse L. , Gagne S. , Dajczman E. , Pierre D. St. , Agulnik J. , Small D.
Published: March 2020

9115

Background: The 6 minute walking distance (6MW) is commonly used to evaluate cardiopulmonary exercise capacity in a variety of patient (pt) populations. Although the 6MW test improved in advanced breast cancer pts who responded to 2 cycles of chemotherapy, (Nieman et al 1995), little is known about exercise capacity of pts with inoperable lung cancer. We prospectively evaluated 6MW in advanced NSCLC pts at diagnosis and following 2 cycles of chemotherapy (CT). Methods: 6MW was performed twice pre (one practice test) and once post 2 cycles of CT. Intent to treat (ITT) analysis was performed in pts who did not complete the last walk. A score of 0 was assigned to those who died and the last observation was carried forward for those with missing data. Results: 59 pts were enrolled though 6 pts withdrew following the practice test due to clinical deterioration (2 pts), pulmonary embolism (1pt), leg pain following the practice walk (1 pt) and withdrawal of consent (2 pts). The mean age of the remaining 53 pts was 61 ±11, PS was 0–1 in 46 (87%) and 2 in 7 (13%) of pts. 8 pts (15%) were stage 3A/3B and 45 (85%) were stage 3B /4 NSCLC. 45 (85%) pts received platinum-based doublets, whereas 8 (15%) had monotherapy. 39 pts completed the study and 14 pts did not complete the second evaluation (4 died, 8 withdrew due to worsening symptoms and 2 were lost for follow-up). The practice 6MW of the 20 pts who dropped out was 361±99 m compared to 448± 93m for the 39 who completed the study (p=0.002). The 6MW decreased from 461±108 m (range 247–748) to 431±98 (range 431–630) in the 39 pts who completed the study (p=0.02) and from 444±106 to 395±107 in the 53 pts using the ITT analysis (p<0.003). There was a clinically significant (>54 m) decrease in 6MW in 11 pts (28%), an increase in 6MW in 2 pts (5%), and no change in 26 (67%) others. The 6MW was higher in men and in pts in stages 3A/B (p<0.05). Conclusions: Exercise capacity, measured by 6MW, declines significantly after two cycles of chemotherapy. This decline may have been underestimated as pts with lower 6MW were more likely to drop out of the study.

No significant financial relationships to disclose.
Phase I/II study of percutaneous vertebroplasty (PVP) for painful malignant vertebral compression fracture(PMVCF): JIVROSG- 0202
Authors: Arai Y. ,   Japan Interventional Radiology in Oncology Study Group (JIVROSG), Kobayashi K. , Takeuchi Y. , Nakajima Y. , Shioyama Y. , Sone M. , Tanigawa N. , Matsui O. , Kadoya M. , Inaba Y.
Published: March 2020

9118

Backgrounds: This multi-center prospective study was conducted to evaluate the safety and efficacy of PVP, a new treatment modality for PMVCF, using techniques of interventional radiology. Methods: Enrolled patients (pts) had PMVCF by primary or metastatic tumor; restricted activities by PMVCF; tumor not exposed into spinal canal; adequate hematologic, hepatic, renal and cardiac functions; 0–3 ECOG performance status (PS); estimated prognosis over 4 weeks; and written consent. In phase I, 9 pts were enrolled; in phase II, 24 pts. Safety and efficacy were evaluated by NCI-CTC Ver. 2 and Visual Analogue Scale (VAS) at week 1 after PVP, respectively. By VAS score decreases, efficacy was classified into significantly effective (SE: =5 or reached 0–2), moderately effective (ME: 2–4), or not effective (NE: <2 or increase). Response rate was the ratio of pts with SE or ME in total pts. PVP was performed by insertion of 14–16 G bone biopsy needle into fractured vertebral body (FVB) using fluoroscopy or CT guidance, injection of bone cement (BC) under real time imaging observation, and discontinuation of BC injection at its distribution to adequate area of FVB or into extra bone space. Results: Procedures were completed in all 33 patients with 42 PMVCF. PS of pts was 0 in 1, 1 in 7, 2 in 12 and 3 in 13. In 30 days after PVP, 2 patients died of primary disease progression, but no major adverse reaction (>Grade 2) was observed. Response rate was 73% (56–85% in 95% CI) (61% (n=20) with SE; 12% (n=4) with ME; 27% (n=9) with NE), and increased to 83% at week 4. Median to PVP effect was 1 day (mean: 2.4). Median pain controlled survival was 73 days. Conclusion: For PMVCF, PVP is a safe and effective treatment modality with immediate responses. A phase III trial comparing PVP and standard radiation therapy is planned to evaluate PVP as the front line treatment.

No significant financial relationships to disclose.
Ostarine increases lean body mass and improves physical performance in healthy elderly subjects: Implications for cancer cachexia patients
Authors: Evans W. , Smith M. R. , Morley J. E. , Barnette K. G. , Rodriguez D. , Steiner M. S. , Dalton J. T.
Published: March 2020

9119

Background: Cancer cachexia results in selective loss of skeletal muscle resulting in weakness, reduced physical activity and a lower quality of life. Cancer cachexia also diminishes response to chemotherapy and survival. Anabolic steroids appear to increase weight and muscle mass in cancer patients, but have the potential for masculinization in women and prostate stimulation in men. A new class of non-steroidal selective androgen receptor modulators (SARMs) is being developed for use in cancer cachexia. SARMs are designed to have predominately anabolic activity in muscle and bone with minimal androgenic effects in most other tissues. We conducted a randomized phase II proof of concept study of ostarine, the first-in-class SARM, in healthy postmenopausal women and elderly men prior to intitiating a phase II study in cancer patients. Methods: Sixty elderly men (mean age 66 years) and 60 postmenopausal women (mean age 63 years) were randomly assigned to ostarine 0.1, 0.3, 1 mg, 3 mg or placebo for three months. The primary end point was change from baseline to three months in total lean body mass (LBM) measured by dual energy x-ray absorptiometry (DXA). The key secondary end point was a stair climb functional performance test that measured speed and power exerted. Evaluations included laboratory safety assessments and additional assessments of androgenic activity including PSA, sebum production and luteinizing hormone. Results: Ostarine treatment resulted in a dose dependent increase in total LBM, with an increase of 1.4 kg compared to placebo (p<0.001) at the 3 mg dose. Increased LBM translated to an improvement in the stair climb test in both speed (+15.5% ± 12.9 faster time, p=0.006) and power (+25.5% ± 20.3 watts, p=0.005). There were no serious adverse events reported. There were no significant changes in PSA, sebum production or luteinizing hormone. Conclusions: Ostarine improves LBM and physical performance in healthy older men and women. Ostarine had no unwanted androgenic side effects. A phase II study is planned to evaluate the safety and efficacy of ostarine in patients with cancer cachexia.

No significant financial relationships to disclose.
Predictors of febrile neutropenia among Medicare patients with breast, lung and colorectal cancer
Authors: Hosmer W. D. , Wong M. D. , Malin J. L.
Published: March 2020

9120

Background: Neutropenia and associated impaired immunity is the major dose limiting toxicity for systemic chemotherapy administration. Current guidelines recommend the prophylactic use of G-CSF when the risk of febrile neutropenia (FN) is approximately 20% because it decreases the duration and risk of FN. Advanced age has been identified as a risk factor for FN; however, little is known about the impact of other factors on the incidence of FN in the elderly. Methods: We analyzed SEER-Medicare data on patients diagnosed between 1995 and 2000 with breast, colorectal, and lung cancer, who received chemotherapy within 11 months of diagnosis. We examined a number of factors that might potentially be associated with FN in the first cycle of chemotherapy, including patient demographics, cancer stage at diagnosis, number of myelosupressive chemotherapeutics, frequency of chemotherapy administration, and comorbid conditions, including previous history of anemia and other blood disorders. Outcome was defined as admission to hospital within 30 days of initial chemotherapy administration with neutropenia (ICD9 288.0) coded as an admission diagnosis. Results: Of 18,637 patients who met inclusion criteria 751 (4.0%) had an episode of FN within 30 days of initial chemotherapy administration. In multivariate logistic regression analysis, independent predictors of FN included cancer type (lung cancer, OR 3.77, CI: 1.02–13.9, as compared to breast cancer) and history of blood disorder (OR 1.49, CI: 1.10–2.0), with a trend towards history of COPD (OR 1.19, CI: 0.98–1.44) and three or more myelosupressive agents (OR 4.01, CI: 0.76–21.2, as compared to non-myelosupressive chemotherapy). Initiating chemotherapy less than 1 month after cancer diagnosis was also associated with a higher odds of developing FN (OR 1.88, CI:1.42–2.49 compared to 3 months or more after diagnosis). Discussion: By utilizing the SEER-Medicare dataset we were able to examine predictors of febrile neutropenia in a large population of elderly patients with common malignancies. Knowledge of predisposing factors for neutropenia will allow more tailored prophylactic use of G-CSF in this at-risk population.

No significant financial relationships to disclose.
Secondary vs. primary cachexia in patients with advanced cancer
Authors: Del Fabbro E. , Dalal S. , Delgado M. , Freer G. , Bruera E.
Published: March 2020

9128

Background: Cachexia results in decreased survival and adherence to chemotherapy, and increased treatment toxicity. Primary Cachexia (PC) is characterized by weight loss, anorexia and fatigue and it is the result of tumor-host interactions producing neurohormonal dysfunction and an aberrant pro-inflammatory response. The clinical effects of PC may be exacerbated by complications capable of decreasing energy intake (Secondary Cachexia) such as dysgeusia, anxiety, depression, pain, early satiety, nausea and constipation. The objective of this study was to determine the causes and the frequency of secondary cachexia (SC) in a cohort of patients with PC. Methods: We reviewed the charts of 50 consecutive advanced cancer patients who underwent a structured assessment in a specialized cachexia clinic at a comprehensive cancer center. Results: All patients gathered criteria for cachexia, including a weight loss of >5% within the preceding 6 months. The most frequent causes of SC were early satiety in 40 patients(80%), constipation in 37(74%), depression or anxiety in 30(60%), uncontrolled pain in 31(62%), chronic nausea in 21(42%), dysgeusia in 14(28%),dental problems in 4(8%), dysphagia in 3(6%)chronic aspiration in 2 (4%) and oral candidiasis in 1 (2%).All 50 patients presented with at least 2 secondary causes of cachexia, and 44(88%) presented with = 3. The median number of causes of secondary cachexia was 4 (range 2–5). 211 interventions were used in these patients to treat secondary causes of cachexia. 14(28%) of the patients referred were already on a medication for appetite stimulation (megestrol acetate, dronabinol, corticosteroids). Conclusions: SC should be ruled out in all patients who have PC since the vast majority of patients referred to a cachexia clinic have 2 or more causes of SC. All cancer patients with involuntary weight loss in our series had “mixed cachexia”. Inexpensive effective treatments are available for most of the causes of SC, but they are frequently underused.

No significant financial relationships to disclose.
Hearing loss in children with osteosarcoma
Authors: Lewis M. , DuBois S. , Fligor B. , Goorin A. , Grier H.
Published: March 2020

9517

Background: Cisplatin is one of the most effective agents against osteosarcoma. Cisplatin is usually administered as a short IV infusion in most contemporary North American osteosarcoma treatment protocols. Ototoxicity from such protocols has not been well defined. The aim of this study was to determine the incidence and the risk factors for hearing loss in children with osteosarcoma. Methods: Eligible patients (pts) in this retrospective cohort study had osteosarcoma diagnosed and treated at our center from 1/1/1995 to 12/31/2004, were 3–18 years of age at diagnosis, and had a normal audiogram prior to the start of chemotherapy. All pts received cisplatin according to either standard practice or current open protocol. Most regimens prescribed a cumulative dose of 480 mg/m2 over 4 cycles. Pts with hearing loss at lower doses had cisplatin held on an individualized basis. Hearing was evaluated using pure-tone audiometry prior to the start of therapy, before each cycle of cisplatin administration, and off-therapy. The primary endpoint was any hearing loss as defined as > 20 dB decrease in hearing above 4,000 Hz. Fisher's exact test and logistic regression methods were used to identify univariate and independent predictors of hearing loss, respectively. Results: The incidence of hearing loss was 16/40 (40%). Six pts discontinued cisplatin early due to hearing loss. Seven of 9 pts (77.8%) who received cisplatin 120 mg/m2 as a short IV infusion on 1 day developed hearing loss compared to 9 of 31 (29.0%) pts who received this same dose as two daily infusions (p=0.018). On univariate analyses, age and cumulative cisplatin dose were not predictive of hearing loss. Logistic regression controlling for age, sex, race, and cumulative dose showed that administration of cisplatin 120 mg/m2 on 1 day compared to 2 days was an independent predictor of hearing loss (odds ratio of 11.6, 95% confidence interval = 1.62–82.87). Conclusions: Cisplatin given as 120 mg/m2/dose on 1 day was associated with greater risk of hearing loss than 60 mg/m2/dose on 2 days. Cumulative dose and age were not found to be predictors of hearing loss in this relatively small cohort.

No significant financial relationships to disclose.
Phase Ib/IIa study of sustained release lipid inhalation targeting cisplatin by inhalation in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung
Authors: Chou A. J. , Bell M. D. , Mackinson C. , Gupta R. , Meyers P. A. , Gorlick R.
Published: March 2020

9525

Background: Pulmonary relapse is the most common site of relapse for patients with osteosarcoma (OS). Few therapeutic options are available for these patients. By encapsulating the drug within liposomes, sustained release lipid inhalation targeting (SLIT) cisplatin is a novel sustained-release formulation of cisplatin designed for administration via inhalation, thereby targeting the lungs with little systemic exposure. Methods: A two-center, open-label, phase Ib/IIa study was designed to characterize the safety and efficacy of SLIT cisplatin in patients with OS metastatic to the lung. Two dose levels were utilized: 24 mg/m2/dose, and 36 mg/m2/dose. Study drug was administered via nebulizer once every two weeks. OS patients with only pulmonary relapse were eligible. Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Response was evaluated radiographically according to the World Health Organization criteria after every 2 cycles. When clinically indicated, metastasectomy was undertaken in patients on study after 2 cycles, and levels of SLIT cisplatin were measured in tumor samples upon metastasectomy. Results: Fourteen patients have been treated on study. SLIT cisplatin has been well tolerated in heavily pre-treated patients who have received multiple cycles of therapy, including one patient, approaching cumulative doses of 840 mg of SLIT cisplatin over one year and a second patient receiving 1,020 mg. Specifically, no patients have experienced hematologic toxicity, nephrotoxicity or peripheral neuropathy. Nausea (= grade 3) was attributed to study drug in 5 patients. Respiratory symptoms (= grade 3) were attributable to study drug in 4 patients. No adverse events required discontinuation of study drug. Two patients are pulmonary disease free one year after initiation of therapy. Conclusions: SLIT cisplatin is well tolerated in patients with pulmonary relapse of OS. Two of 14 patients are pulmonary disease free one year after initiation of therapy. SLIT cisplatin provides a novel therapeutic modality for patients with pulmonary relapse of OS, and warrants further study.

No significant financial relationships to disclose.
Vancomycin-resistant enterococcus (VRE) in pediatric oncology patients: An analysis of potential consequences of colonization and infection
Authors: Dunkel I. J. , Kosack A. , Riedel E. , Kiehn T. E. , Small T. N. , Wexler L. H.
Published: March 2020

9537

Background: VRE colonization and infection have emerged as an issue for pediatric oncology patients, but little is known about the long-term risks following initial VRE positivity in this population. The purpose of this study was to determine the risk of subsequent VRE infection in colonized or infected pediatric oncology patients and to try to identify risk factors. Methods: A retrospective analysis was performed of the 57 pediatric oncology patients who had a positive VRE culture at MSKCC from 1996–2000 and subsequently received chemotherapy and/or radiation therapy. Patients whose only subsequent treatment was allogeneic stem cell transplantation were excluded. The incidence of subsequent VRE infection was calculated using a competing risk analysis accounting for death from non-VRE causes as a competing risk. Data regarding hypothesized risk factors for subsequent VRE infections were collected. Results: Ten of the 57 patients had subsequent VRE infection, but none was the primary cause of death. The cumulative incidence of subsequent infection was 14% (7–27%, 95% confidence interval) at 1 year and 16% (9–29%, 95% confidence interval) at 2 years. Eight developed their subsequent infection within 3 months; the other 2 occurred at 15 and 30 months. A formal analysis of risk factors was not attempted due to the small number of events; however, none of the hypothesized risk factors (initial VRE colonization versus infection, number of chemotherapy or radiation therapy regimens, number of neutropenic or mucositis episodes, number of hospitalizations, number of abdominal surgeries or stem cell transplantations) appeared to differ between those who developed a subsequent infection and those who did not. Conclusions: Pediatric oncology patients with VRE colonization or initial infection are at risk for subsequent VRE infection, particularly within the first 3 months of initial diagnosis of VRE positivity.

No significant financial relationships to disclose.
Cloning and characterization of the sympathetic nervous system mutant, Sym3, in zebrafish
Authors: George R. , Lee J. , Stewart R. , Bayul T. , Campisi N. , Olale F. , Schier A. , Kanki J. , Look A. T.
Published: March 2020

9541

Background: Neuroblastoma (NB) is a neural crest tumor manifesting in the adrenal gland and the sympathetic ganglia. The goal of this project was to use the zebrafish model to identify genes involved in the development of the peripheral sympathetic nervous system (PSNS). We used the expression of tyrosine hydroxylase (TH) in the cervical sympathetic ganglion (cervical complex, CC), as a marker for PSNS development. TH expression can be observed by whole-mount RNA in situ hybridization in 2–3-day zebrafish embryos in the CC. Methods: In an ethyl nitrosourea mutagenesis screen for mutations that affect PSNS development, we identified a putative mutant, Sym3, showing a change in modeling of the TH staining cells in the region of the CC. Results and Conclusion: The TH-positive cells were scattered rather than conglomerated together as is typical of cells in the normal CC. The mutant was also characterized by a “curly-tail” phenotype. After the mutation was recovered from the F3 generation, heterozygous pairs harboring the mutation were identified. Using genome wide scanning PCR assay, linkage of the Sym3 mutation to microsatellite markers z9704 and z1351, located on Linkage Group 1, was established. Complementation assays were performed with other known “curly tail” mutants in the genetic interval, which revealed that Sym3 and a previously described vic mutant were in the same complementation group. The vic mutant is characterized by curved body axis, left to right asymmetry and kidney cysts and results from a mutation in the ARL13b gene, a protein of the Ras superfamily involved in intracellular trafficking and cilial motility. The vic mutation is a C to A transition at position 104 in the second exon of the open reading frame (T35L). The ARL13b gene in Sym3 has a four aa insertion at the 5’ end of the 4th exon of the coding region.The mutant Sym3 phenotype can be rescued by overexpression of the normal ARL13b gene. The vic mutant showed defective cilia formation in the kidney. However, immunocytochemistry showed normal cilia in the Sym3 mutant, suggesting that the Sym3 allele of ARL13b affects the development of alternative tissues during development, such as the aggregation of sympathetic neurons into discrete ganglia. Further functional characterization of the Sym3 mutation is ongoing.

No significant financial relationships to disclose.
Long-term complications of neuroblastoma: A report from the Childhood Cancer Survivor Study
Authors: Laverdiere C. , Liu Q. , Yasui Y. , Nathan P. C. , Gurney J. , Stovall M. , Diller L. , Cheung N. K. , Wolden S. , Robison L. L. , Sklar C. A.
Published: March 2020

9544

Background: Neuroblastoma (NB) survivors can develop many complications from their treatment. We evaluated long-term morbidity and mortality in a large cohort of NB survivors. Procedures: Late effects data from 5-year NB survivors diagnosed between 1970–1986 enrolled in the Childhood Cancer Survivor Study (CCSS) were collected from self-administered questionnaires. 832 survivors and 3,899 siblings were included. Treatment data were abstracted from the medical records of all survivors. Late mortality, second malignant neoplasm (SMN), and chronic health conditions were analyzed in relation to treatment factors. Results: 42 survivors (6%) died more than 5 years after their diagnosis (standardized mortality ratio [SMR]:4.8; 95% CI 3.5–6.5). Causes of death included: disease recurrence (n=23), SMN (n=6) (SMR: 8.5; 95% CI 3.1–18.4), cardiac (n=1) (SMR 2.9; 95% CI 0.04–16.0), pulmonary (n=1) (SMR 4.8; 95% CI 0.1–26.5), external causes (n=4), other and unknown (n=11). 33 developed a SMN (standardized incidence ratio [SIR] 8.6; 95% CI 5.9–12.1): thyroid (n=7), renal (n=6), soft tissue sarcomas (n=3), acute myeloid leukemia (n=2), breast cancer (n=2) and other (n=13). Exposure to radiation therapy (RT) (p=0.003) and to VP-16 (p=0.04) were significant risk factors for SMN. 38% of the survivors reported at least one chronic health condition. Compared to siblings, they were more likely to report any chronic condition (risk ratio [RR] 14.7; 95% CI, 12.4–17.6). The most common prevalent conditions included: musculoskeletal (RR 49.8; 95% CI, 27.9–88.8), endocrine (RR 36.2; 95%CI 24.1–54.5), sensory (RR 21.5; 95%CI, 14.6–31.7) and neurological (RR 13.1; 95% CI 10.8–16). A multivariable Poisson regression analysis revealed the following associations: laminectomy (RR 8.6; 95% CI 3.5- 21) and chest RT (RR 2.8; 95% CI 1.3–6.5) as risk factors for scoliosis; age < 1 year at diagnosis (RR 1.9; 95% CI 1.4–2.6) and laminectomy (RR 3.5; 95% CI 2.4–5.3) for neurological complications; for hearing loss, increasing cumulative dose of cisplatin (for ≥ 600 mg/m2 RR 52.8; 95% CI 10.2–272.5); and RT to the neck (RR 6.6; 95% CI 2.4–18) for hypothyroidism. Conclusions: NB survivors are at risk of developing chronic conditions. Long-term surveillance is required for early detection of these complications.

No significant financial relationships to disclose.
Both age and location predict survival in childhood ependymoma: A SEER study
Authors: McGuire C. S. , Cobb K. L. , Fisher P. G.
Published: March 2020

9545

Background: Supratentorial (SUP) ependymoma in childhood has been reported in studies with limited samples to carry improved overall survival (OS) compared to infratentorial (INF) tumors, with spinal (SPI) ependymoma having the best outcome. Moreover, radiation therapy (XRT) for INF tumors has been considered standard of care, though there have been case reports of children treated successfully without XRT. Thus, we aimed to examine how age, gender, location, XRT and race influence OS in childhood ependymoma by rigorous analysis of a large registry. Methods: We queried the Surveillance Epidemiology End Results (SEER) registry from 1973 to 2003, strictly defining ependymomas by histology (ICD-O-3: 9391–9394). ICD-0–2 site codes, when available, were used to distinguish SUP, INF, and SPI tumors. OS was compared by age, gender, race, location, and XRT, using Kaplan-Meier analysis with logrank tests in SPSS 12.0 (Chicago, IL). Cox regression incorporated all significant covariates from univariate analysis. A similar analysis was conducted to determine whether findings differed in adults. Results: 635 children <18 years at diagnosis were identified (265 females; 510 whites, 77 blacks; 106 SUP, 193 INF, 55 SPI) with 5-year OS 57.1% ± standard error 2.3%. With univariate analysis, OS did not differ by gender or race. For location, 5-year OS did not differ between SUP 59.5% ± 5.4% and INF 57.1% ± 4.1%, but was significantly better for SPI 86.7% ± 5.2%. With multivariate analysis, location and age remained significant predictors for OS, with younger children having worse outcome. A similar multivariate analysis in 1388 adults again showed age and location to be significant. Adults fared better than children (logrank p <0.0001). XRT of INF tumors was associated with significantly improved OS in children (logrank p <0.018), but did not lead to an OS difference among adults. Conclusions: Age and location directly influence OS in childhood ependymoma. SPI tumors are associated with a significantly better prognosis than other ependymomas. This study could not show a difference in OS between SUP and INF tumors, proposed recently to have different stem cell origins. SPI tumors may represent a distinct biological entity. Curiously, XRT is associated with improved OS in pediatric, but not adult, INF ependymomas.

No significant financial relationships to disclose.
Characteristics and outcome of patients (pts) enrolled on phase I trials: A report from the Pediatric Oncology Branch, NCI
Authors: Kim A. , Fox E. , Warren K. , Blaney S. , Berg S. , Adamson P. , Libucha M. , Byrley E. , Balis F. , Widemann B.
Published: March 2020

9550

Background: Knowledge of the characteristics and outcomes of pts enrolled on pediatric phase I trials may aid in the design of future phase I trials and selection of pts. Methods: Pre-enrollment characteristics and treatment outcomes (toxicity, response, survival) were retrospectively analyzed from pts with refractory solid tumors enrolled in 16 phase I trials with similar eligibility criteria from 1992 to 2005. The relationship between patient characteristics and dose-limiting toxicity (DLT) was evaluated using multivariate analysis. Results: Of 262 pts (62% M, 38% F) eligible for analysis, 147 were on trials of myelosuppressive drugs (MS) and 115 were enrolled on trials of non-MS. 50 pts (19%) participated in =2 separate trials. Median (range) or (frequency) entry characteristics were: age 13.5 yrs (1–24); ECOG performance score 0 (30%), 1 (50%), 2 (19%); prior regimens 2 (0–9); prior stem cell transplant (20%); prior radiation (66%); concomitant medications 1 (0–12); and presence of metastatic disease (65%). 94% of pts were evaluable for the primary trial outcome, and 92% participated in pharmacokinetic (PK) studies. 17% of pts had grade 3 as their highest-grade toxicity. 22% of pts had grade 4 as their highest-grade toxicity, of which 91% were hematological. DLT rate was 18%. 5% of pts came off study due to toxicity, and treatment related death occurred in 0.3%. Age, prior radiation, medications, prior regimens, performance status, gender, transplant history, and drug dose expressed as a fraction of the maximum tolerated dose were included in the multivariate analysis. Only drug dose (OR 14.2, 95% CI 3.0–67.8) and prior radiation (OR 3.4, 95% CI 1.1–10.7) were statistically significantly associated with increased risk of developing DLT after adjusting for all other variables. The median number of cycles was 1 (range 0–31). Complete and partial response rate was 3%, however, 18% of pts had stable disease (received = 3 cycles). The median survival (Kaplan Meier analysis) from time of enrollment was 5 months. Conclusion: Standard phase I eligibility criteria selected a population of pts who tolerated the investigational agents well and >90% were evaluable for the toxicity and PK endpoints. Prior radiation was associated with a greater risk for DLT.

No significant financial relationships to disclose.
Long-term evaluation of ifosfamide-related nephrotoxicity in children: The French experience
Authors: Fawaz O. , Rey A. , Niaudet P. , Orbach D. , Bergeron C. , Gentet J. , Corradini N. , Munzer M. , Rubie H. , Oberlin O.
Published: March 2020

9551

Background: Ifosfamide-induced nephrotoxicity is a significant issue in patients treated for tumours during childhood. This study aimed at documenting incidence of late renal toxicity of ifosfamide and its risk factors. Methods: 183 patients have been investigated. 100 were male. Median age at treatment was 9.3 years (0.4–18 years). Median dose of ifosfamide was 54 g/m2 (18–77 g/m2). No patients received cisplatin and/or carboplatinum. Diagnoses included rhabdomyosarcoma (77), other soft tissue sarcoma (39), Ewing (39), and osteosarcoma (28). Investigations were performed at a median interval of 10.3 years (5–20.7) after the end of the treatment, at a median age of 21.6 years (7.1–44.2). No patient had electrolyte or vitamine supplementation. Glomerular and tubular functions were graded according to the Skinner's system. Results: After 5 year minimal follow-up 55% had normal tubular and 79% had normal glomerular functions. Natraemia, kalaemia, serum HCO3 and calcaemia were normal in all patients. Hypomagnesaemia was observed in 4, hypophosphaetemia in 8 %. The tubular threshold for phosphate was reduced in 44% of the patients (grade 2 or 3 in 15%, grade 3 in 1 pt). Significant glycosuria (> 0.5 g/24h) was detected in 5 % of the patients but it was clearly abnormal only in 5 patients. 34% of the patients had beta2 microglobulinuria, however, proteinuria was observed in only 12%. Cumulative dose of ifosfamide, older age at treatment and follow-up since treatment were predictor for tubulopathy in univariate and multivariate analyse. The glomerular filtration rate was normal in 79% of the patients. 21% had a grade 1 toxicity and 1 patient a grade 2. Univariate analysis did not find any prognostic factor for glomerular toxicity apart from the association with tubular toxicity. Conclusions: Since ifosfamide-induced renal toxicity can be severe, long term evaluation is important and this risk should be balanced carefully against efficacy.

No significant financial relationships to disclose.