FDG PET/CT for Evaluating Early Response to Neoadjuvant Chemotherapy in Pediatric Patients with Sarcoma: A Prospective Single-Center Trial

In aging societies like Japan, the number of elderly bone sarcoma (BS) and soft-tissue sarcoma (STS) patients is increasing. However, these malignancies' behavior is incompletely understood. We investigated clinical features, treatment modalities, survival, and prognostic factors for elderly BS and STS patients using Japan's National Cancer Registry (NCR). We identified data for 11,015 individuals ≥ 70 diagnosed with BS or STS in 2016-2019 by ICD-O-3 cancer topography and morphology codes and analyzed patient characteristics, disease information, initial diagnostic process, treatment, and prognosis. We analyzed 1072 BS cases and 9933 STS cases. There was no significant sex difference among BS or STS. The most common histological subtypes were chondrosarcoma (N = 310, 29%) and liposarcoma (N = 1533, 15%). Twelve percent of BS and 11% of STS patients had distant metastasis at first presentation. Forty-six percent of BS and 50% of STS patients underwent surgery. The number of patients > 80 who underwent surgery or had chemotherapy was significantly smaller than patients 70-79 (P < 0.001; P < 0.001). Three-year overall survival (OAS) was 46% among BS and 50% among STS patients. Adjusted analyses provided significant associations between OAS and age, histological subtype, treatment, and extent of disease in BS, and age, sex, histological subtype, tumor location, treatment, and extent of disease in STS. This study featured elderly BS and STS patients, presenting epidemiology, clinical characteristics, treatment, and oncological outcomes based on the NCR. It gives clinicians valuable information to develop treatments for elderly BS and STS patients for future aging societies.

e22544 Background: Sarcoma clinical guidelines often emphasize the evaluation of patients by an expert multidisciplinary team, and thus in many countries, care is centralized to treatment centers. However, there are no standard guidelines for referrals of sarcoma patients in Japan, and the overall picture of where and by whom they are treated has never been systematically investigated. Methods: We used hospital-based cancer registry and health claims data of sarcoma patients diagnosed in Japan in 2012 and 2013. We analyzed the distribution of patients across hospitals and the extent of centralization of care across treatment modality and cancer topography. Results: We identified 1032 bone and 7257 soft-tissue sarcoma (STS) patients who were newly diagnosed in 2012 and 2013. Bone sarcomas occurred in the limbs in 55% of the patients, with 73% treated by orthopedic surgeons. Care was weakly centralized to 9 high-volume hospitals ( > 10 new cases per year) and 120 hospitals with 1-9 new cases. Care was greatly decentralized for STS (particularly surgical care). STS patients were treated in 382 hospitals in total, including 272 hospitals with 1-9 new cases. The distribution of medical specialties depended heavily on cancer topography: 50% of STS occurred in connective tissues (among them, 70% were treated by orthopedic surgeons), 12% in the peritoneum and retroperitoneum (33% urologists, 38% general surgeons, 9% gynecologists), 11% in the uterus (95% gynecologists), and 8% in the skin (64% dermatologists and 23% plastic surgeons). Analysis of medical specialties administering chemotherapies to 318 connective tissue STS patients revealed that orthopedic surgeons provided neoadjuvant/adjuvant chemotherapies to much ( > 60%) of the patients. Conclusions: We found that sarcoma treatment is not only decentralized, but also uncoordinated across medical specialties in Japan due to its diverse cancer topography and lack of standard guidelines for referrals of sarcoma patients. Results of this study suggest the need to establish strategies to centralize patients, especially for STS, to treatment centers where they can be managed by a multidisciplinary team.

Fertility preservation in female sarcoma patients

Background: Cancer is a highly debilitating non-communicable disease and an essential contributor to the global burden of disease. Pediatric patients are highly exposed to multiple drugs for the management of cancer. Monitoring drug utilization patterns helps to provide feedback to healthcare providers to ensure the rational use of medicines; as a result, it increases the therapeutic efficacy and decreases the frequency and severity of adverse drug reactions (ADRs). Therefore, this study assessed the utilization pattern and ADRs of chemotherapy in pediatric patients at Muhimbili National Hospital (MNH). Methods: A descriptive cross-sectional study was conducted for three months from February to April 2021 in pediatric cancer patients undergoing chemotherapy at MNH. A total of 123 children diagnosed with cancer and on chemotherapy were enrolled in this study. Patients' socio-demographics, clinical information, chemotherapy status, prescribed medications, and prevalence of ADRs were collected. Descriptive statistics was used in data analysis, whereby frequency and proportions were used to summarize data. Results: Out of 123 patients, 62.6% were male. Most patients received an average of four anticancer drugs. Vincristine (55.3%) was the most used anticancer drug, followed by cytarabine (44.7%) and methotrexate (42.3%). The most used adjuvant drugs were ondansetron (30.9%), hydrocortisone (27.6%), and piperacillin/tazobactam (23.6%). The percentage of drugs prescribed from the Tanzania Essential Medicine List (TEML) and World Health Organization (WHO) list was 66.4% and 93%. Most (87%) of the patients reported having experienced ADRs whereby nausea and vomiting (45.8%), hair loss (33.6%), and neutropenia (32.7%) were more prevalent ADRs reported. Conclusions: This study found the drug prescribing pattern to be in line with the essential medicine list, but the average number of drugs prescribed was higher than recommended. ADRs were prevalent among pediatric cancer patients.

Faculty of 1000 evaluation for Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients.

背景与目的肺是骨与软组织肉瘤最常见的远隔转移脏器，肺转移严重影响患者长期生存。肺转移瘤切除术有助于改善预后，然而对其临床地位、适应证及预后影响因素的认识目前仍存在争议。由于发病率较低难以开展随机对照研究，同时国际单中心大宗病例回顾研究也极为罕见，国内尚无类似报道。本研究旨在回顾本组单中心大样本肺转移性骨与软组织肉瘤的外科治疗结果，并且对预后影响因素进行分析。方法2007年1月-2015年12月期间，经病理确诊为骨与软组织肉瘤，已在多学科综合治疗框架下完成原发病灶根治性切除，并且至少经过1次肺转移瘤切除术的所有患者均纳入分析。收集相关临床变量，运用Cox风险比例回归法进行单因素及多因素分析寻找与预后影响因素。结果144例骨与软组织肉瘤患者符合纳入标准，总共行155次肺转移瘤切除术。多因素分析结果提示非R0切除、无病间期 < 1年、肺转移灶数目≥3枚、肺转移灶的长径总和≥45 mm均是预后的独立危险因素。结论积极行肺转移瘤外科治疗有助于改善转移性骨与软组织肉瘤患者的长期预后。R0切除，无病间期时间较长，转移瘤数目较少及长径总和较小是本组患者良好的预后因素。

e15074 Background: CDK4/6 kinases associate with cyclin D proteins during transition from G1 to S phase of the cell cycle. Amplification of CDK4/6 may elicit the activity of cyclin D, which hyperphosphorylates RB, ultimately leading to uncontrolled cell proliferation. Currently, three CDK4/6 inhibitors are used in breast cancer, ovarian cancer and sarcoma. Herein, we investigate the prevalence of CDK4/6 amplification in Chinese and Western cancer patients, hope to find more cancer subtypes with CDK4/6 amplification. Methods: Next-generation sequencing data and clinical data were collected from 10828 TCGA pan-cancer patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 4181 Chinese pan-cancer patients (Chinese cohort). CDK4 and CDK6 amplification were calculated on the two cohorts following the same criteria. Results: In total, 182 (4.4%) of the 4181 Chinese patients and 529 (4.9%) of the 10828 Western patients had CDK4 amplification, 133 (3.2%) of the 4181 Chinese patients and 475 (4.4%) of the 10828 Western patients had CDK6 amplification. In Western cohort, the top 5 CDK4 amplification-associated cancer types were sarcoma, glioblastoma multiforme, lung adenocarcinoma, ovarian carcinoma, and adrenocortical carcinoma, and the top 5 CDK6 amplification-associated cancer types were esophageal carcinoma, ovarian carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, sarcoma. In Chinese cohort, the top 5 CDK4 amplification-associated cancer types were lung adenocarcinoma, melanoma, sarcoma, stomach carcinoma, liver cancer, and the top 5 CDK6 amplification-associated cancer types were lung adenocarcinoma, stomach carcinoma, liver cancer, melanoma, glioma. In addition, CDK4 amplification in Chinese cohort, 22 (11%) of the 203 Chinese bone and soft tissue sarcoma patients had CDK4 amplification, and 4 (2%) of the 203 had CDK6 amplification. Bone and soft tissue sarcoma types with CDK4 / 6 amplification including soft tissue sarcoma, bone cancer, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, synovial sarcoma. Conclusions: Our study provided a characteristic of CDK4/6 amplification in Chinese and Western pan-cancer patients. Analysis revealed frequent CDK4 / 6 amplification in lung cancer, sarcoma, stomach carcinoma, ovarian carcinoma and liver cancer. It is suggested patient with these cancer types may potentially benefit from CDK4/6 inhibitor.

Introduction Sarcomas of bone and soft tissue are rare neoplasms with diverse histology and biologic behavior. Approximately 6,600 new cases of soft-tissue sarcoma and 2,500 new cases of bone sarcoma present each year.1 Most of these tumors develop in the extremities. An increased understanding of sarcoma biology, advances in diagnostic imaging modalities, the development of effective adjuvant therapy regimens, and the application of new technologies and techniques for surgical resection and reconstruction have changed the nature and scope of treatment for these tumors. These advances have helped shape current surgical strategies and have prompted an increase in technically demanding limb-sparing surgical procedures. Successful limb conservation preserves, repairs, or reconstructs critical structures necessary for limb function without compromising the oncologic objective of complete tumor extirpation. Because of several factors, the number of patients who are candidates for limb conservation is increasing without a significant increase in the risk of local tumor recurrence or an adverse effect on overall patient survival.2-4 The factors causing this result include refinements in diagnostic and extirpative approaches, improvements in bone and joint reconstruction, and better techniques for coverage of soft-tissue defects. These developments have prompted a critical evaluation of the variables affecting limb preservation, functional outcome, and quality of life for the sarcoma survivor. This report discusses the strategies used at The University of Texas M.D. Anderson Cancer Center to improve the quality of life for patients diagnosed with these complex extremity tumors. Four case examples illustrate the range of clinical challenges confronting the sarcoma oncology team as members try to attain a better patient outcome using multimodality therapy and limb-sparing surgery.

Background: It is a common practice in oncology in general and musculoskeletal oncology that the biopsy tract must be resected together with the tumor while performing limb-sparing surgery. Our study aims to assess the need for routine excision of biopsy scars in musculoskeletal malignancies by analyzing the presence of tumor in the biopsy tracts. Methods: We conducted a prospective study from January 2021 to April 2023, including 48 soft tissue and bone sarcoma patients. Neoadjuvant chemotherapy was administered to all cases of Ewings sarcoma and osteosarcoma. All of them underwent surgical resection with appropriate reconstruction. Biopsy tracts were sent separately and analyzed for tumor infiltration. Results: Two of the 48 patients included in the study had tumor deposits in their biopsy tracts. One patient with undifferentiated pleomorphic sarcoma and another patient with high-grade myxoid liposarcoma had tumor seeding in their biopsy tracts. Conclusions: The rate of biopsy tract seeding in our study was 4.2% (2 out of 48). Even though this might seem very less, it is still significant considering the rarity of bone and soft tissue sarcomas. Despite the low risk of tumor seeding, it is advisable to continue routinely excising the biopsy tract. Whether inappropriately placed biopsy tracts warrant an amputation instead of limb salvage is a question that will be best answered in the future with large-scale prospective randomized studies.

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or &gt; 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC &lt; 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR &lt; 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.

Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.

Retinoblastoma is a childhood malignancy of the retina. To increase the exposures of systemic chemotherapy, high-dose cyclosporine, as a P-glycoprotein modulating agent, has been combined with a standard chemotherapy. However, the effective and safe dose of cyclosporine has not been well evaluated. This study is to optimize cyclosporine dose using population pharmacokinetic modeling. Clinical data were obtained from 161 systemic chemotherapy cycles of 34 pediatric retinoblastoma patients between December 2006 and April 2015. Total 15 scenarios were simulated by 5 different doses (12, 14, 15, 17, and 20 mg/kg) of cyclosporine in 3 different weight groups (5-10, 10-15, and 15-20 kg). Numerical success ratio was obtained after assessing the simulated target cyclosporine concentration in the range of 2,000-2,500 ng/mL using NONMEM version 7.3 software. A final model was built based on a 1-compartment model with weight-normalized allometric scaling to minimize the variability of pediatric size. In simulations, numeric success ratio with 15 mg/kg/day and the above were higher than that of traditional doses in all of the scenario groups. No significant adverse responses were reported. Conclusion and Relevance: High-dose cyclosporine regimen as a P-gp modulator is required to improve the efficacy of systemic chemotherapy with caution in pediatric patients with retinoblastoma. Clearance, volume of distribution, and body weight are important parameters to consider in selecting adequate dosing regimen.

Obesity correlates with adverse events (AEs) in children with acute myelogenous leukemia and during maintenance therapy for acute lymphoblastic leukemia (ALL). Less is known about AEs in obese ALL patients during pre-maintenance chemotherapy. We evaluated the relationship between obesity (body mass index (BMI) ≥ 95th percentile) and AEs during pre-maintenance chemotherapy in pediatric patients with ALL. One hundred fifty-five pediatric ALL patients diagnosed at a single institution between 2006 and 2012 were retrospectively evaluated for infections, treatment-requiring hypertension, insulin-requiring hyperglycemia, pancreatitis, pediatric intensive care unit admissions, sepsis, febrile neutropenia (FN) admissions, thrombosis, hepatotoxicity, and nephrotoxicity. Univariate and multivariable analyses compared proportions of obese versus nonobese patients experiencing AEs. AEs occurring significantly more frequently in obese patients by univariate analysis included treatment-requiring hypertension (17.5% vs 6.1%; OR, 3.27; 95% CI, 1.1-10.0, P=0.0497) and insulin-requiring hyperglycemia (25.0% vs 11.3%; OR, 2.62; 95% CI, 1.04-6.56, P=0.04). Obese patients had greater incidence rates for recurrent admission-requiring infections (incidence rate ratio (IRR) 1.64; 95% CI, 1.08-2.48, P=0.02) and recurrent FN admissions (IRR, 1.53; 95% CI, 1.10-2.12, P=0.01). Accounting for combined age and NCI risk status, obesity was a risk factor for treatment-requiring hypertension (OR, 3.90; 95% CI, 1.19-12.76, P=0.02), insulin-requiring hyperglycemia (OR, 3.92; 95% CI, 1.39-11.05, P=0.01), and FN admission (OR, 2.92; 95% CI, 1.27-6.73, P=0.01). During pre-maintenance chemotherapy for ALL, obesity is a risk factor for the development of hypertension, hyperglycemia, and FN admissions. This research provides implications for augmented preventive and supportive care guidelines in obese ALL patients.

Human thymic epithelial monolayer-conditioned medium (TEM-CM) enhanced concanavalin A (ConA)-induced suppressor T-lymphocyte activity in 15 of 17 studies of fractionated light-density bone marrow mononuclear cells (LD-BMMC) obtained from pediatric cancer patients within 7 days of chemotherapy (P less than 0.001). However, TEM-CM depressed ConA-induced suppressor T-lymphocyte activity in 14 of 18 studies of LD-BMMC obtained from patients who had received their chemotherapy 14-21 days previously (P less than 0.05). In studies of LD-BMMC from normal subjects, TEM-CM did not show any significant effect on suppressor cell activity, nor did TEM-CM significantly affect spontaneous suppressor cell activity in patients or normals. The effect of direct culture on thymic epithelial monolayers was equivalent to the effect of TEM-CM in both ConA-induced and spontaneous suppressor cell assays. These data demonstrate thymic factor-mediated changes in suppressor T-cell activity of pediatric cancer patients and suggest a postchemotherapy alteration in the bone marrow population of inducible prethymic T cells.

Bone and soft tissue sarcomas are rare diagnoses in the orthopedic patient population. Without rapid evaluation and proper treatment, mortality is increased in these patients. The purpose of our study is to identify factors associated with a variance of care in bone and soft tissue sarcoma patients within a large urban hospital system. Our study retrospectively reviewed the charts of 117 patients with orthopedic tumors at both private and public hospital settings, and we recorded their treatment course. Race, insurance type, and hospital type were associated with variations in sarcoma care in our large urban hospital system. Surgeons should be aware of these variances when treating these groups of patients.