Pediatric primary lymphoma of bone in epiphysis case report.

Primary lymphoma of the bone (PLB) is a rare entity, with a majority of pediatric cases presenting in the metaphysis of long bones. There have been only seven reported cases to date of pediatric lymphoma of the bone arising from the epiphysis, of which only two have been described in the proximal tibia. We report a pediatric case of PLB in the tibial epiphysis which presented initially with knee pain. Imaging was performed with X-ray, MRI, CT, and PET-CT with bone biopsies revealing diffuse large B-cell lymphoma. This patient also showed a second, synchronous lesion in the left iliac bone, which was also biopsy proven to diffuse large B-cell lymphoma. Lymphoma in the epiphysis for children is rare and often confused with infectious etiologies or other types of tumors. Misdiagnosis may result in inappropriate treatment and possible progression of the disease, thus making early identification important to initiate therapy.

Pseudoaneurysm within a desmoid tumor in an extremity: report of 2 cases.

Desmoid tumor is considered a benign neoplasm, yet substantial morbidity can result from local invasion of structures adjacent to the tumor or from complications related to its treatment. We report two patients with extremity desmoid tumor who were each found at MRI to have an unsuspected pseudoaneurysm within their tumor after prior treatments (surgery and systemic therapy in one, surgery alone in the other). Such a pseudoaneurysm probably results from weakening of an arterial wall by adjacent desmoid tumor, as well as from local trauma. Due to the potential risk for life-threatening rupture of a pseudoaneurysm, one patient underwent surgical repair and the other, coil embolization. To our knowledge the presence of pseudoaneurysm has been reported within a few cases of abdominal desmoid tumor but not within an extremity desmoid tumor. This diagnosis has not been reported to have been made at MRI, either.

Respiratory Failure in a Child With Pulmonary Metastatic Osteosarcoma and COVID-19.

The novel coronavirus, SARS-CoV-2, causes much more severe disease in adults than in children. Although it is anticipated that immune compromised children and children with cancer may be at higher risk of developing severe or fatal COVID-19, there are no currently published reports of fatal disease in a child with cancer. Because of the discrepancy in disease severity between adult and pediatric patients, we report the case of an adolescent with pulmonary metastatic osteosarcoma who died of COVID-19 early in the course of the pandemic in New York City in the hope that heightening awareness that pulmonary metastatic disease may predispose to a more severe outcome will increase surveillance in this vulnerable population.

A recurrent novel MGA-NUTM1 fusion identifies a new subtype of high-grade spindle cell sarcoma.

NUTM1-rearranged tumors are defined by the presence of a gene fusion between NUTM1 and various gene partners and typically follow a clinically aggressive disease course with poor outcomes despite conventional multimodality therapy. NUTM1-rearranged tumors display histologic features of a poorly differentiated carcinoma with areas of focal squamous differentiation and typically express the BRD4-NUTM1 fusion gene defining a distinct clinicopathologic entity-NUT carcinoma (NC). NCs with mesenchymal differentiation have rarely been described in the literature. In this report, we describe the characterization of two cases of high-grade spindle cell sarcoma harboring a novel MGA-NUTM1 fusion. Whole-genome sequencing identified the presence of complex rearrangements resulting in a MGA-NUTM1 fusion gene in the absence of other significant somatic mutations. Genetic rearrangement was confirmed by fluorescence in situ hybridization, and expression of the fusion gene product was confirmed by transcriptomic analysis. The fusion protein was predicted to retain nearly the entire protein sequence of both MGA (exons 1-22) and NUTM1 (exons 3-8). Histopathologically, both cases were high-grade spindle cell sarcomas without specific differentiation markers. In contrast to typical cases of NC, these cases were successfully treated with aggressive local control measures (surgery and radiation) and both patients remain alive without disease. These cases describe a new subtype of NUTM1-rearranged tumors warranting expansion of diagnostic testing to evaluate for the presence of MGA-NUTM1 or alternative NUTM1 gene fusions in the diagnostic workup of high-grade spindle cell sarcomas or small round blue cell tumors of ambiguous lineage.

Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. METHODS: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. RESULTS: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to >73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. CONCLUSION: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment.

Morbidity and mortality after treatment of Ewing sarcoma: A single-institution experience.

BACKGROUND: Children, adolescents, and young adults treated for Ewing sarcoma (ES) are at risk for disease-related and treatment-related complications. We aimed to describe early and late overall mortality, cause-specific mortality, and key adverse health outcomes in a large, single-institutional cohort of patients with ES. METHODS: Patients with ES diagnosed at age less than 40 years and treated at Memorial Sloan Kettering between 1974 and 2012 were included. Overall survival was estimated using Kaplan-Meier methods. Cox proportional hazards were used to examine the association of clinical and pathologic variables with overall survival. Cause-specific mortality was evaluated with the cumulative incidence function accounting for competing risks. RESULTS: Three hundred patients with ES (60.3% male; median age at diagnosis: 16.8 years [range: 0.3-39]; 30.0% with metastatic disease at diagnosis) were followed for a median of 7.8 years (range: 0.2-37). Five-year overall survival was 65.2% (95% confidence interval [95% CI], 59.8-71.1%) for the entire cohort; 78.6% for those with localized disease; 40.1% for those with isolated pulmonary metastases; and 28.1% for those with extrapulmonary metastases. In multivariable analysis, older age at diagnosis, minority race/ethnicity, and metastatic disease at diagnosis were associated with inferior survival. Ten-year cumulative incidence of relapse/progression was 40.1%, with eight late relapses occurring at a median of 6.3 years after diagnosis (range: 5-14). Seventeen patients developed subsequent neoplasms (treatment-related myelodysplastic syndrome/acute myelogenous leukemia = 9; solid tumors = 6; nonmelanoma skin cancer [NMSC] = 4). Excluding NMSC and melanoma in situ, the cumulative incidence of subsequent malignant neoplasms at 25 years was 15% (95% CI, 4.8-25.1%). CONCLUSION: Patients with ES are at high risk for relapse/progression and second cancers.

Retrospective Evaluation of Palifermin Use in Nonhematopoietic Stem Cell Transplant Pediatric Patients.

BACKGROUND: Palifermin has been proven to decrease the frequency of severe oral mucositis in adult patients with sarcoma and metastatic colorectal cancer receiving chemotherapy. The impact of palifermin on the incidence of mucositis in nonhematopoietic stem cell transplantation (HSCT) pediatric population receiving chemotherapy has never been reported to date. PATIENTS AND METHODS: This is a retrospective analysis of pediatric patients who received palifermin as secondary prophylaxis to prevent chemotherapy-induced mucositis at Memorial Sloan Kettering Cancer Center from January 1, 2008 to 2014. Data from electronic medical records on days to mucositis resolution, use of opioids, use of total parenteral nutrition, duration of hospitalization, and antibiotics are collected and presented here. RESULTS: A total of 18 patients received palifermin for secondary prophylaxis after developing mucositis from the prior chemotherapy cycle. Mucositis did not reoccur in the subsequent cycle for 13 of the 18 patients. The majority of patients who received palifermin prophylaxis had decreased opioids and antibiotics use and decreased duration of hospitalization. Six of the 7 patients previously requiring total parenteral nutrition due to mucositis had decreased supplemental nutritional needs following the use of palifermin. CONCLUSION: Palifermin may provide benefit as secondary prophylaxis in pediatric patients to prevent chemotherapy-induced mucositis.

Intracardiac Low-grade Sarcoma Following Treatment for Ewing Sarcoma.

A 16-year-old male was diagnosed with Ewing sarcoma of the ribcage with pulmonary metastases. Six months after completion of scheduled therapy, he was found to have a new intracardiac mass, presumed recurrent Ewing sarcoma. EWSR1 fusion was not detected by droplet digital polymerase chain reaction from blood plasma. After no improvement with salvage chemotherapy, he underwent surgical resection that identified a low-grade spindle cell sarcoma. Despite the near-synchronous presentation of 2 unrelated sarcomas, extensive genomic analyses did not reveal any unifying somatic or germline mutations nor any apparent cancer predisposition. This case also highlights the potential role of utilizing plasma cell-free DNA for diagnosing tumors in locations where biopsy confers high morbidity.

A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: A single-center review.

PURPOSE: Cooperative studies support complete metastasectomy in osteosarcoma (OS). Pre-operative CT is used to identify and quantify metastases and can facilitate minimally invasive techniques. Here we assess the accuracy of pre-operative CT compared to findings at thoracotomy and its change over time. METHODS: We reviewed OS thoracotomies performed at our institution from 1996 to 2015. The number of metastases identified on pre-operative chest CT was compared to the number of metastases seen on pathology (both metastases with viable cells and non-viable, osteoid-only metastases). RESULTS: Eighty-eight patients underwent 161 thoracotomies with a median of 14days (range, 1-85) between CT and surgery, a median of 2 CT-identified lesions (range, 0-15), and a median of 4 resected lesions (range, 1-25). In 56 (34.8%) cases, more metastases were found surgically than were seen on CT, and among these, 34 (21.1%) had a greater number of viable metastases. There was poor overall correlation between CT and pathology findings (Kendall Tau-b=0.506), regardless of CT slice thickness, decade of thoracotomy, or total number of CT-identified lesions. CONCLUSIONS: CT accuracy in pre-operatively quantifying OS pulmonary metastases has not improved in recent decades. Consequently, we recommend an open technique with direct lung palpation for complete identification and resection of OS pulmonary metastases. LEVEL OF EVIDENCE: Level IV, retrospective study with no comparison group.

Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas.

Purpose: Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumors (DSRCT) are aggressive sarcomas molecularly characterized by EWSR1 gene fusions. As pathognomonic genomic events in these respective tumor types, EWSR1 fusions represent robust potential biomarkers for disease monitoring. Patients and Methods: To investigate the feasibility of identifying EWSR1 fusions in plasma derived cell-free DNA (cfDNA) from ES and DSRCT patients, we evaluated two complementary approaches in samples from 17 patients with radiographic evidence of disease. The first approach involved identification of patient-specific genomic EWSR1 fusion breakpoints in formalin-fixed, paraffin-embedded tumor DNA using a broad, hybridization capture-based next generation sequencing (NGS) panel, followed by design of patient-specific droplet digital PCR (ddPCR) assays for plasma cfDNA interrogation . The second approach employed a disease-tailored targeted hybridization capture-based NGS panel applied directly to cfDNA which included EWSR1 as well as several other genes with potential prognostic utility. Results: EWSR1 fusions were identified in 11/11 (100%) ES and 5/6 (83%) DSRCT samples by ddPCR, while 10/11 (91%) and 4/6 (67%) were identified by NGS. The ddPCR approach had higher sensitivity, ranging between 0.009-0.018% sensitivity. However, the hybrid capture-based NGS assay identified the precise fusion breakpoints in the majority of cfDNA samples, as well as mutations in TP53 and STAG2, two other recurrent, clinically significant alterations in ES, all without prior knowledge of the tumor sequencing results. Conclusion: These results provide a compelling rationale for an integrated approach utilizing both NGS and ddPCR for plasma cfDNA-based biomarker evaluations in prospective cooperative group studies.

A single-center experience with undifferentiated embryonal sarcoma of the liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive mesenchymal pediatric tumor. Previously, reported outcomes have been very poor. Here, we report a single-center experience of five patients with UESL treated with upfront gross total resection and adjuvant chemotherapy. We have a median follow-up of 8 years with a range from 5 to 19 years with 100% event-free survival.

Osteosarcoma With Apparent Ewing Sarcoma Gene Rearrangement.

Poorly differentiated round cell sarcomas present diagnostic challenges because of their variable morphology and lack of specific immunophenotypic markers. We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene. Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma. This illustrates the potential of clinical genomic profiling to improve diagnosis and enable specifically targeted therapies for cancers with complex pathologies.

Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee.

BACKGROUND: The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery. METHODS: Retrospective analysis was performed for patients aged <22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as <5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology. RESULTS: Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P < 0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1). CONCLUSION: We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.

Immunotherapy of Childhood Sarcomas.

Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed.

Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma.

BACKGROUND: Outcomes for patients with metastatic Ewing sarcoma (ES) remain poor. We investigated whether the intensification of ifosfamide improved survival for patients with metastatic ES. PROCEDURE: We conducted a retrospective chart review of 30 patients with metastatic ES treated with the MSKCC "EFT regimen." The regimen included an intensification of ifosfamide dosing from 1,800 mg/m(2) /day × 5 days per cycle to 2,800 mg/m(2) /day × 5 days per cycle. RESULTS: Twenty six of the 30 patients completed planned chemotherapy. Two patients experienced disease progression during therapy. There were no toxic deaths. One patient developed secondary leukemia. The 4-year event free survival (EFS) was 27% and the overall survival (OS) was 39%. CONCLUSIONS: Intensification of ifosfamide was tolerated and did not increase toxicity in patients with metastatic ES. The intensification did not improve outcomes for these patients with metastatic disease.

Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma.

BACKGROUND: The role, optimal dose, and efficacy of radiotherapy (RT) for the treatment of bone metastases in rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are unclear. PROCEDURE: All patients with ES or RMS who received RT for bone metastases with curative intent during frontline therapy at Memorial Sloan Kettering Cancer Center (MSKCC) between 1995 and 2013 were reviewed. Among the 30 patients (8 RMS and 22 ES), 49 bone metastases were irradiated. RESULTS: Median biologically effective dose (BED) was 42.4 Gy (range, 34.9-59.7) for RMS and 50.7 Gy (range, 31.3-65.8) for ES. Tumor recurrence occurred in six of 49 irradiated bone metastases. Cumulative incidence of local failure at a treated metastatic site was 6.6% at 1 year and 9.0% at 3 years. Dose, fractionation, and RT technique did not impact local control at an irradiated site. The presence of >5 bone metastases was associated with worse local control at an irradiated site (P = 0.07). The 3-year EFS was 33% in RMS and 16% in ES. CONCLUSIONS: RT appears to be an effective modality of local control for bone metastases in ES and RMS. Local control at sites of metastatic bone irradiation is similar to local control at the primary site after definitive RT. Doses in the biologic range prescribed for the definitive treatment of primary disease should be used for metastatic sites of disease.

20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations.

PURPOSE: To assess outcomes and toxicity of high-dose-rate intraoperative radiation therapy (HDR-IORT) in the management of pediatric sarcoma. METHODS AND MATERIALS: Seventy-five pediatric patients underwent HDR-IORT for sarcoma from May 1993 to November 2013. The median age was 9 years old (36 patients were ≤ 6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR-IORT and postoperative external beam RT (PORT), and 22 patients (29%) were previously treated with external beam radiation therapy to the IORT site. Local control (LC), overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier methods. RESULTS: At a median follow-up of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% confidence interval [CI] 50%-76%), 33% (95% CI 21%-45%), and 43% (95% CI 30%-55%), with a median survival of 3.1 years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28%-64%), 30% (95% CI, 13%-46%), and 36% (95% CI, 18%-54%). Acute toxicity ≥ grade 3 occurred in 2 (2.5%) treatments; late toxicity ≥ grade 3 occurred in 4 (5.3%) patients 0.3-9.9 years after HDR-IORT. The incidence of toxicity ≥ grade 3 was not associated with HDR-IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, but all toxicity ≥ grade 3 occurred in patients ≤ 6 years treated with HDR-IORT doses ≥ 12 Gy. CONCLUSIONS: HDR-IORT is a well-tolerated component of multimodality therapy for pediatric sarcoma, allowing additional local treatment while reducing external beam exposure. Taking clinical considerations into account, doses between 8-12 Gy are appropriate for HDR-IORT in patients ≤ 6 years of age.

Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.

Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

Inhaled lipid cisplatin (ILC) in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung.

BACKGROUND: Osteosarcoma treatment failure is most often from the inability to control metastatic disease in the lungs. Encapsulating cisplatin within lipid complexes and delivering the agent via inhalation targets lung metastases with minimal systemic exposure. An open-label, phase Ib/IIa study was performed to characterize the safety and efficacy of inhaled lipid cisplatin (ILC) in recurrent osteosarcoma patients who only had pulmonary metastases. PROCEDURE: ILC was administered via nebulizer every 2 weeks (=1 cycle). Response was evaluated radiographically every 2 cycles. Cisplatin levels were measured in patients. When possible, metastasectomy was undertaken in patients after 2 cycles. RESULTS: Nineteen patients were treated. No patients experienced hematologic toxicity, nephrotoxicity or ototoxicity. Nausea/vomiting (≥grade 3) was attributed to study drug in one patient. Respiratory symptoms were observed in 13/19 patients with only one patient experiencing a ≥grade 3 respiratory symptom (not related to study drug). Systemic cisplatin exposure was minimal. Eleven patients had bulky disease, and all progressed prior to cycle 7. Eight patients had all lesions ≤2 cm. One patient had a sustained partial response. An additional two patients had stable disease after 2 cycles, underwent metastasectomy, and remained free from pulmonary recurrence 1 year after initiation of therapy. CONCLUSIONS: ILC is well tolerated in heavily treated osteosarcoma patients and did not appear to have the typical toxicities associated with intravenous cisplatin. Three of eight patients with less bulky disease had sustained benefit. Further study of ILC is warranted.