Novel longitudinal Multiple Overall Toxicity (MOTox) score to quantify adverse events experienced by patients during chemotherapy treatment: a retrospective analysis of the MRC BO06 trial in osteosarcoma

ObjectivesThis study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.DesignRetrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.SettingInternational multicentre population-based study.ParticipantsA total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).InterventionsPatients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measuresThe MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.ResultsA cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients’ health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient’s history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2–3 (p<0.05).ConclusionsThe novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning.Trial registration numberISRCTN86294690; Post-results.

Prognostic nomogram for predicting 5-year overall survival in Chinese patients with high-grade osteosarcoma

This study aimed to construct a widely accepted prognostic nomogram in Chinese high-grade osteosarcoma (HOS) patients aged ≤ 30 years to provide insight into predicting 5-year overall survival (OS). Data from 503 consecutive HOS patients at our centre between 12/2012 and 05/2019 were retrospectively collected. Eighty-four clinical features and routine laboratory haematological and biochemical testing indicators of each patient at the time of diagnosis were collected. A prognostic nomogram model for predicting OS was constructed based on the Cox proportional hazards model. The performance was assessed by the concordance index (C-index), receiver operating characteristic curve and calibration curve. The utility was evaluated by decision curve analysis. The 5-year OS was 52.1% and 2.6% for the nonmetastatic and metastatic patients, respectively. The nomogram included nine important variables based on a multivariate analysis: tumour stage, surgical type, metastasis, preoperative neoadjuvant chemotherapy cycle, postoperative metastasis time, mean corpuscular volume, tumour-specific growth factor, gamma-glutamyl transferase and creatinine. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.795 (range, 0.703–0.887). Moreover, the decision curve analysis curve also demonstrated the clinical benefit of this model. The nomogram provides an individualized risk estimate of the 5-year OS in patients with HOS aged ≤ 30 years in a Chinese population-based cohort.

A Primary Cardiac Osteosarcoma: Case Report and Literature Review

Background: Primary cardiac osteosarcoma is an uncommon condition, which is challenging to diagnose, and rarely reported.Case presentation: Here, we present a previously healthy 27-year-old patient referred to our hospital with a long-term fever. Echocardiography and thoracic computed tomography (CT) presented two masses in the left atrium (LA) and left ventricle (LV), and surgical excision of the masses revealed cardiac high-grade osteosarcoma. Unfortunately, the left ventricular tumor recurred three months later, and the patient was administered periodic chemotherapy. Then, chest CT showed that the left ventricle was almost occupied by the tumor and also involved the left ventricular outflow tract, the left atrial appendage mass increased significantly, and multiple metastatic small nodules appeared in both lungs.The patient is still in follow-up.Conclusions: The prevalence of primary cardiac osteosarcoma is very low and did not involve LA and LV simultaneously. This patient was hospitalized in our hospital complaining of a long-term fever of unknown origin, which has never been reported in the previous literatures. Our case report findings suggest that primary cardiac osteosarcoma should not be ignored in the differential diagnosis of fever of unknown origin.

Dedifferentiated Osteosarcoma of the Distal Ulna: A Case Report

Osteosarcoma is the most common malignant primary bone tumor that occurs most frequently in the second decade of life but rarely in patients over 40 years of age. The most common primary sites of osteosarcoma are the distal femur followed by proximal tibia and proximal humerus, and involvement of the wrist is extremely rare. Moreover, dedifferentiated osteosarcoma is also a rare condition that progresses to high-grade osteosarcoma from low-grade osteosarcoma, usually central low-grade osteosarcoma or parosteal osteosarcoma that bears MDM2 and/or CDK4 gene amplifications. We herein report an extremely rare case of dedifferentiated osteosarcoma arising in the distal ulna of an adult over 40 years of age. The patient was a 46-year-old man with a 2-month history of pain in his left swollen wrist. The initial radiological findings suggested a benign bone tumor in the distal ulna, and the lesion was marginally excised at the nearby hospital. Although the pathological diagnosis at the nearby hospital suggested a benign cartilaginous tumor, the tumor recurred in an aggressive manner 8 months after the initial surgery. The patient was referred to our hospital, and an incisional biopsy showed a high-grade osteosarcoma. The primary tumor was retrospectively re-evaluated at our hospital and diagnosed as low-grade osteosarcoma. Since neoadjuvant chemotherapy failed to shrink the tumor, the patient had to undergo below the elbow amputation to cure the disease. Although the tumor was negative for MDM2 nor CDK4, the definitive diagnosis of dedifferentiated osteosarcoma was made according to the clinical course and the histological findings. Lung metastases were found 10 months after the amputation, which were successfully treated by neoadjuvant chemotherapy and surgery. The patient has been doing well with no evidence of disease for 1 year and 6 months. Surprisingly, the literature review revealed that many low-grade osteosarcomas of the distal ulna progressed to high-grade dedifferentiated osteosarcomas. One should bear in mind that the diagnosis and treatment for bone-forming tumors of the distal ulna should be made very carefully because, although rare, it is possible that the tumor may initially appear as a benign or low-grade malignant tumor and may progress to high-grade osteosarcoma.

Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.