Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

[Osteosarcoma Secondary to Polyostotoic Fibrous Dysplasia of the Ribs].

Sarcomatous transformation of fibrous dysplasia is extremely rare. We present the case of a 54-yearold man with multiple rib masses, multiple enlarged lymph nodes throughout the body, and multiple osteolytic lesions on computed tomography( CT). A positron emission tomography( PET) scan showed abnormal enhancement in each. A needle biopsy of the right supraclavicular fossa lymph node revealed sarcoidosis. Considering the possibility of malignancy associated with sarcoidosis, a rib tumor resection and mediastinal lymph node biopsy were performed to confirm the diagnosis of the rib lesion. The pathology results showed that the rib mass was a low-grade central osteosarcoma and the mediastinal lymph node was sarcoidosis. The distribution of the lesions was consistent with osteosarcoma secondary to multiple fibrous bone dysplasia. As the osteosarcoma was low grade, the patient was followed up. Three years after surgery, there was no increase in residual disease.

Secondary osteosarcoma associated with osteofibrous dysplasia: a case report.

Secondary osteosarcoma is a rare complication of primary malignancies and benign bone lesions. There are various types of diseases that cause secondary osteosarcoma. A 15-year-old male presented at our medical center complaining of pain and redness in the right lower leg. He had been diagnosed with osteofibrous dysplasia in the right tibia when he was 2 years old and since then had been followed up. Although he had a pathological fracture of the right tibia at the age of 7, his fracture healed with a plaster cast and did not require surgery. At the time of the patient's last visit, a radiograph revealed a periosteal reaction as well as erosion of the bone cortex. Magnetic resonance imaging revealed an infiltrative area in the soft tissue surrounding the osteofibrous dysplasia lesion in the tibia. Consequent to pathological examination (through bone biopsy), the patient was diagnosed with secondary osteosarcoma. The patient underwent chemotherapy and extensive resection with liquid nitrogen. He has been progressing satisfactorily after the operation. The present case is the first report of secondary osteosarcoma associated with osteofibrous dysplasia. During the long-term follow-up of osteofibrous dysplasia, oncologists should be aware of the possibility of secondary osteosarcoma.

Three, dynamic variants of ST segment elevations in a patient with osteosarcoma and cardiac metastasis.

In the right clinical setting, ST segment elevation (STE) on electrocardiogram (ECG) is most concerning for acute injury due to transmural myocardial ischemia. This frequently points to significant epicardial coronary artery disease, mandating emergent cardiac intervention. In rare cases, cardiac metastases may cause transient STE. We present a case of a 28-year-old male patient with metastatic osteosarcoma with STE in three different ECG territories over ten months. Several transient, dynamic patterns of STE were noted: anteroseptal leads concerning for acute injury with reciprocal ST depressions in inferior leads, lateral leads, inferior leads with reciprocal ST depression in lateral leads, followed by STE again in lateral leads. Given the patient's young age, absence of cardiac history or symptoms, personal preference, bleeding risk, and cancer prognosis, cardiac catheterization was never pursued. We present this case to remind providers to include metastatic cancer in the differential diagnosis of STE on ECG, and that these changes can be dynamic.

Osteosarcoma emboli presenting as chronic thromboembolic pulmonary hypertension in a child.

A 13-year-old girl presented with hypoxemia during adjuvant chemotherapy for an osteosarcoma of the left distal femur. She underwent an amputation complicated by a post-operative pulmonary embolism (PE). Three months post-operatively, she was admitted to hospital with severe hypoxemia and diagnosed with pulmonary hypertension on echocardiogram in the context of extensive bilateral PE on computed tomography. She was planned for elective pulmonary thromboendarterectomy, but rapidly deteriorated requiring emergent surgery. At the time of surgery, she was found to have extensive tumor emboli throughout both pulmonary arteries. She recovered well post-operatively but died 2 months later from progressive disease.

The Dilemma of Balance between Benefits and Losses for Chondromyxoid Fibroma-like Osteosarcoma in Thoracic Spine with Azygos Tumor Thrombosis: A Case Report.

Background: Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is an extremely rare subtype of osteosarcoma, its clinical data are scarce, and our understanding of it is far from sufficient. As it has few typical imaging manifestations, it is not uncommonly misdiagnosed clinically. Azygos vein thrombosis is also a rare entity, and there is a big controversy over treatments for it. Case presentation: Herein, we report a case of CMF-OS that occurred in the spine, coincidently, azygos vein thrombosis was found. A young male patient came to our clinic because of continuous back pain, and a neoplastic lesion was suspected in the thoracolumbar vertebrae. The pathological results of the biopsy showed a low grade of osteosarcoma, and chondromyxoid fibroma-like osteosarcoma was the primary diagnosis. Since the tumor cannot be en-bloc resected, he received palliative decompression surgery, followed by radio and chemotherapy. Azygos vein tumor thrombosis was not treated and, unfortunately, he died of heart failure caused by the thrombus migrating from the azygos vein to the right atrium. Before the palliative decompression surgery, both the patient and the clinical team were trapped in the dilemma of how big a surgery should be carried out to maximize the benefits of this patient. Results and complications: CMF-OS is indeed more aggressive than its pathological sections suggest. Guidelines for osteosarcoma should be followed. Furthermore, it is important to recognize the danger of tumor thrombosis in the azygos vein. Preventive measures have to be performed in a timely manner to avoid catastrophic results.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.

BACKGROUND: The incidence of osteosarcoma as a secondary neoplasm in glioblastoma patient is extremely rare. The genetic characteristic still remains unclear until now. CASE DESCRIPTION: We reported a 47-year-old female patient with multiple intracranial disseminations and infiltrations (splenium of the corpus callosum and lateral ventricular wall) of a rapid progressive glioblastoma underwent occipital craniotomy and total resection of all the enhancing lesions. Whole-exome sequencing and pathological examination revealed glioblastoma, IDH1 wild type, PTEN deficient, TERT mutated, NF1mutated, MGMT unmethylated. After surgery, the patient received combined therapeutic regimen of TTFields (tumor-treating fields) plus pembrolizumab plus temozolomide and TTFields plus everolimus, which displayed significant clinical benefits. During the combined therapeutic course, an extremely rare secondary malignant neoplasm occurred, femur MR and pathological detection of biopsy tissue demonstrated osteosarcoma. The result of whole-exome sequencing revealed 7 germline mutated genes (EPAS1, SETD2, MSH3, BMPR1A, ERCC4, CDH1, AR). Bioinformatic analysis showed the two germline mutations (MSH3 and ERCC4) induced deficiency in the DNA repair machinery, which resulting in the accumulation of mutations and may generate neoantigens contributing to the development of a secondary osteosarcoma in this case. CONCLUSION: Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.

Bone Health in Osteosarcoma at Presentation and Its Impact on Cancer Treatment: A Case Series of 3 Pediatric Patients.

Osteosarcoma is the most common pediatric malignant bone tumor. Concomitant osteoporosis has typically been attributed to oncologic therapy. The present case series is aimed to describe 3 patients who presented with osteoporosis or osteopenia before, or early in, their oncology treatment. In our patients, bone health and its complications had significant impacts including pain, reduced mobility, prolonged admission, and delays in recovery. Our patients experienced improvement with resection of their primary tumor and with bisphosphonate infusion. Future studies are required to determine the prevalence osteoporosis at presentation of osteosarcoma and the role of bisphosphonates.

Germline RET variants underlie a subset of paediatric osteosarcoma.

BACKGROUND: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS: After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.

Primary Osteosarcoma of Left Atrial Appendage in a Patient with Rheumatic Heart Disease.

Primary cardiac osteosarcoma is extremely rare, with all arising from the atrium, right ventricle, and cardiac valve, according to previous reports. We report a case of primary osteosarcoma of the left atrial appendage in a patient. We present a process of preoperative misdiagnosis, intraoperative confirmed diagnosis, and complete resection.

Second Osteosarcoma in a 16-Year-old Woman Diagnosed With Rothmund-Thomson Syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma (OS) when it is caused by concrete mutations in the RECQL4 gene. Most OSs arise sporadically, but it can also be the first manifestation of a cancer predisposition syndrome as Rothmund Thompson. The early onset, multifocality and metachronism, and a family history of the disease, may suggest a tumor predisposition syndrome. We present the case of a patient with a polymalformative syndrome, who, at 6 years of age, was diagnosed with OS in the right femur. This led to the diagnosis of a RTS type 2. She was cured and surveillance showed no sign of disease. Ten years later, the patient developed a second OS in the contralateral femur. Fortunately, she is in complete remission again after treatment. We describe our patient treatment and recommend a possible screening-surveillance for RTS type II patients.

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.

Osteosarcoma and Metastasis Associated Bone Degradation-A Tale of Osteoclast and Malignant Cell Cooperativity.

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.

Psychosocial Factors and Psychological Interventions: Implications for Chronic Post-Surgical Pain in Pediatric Patients with Osteosarcoma.

This study retrospectively investigated psychological factors contributing to chronic post-surgical pain (CPSP) in pediatric patients after limb-sparing or amputation surgery for extremity osteosarcoma. Psychological factors were identified and analyzed by the Wilcoxon rank-sum and median two-sample tests. Univariate and multivariate Cox regressions were performed using gender, age, psychological factors, and psychological interventions related to CPSP duration as covariates. Duration of pain treatment was significantly longer in patients resistant to psychological interventions (p = 0.01) than those receptive to interventions. Shorter duration of pain treatment was associated with older age (p = 0.03) and receptiveness to psychological interventions (HR = 4.19, 95% CI [1.22, 14.35]). Older age and receptiveness to psychological interventions as part of pain management care are associated with needing a shorter duration of pain treatment. Our results highlight the importance of prospective investigations evaluating motivation to engage in psychotherapy and psychological interventions and identify risk factors for CPSP in pediatric oncology.

Subsequent primary neoplasms among bone sarcoma survivors; increased risks remain after 30 years of follow-up and in the latest treatment era, a nationwide population-based study.

BACKGROUND: The long-term risks and time trends of subsequent primary neoplasms (SPNs) among Ewing (ES) and osteosarcoma (OS) survivors are not fully understood. METHODS: We performed a nationwide study of all ES and OS patients identified in the Swedish Cancer Registry from 1958 to 2015 with up to 58 years of follow-up. The risk of SPN was compared with that of the general population using standardised incidence ratios (SIRs) and absolute excess risks (AERs). RESULTS: One hundred and fifteen SPNs were diagnosed among 1779 patients with ES or OS, yielding an overall SIR of 2.3 (95% confidence interval (CI), 1.9-2.7). The risk remained significantly increased in the latest treatment era (SIR2000-2015 2.0; 95% CI, 1.1-3.5). The highest absolute excess risks (AER) was due to breast cancer (AER 15.2/10,000 person-years; 95% CI, 5.0-29.8) followed by female genital malignancies (AER 9.5/10,000 person-years; 95% CI, 2.4-21.5). The excess breast cancer risk among ES survivors was noted also after 30 years of follow-up with 127 extra breast cancers/10,000 person-years (95% CI, 6.6-419). CONCLUSIONS: Breast- and female genital malignancies contribute most to the excess risk of SPN among ES and OS survivors. Importantly, excess risks did not decline over calendar time or long-term follow-up.

Hurthle cell carcinoma in childhood: A retrospective analysis of five cases and review of pediatric literature.

BACKGROUND: the available studies on Hurthle cell carcinoma (HCC) in pediatric age are scarce and based on isolated case reports. Aims of the present study were to review the available pediatric literature on HCC (2000-2019), to describe the cohort of children with this cancer histotype, and to estimate its relative prevalence in pediatric age. PROCEDURE: We retrospectively reconstructed an HCC course in five patients < 19 years who were identified in our departments during the period 2000-2019, and we reviewed the available pediatric studies on this differentiated thyroid cancer (DTC) variant. RESULTS: HCC occurred with a relative prevalence of 5.8% at a median chronological age of 12.5 years. None of HCC patients exhibited, at diagnosis, thyroid dysfunction, extensive lateral neck disease, or distant metastases, and all showed a persistent remission over time. Three patients showed, at diagnosis, antecedents of other diseases (Hashimoto's thyroiditis, neurofibromatosis type 1, and osteosarcoma). CONCLUSIONS: (1) In childhood, the relative prevalence of HCC among different thyroid cancer histotypes is 5.8%, that is close to the one previously reported both in the general population and in other less numerous children's cohorts; (2) HCC may develop even early, at the age of 7; (3) in childhood, HCC does not seem to have a more aggressive behavior when compared with other DTC histotypes; (4) antecedents of other diseases are not infrequent in the history of children with HCC.

Characteristics and Outcomes of Critically Ill Pediatric Patients with Posterior Reversible Encephalopathy Syndrome.

BACKGROUND/OBJECTIVE: Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiologic entity, typically manifesting as reversible neurological symptoms and signs of white matter edema on magnetic resonance imaging. PRES has been widely described in adults. Studies of PRES in children are mostly limited to case series and case controls. METHODS: Retrospective chart review of patients under 21 years with PRES admitted at a tertiary children's hospital from 2011 to 2016. They were compared to controls matched for age and mortality risk using the Pediatric Index of Mortality-2 score. RESULTS: Sixteen cases of PRES were identified in 13 patients (ages 5-17 years, 46% male). PRES presented with altered mental status (75%), seizures (77%), headache (31%), and vision changes (23%). In patients who recovered (n = 11), median days to symptom resolution was three (range 1-8). PRES patients had a higher mortality rate (15% vs. 5%, p < 0.05) and higher mean length of stay (13.1 vs. 4.6 days) and were more likely to have autoimmune disease (p < 0.05), immunosuppression (p < 0.05), and anemia (p < 0.05). No PRES patients were diagnosed with epilepsy by last known follow-up, and all of whom had been started on an antiepileptic drug were discontinued within 13 months. Sepsis was suspected in 53% of PRES patients and 59% of controls (p = 1.00). All PRES patients had stage II hypertension, versus 41% of controls (p < 0.05). Average creatinine in PRES was 2.35 mg/dL compared to 0.90 mg/dL in controls (p < 0.05). PRES patients had lower serum calcium (p < 0.05). After correcting for albumin, no association between PRES and hypocalcemia remained. PRES patients had a higher length of stay (13.1 vs. 4.6 days, p < 0.05) and mortality rate (15% vs. 3%, p < 0.05). CONCLUSIONS: Immunosuppression, autoimmune disease, renal insufficiency, anemia, and hypertension are associated with PRES after controlling for mortality risk in critically ill children. There was no association between corrected serum calcium and sepsis with PRES.

Prognostic Importance of Pathological Fractures in Osteosarcomas.

Aims To investigate whether pathological fractures impact on osteosarcoma patient prognosis in Ireland. Methods This was a retrospective study over 22 years in a National Orthopaedic Oncology Centre. There were 117 nonfracture cases and 15 fracture cases. Outcome measures included 5 and 10 year event-free (EFS) and overall survival (OS). Kaplan-Meier curves assessed length of survival and time to death. Results Pathological fracture has no significant effect on 10 year EFS or 10 year OS. 3 factors strongly associate with 10 year OS rates: American Joint Committee on Cancer (AJCC) classification (p<0.001), Metastases site (p<0.001) and Distant recurrence (p<0.001). Fractures had poorer post-chemotherapeutic necrosis rates (p=0.005). Conclusion Pathological fractures have no significant effect on survival rates or length of survival in an Irish population. The effect of pathological fractures on necrosis rates must be explored in future research.

Evaluation of sleep quality in adolescent patients with osteosarcoma using Pittsburgh Sleep Quality Index.

The sleep quality of patients with osteosarcoma (OS) was poorly understood. We aimed to evaluate the prevalence of sleep dysfunction in adolescent patients with OS using the Pittsburgh Sleep Quality Index (PSQI) and to further investigate the psychometric properties of the PSQI in this cohort of patients. Fifty four adolescent patients with OS who underwent chemotherapy treatment in our clinic centre were included. Sleep quality was assessed with the Chinese PSQI. Cronbach's alpha was calculated to evaluate the internal consistency. The confirmatory factor analysis (CFA) was used to determine the fitness of a two-factor structure. Sleep disturbance was observed in 57.4% (31/54) of the patients. Patients with the presence of metastasis or more than 2 cycles of chemotherapy were found to have remarkably higher median global score. The overall Cronbach's alpha was 0.87. The CFA showed an overall comparative fit index of 0.97, a root mean square error of approximation of 0.06 and a standardised root mean square residual of 0.07 respectively. PSQI was a reliable instrument to evaluate the sleep quality of adolescent patients with OS. Over half of the patients may experience sleep disturbance during the treatment. Early psychological interventions were recommended to improve the sleep quality of the patients.

Treatment of Pulmonary Embolism with Chemotherapy in a Case of Newly Diagnosed Osteosarcoma.

A 21-year old female, recently diagnosed with osteosarcoma of right humerus, presented to the emergency with history of fever, productive cough, chest pain and progressive respiratory distress for six days. Initial investigations suggested pneumonia but she did not respond to parenteral antibiotics. CT pulmonary angiogram revealed bilateral pulmonary artery embolism. Thrombolysis was performed using alteplase, which failed to improve the clinical condition. In view of underlying malignancy, a possibility of tumour-embolism was considered and she was started on chemotherapy for osteosarcoma. There was dramatic improvement in her respiratory symptoms after the first chemotherapy cycle, along with radiological resolution of the embolism. This case highlights the importance of suspecting tumour embolism in a known case of malignancy with respiratory distress.