Universal Marker and Detection Tool for Sarcoma Circulating Tumor Cells
To date, no specific marker exists for the detection of circulating tumor cell from different types of sarcomas, though tools are available for detection of circulating tumor cell (CTC) in peripheral blood of cancer patients for epithelial cancers. Here the investigators report cell-surface vimentin (CSV) as an exclusive marker on sarcoma CTC regardless of the tissue origin of the sarcoma as detected by a novel monoclonal antibody. Utilizing CSV as a probe they isolated and enumerated sarcoma CTC with high sensitivity and specificity from the blood of patients bearing different types of sarcoma, validating their phenotype by single cell genomic amplification, mutation detection and fluorescence in situ hybridization. Their results establish the first universal and specific CTC marker described for enumerating CTC from different types of sarcoma, thereby providing a key prognosis tool to monitor cancer metastasis and relapse.
Bone sarcomas: ESMO Clinical Practice Guidelines
This paper presents the European Society for Medical Oncology's practice guidelines for the treatment of bone sarcomas. One of the main recommendations of this guideline is that all patients with a suspected primary malignant bone tumor should be referred to a bone sarcoma reference center or an institution belonging to a specialized bone sarcoma network before biopsy.
Follow-up of the STS Patient
Despite optimal treatment, patients with soft tissue sarcoma are at risk for recurrence and therefore appropriate surveillance is critical. At minimum, regularly scheduled clinical assessments and chest X-rays are necessary. Consensus guidelines are available; however, surveillance strategies must be personalized based on the risk for recurrence and inherent disease biology. In this review article the authors discuss surveillance of the STS patient who has undergone optimal treatment to render no gross evidence of disease. This is the patient who has received treatment with curative as opposed to palliative intent. They focus on tumors of the extremity, where the majority (70–80%) of cases are seen, with some mention of retroperitoneal tumors, which can present unique challenges in clinical management. As they will highlight, a number of unresolved and even controversial issues exist and there is certainly the need for further research to define the appropriate surveillance strategy for the STS patient.
Targeting the DNA Repair Pathway in Ewing Sarcoma
Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.
Internal Hemipelvectomy and/or Radiation Therapy in Pelvic Ewing Sarcoma
Pelvic Ewing sarcoma (ES) is commonly associated with a worse prognosis. Large size and location limit local control options to radiation therapy, and local recurrences are common. The investigators evaluated the impact of hemipelvectomy and radiation on outcomes, including function. Thirty-nine patients (median age 13.5 years) with ES of the pelvis and sacral bones were treated during the period 2000–2012. Fifteen were treated with definitive radiotherapy (RT), 9 patients underwent hemipelvectomy alone, and 15 were treated with combined hemipelvectomy and RT. Results were as follows: Twenty patients (51.2%) are alive with a median follow-up 3.2 years from diagnosis. Median time from diagnosis to relapse was 1.3 years. Three-year estimates of EFS and OS were 47% and 61%, respectively. Patients treated with surgery or surgery with RT had better outcome than patients treated with RT only (3-year OS 78% or 81% vs. 36%, respectively, p = 0.00083). The outcome of patients with pelvic ES treated with hemipelvectomy was not significantly different from the outcome of all patients with Ewing sarcoma treated on the national Polish protocol. Conclusions: Internal hemipelvectomy offers good chances of cure for patients with pelvic ES, with a reasonable rate of complications and good function.
Hypoalbuminaemia, Predictor of Poor Outcome in Metastatic Ewing's Sarcoma
Data on metastatic Ewing's sarcoma family of tumours (ESFT) with uniform chemotherapy protocol are minimal. This was a single institutional patient review of patients treated between June 2003 and November 2011 and evaluated on an intent-to-treat analysis. All patients received uniform chemotherapy: neoadjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by adjuvant chemotherapy. Local treatment was offered if the patient achieved a complete response and/or a partial response at both the primary and the metastatic site. Results were as follows: In total, 150/374 (40%) ESFT patients were metastatic, with a median age of 15 years (range: 2–50); a tumor diameter of 10 cm (range: 1.8–26). Most common metastatic sites were lung only (53; 35%), bone only (35; 23%) and combined bone/lung (25; 17%). Twenty patients underwent surgery; 55 patients received radical radiotherapy after NACT. After a median follow-up of 26.1 months (range: 1.6–101.6), 5 year event-free survival (EFS), overall survival and local control rate (LCR) were 9.1 ± 3.3%, 16.9 ± 5.2% and 31.8 ± 7.9%, respectively. Univariate analysis showed serum albumin ≤3.4 g/dl (P < 0.001) to predict inferior EFS. Tumor size >8 cm (P = 0.05), haemoglobin ≤10 g/dl (P = 0.04), hypoalbuminaemia (P = 0.003) and radical radiotherapy as local treatment (P = 0.03) predicted inferior overall survival. No factor significantly predicted LCR, although age ≤15 years (P = 0.08) and radical radiotherapy as local treatment (P = 0.09) had a trend towards inferior LCR. Hypoalbuminaemia was the only prognostic factor to predict EFS on multivariate analysis. Conclusion: This was the largest study of metastatic ESFT from Asia and identified a unique prognostic factor. In view of dismal prognosis with conventional chemotherapy in metastatic ESFT with hypoalbuminaemia, palliative intent therapy may be a potential therapeutic alternative for this subgroup of patients, especially in resource-challenged situations.
Resection of Primary LMS of the Inferior Vena Cava (IVC) with Reconstruction
Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor which presents a unique surgical challenge. The authors present a series of six cases of leiomyosarcoma resection performed with IVC reconstruction. Retrospective chart review was performed for patients undergoing initial operative resection of primary leiomyosarcoma with IVC reconstruction, at a tertiary care center. Results were as follows: Between 2005–2013, six patients underwent resection with reconstruction. Half were female, and the mean age at presentation was 57±15.4 years. Three patients required en bloc resection with adjacent organs. Three patients were resected on venovenous bypass, and one on cardiopulmonary bypass. Three underwent IVC patch repair (bovine pericardium, n=2; saphenous vein, n=1), and three had IVC reconstruction with graft (Dacron, n=1; PTFE, n=1; aortic homograft, n=1). All achieved grossly negative margins. Median disease-free survival was 34 months (IQR 7–52 months), and median disease-specific survival was 51 months (IQR 20–108). Five year disease-free and disease-specific survival rates were 30% and 66.7%, respectively. Conclusions: Leiomyosarcomas of the IVC present a technical challenge to the surgeon. Careful preoperative workup and a collaborative team consisting of experienced cardiac and vascular surgeons and surgical oncologists can allow for a safe and successful operation despite extensive tumor involvement.
Translational Biology of Osteosarcoma
For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signaling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome. And while this review article states that surgery and chemotherapy will probably remain the backbone of conventional treatments for non-metastatic disease, in the future, interventions will ideally shift to adjuvant therapy, as it is thought that immunotherapies will have their greatest effect in the setting of micrometastatic disease.
Orbital Rhabdomyosarcoma in Children
Orbital rhabdomyosarcoma (ORMS) treatment is based on combination chemotherapy associated with best local therapy, sometimes surgery but more often radiation therapy. A retrospective single-center analysis was conducted to more clearly define the long-term outcome of patients with ORMS, to identify patients in whom aggressive first-line local therapy can be avoided. A total of 95 patients with localized parameningeal (PM) or nonparameningeal (NPM) ORMS, treated at the Institut Curie between 1975 and 2010, were analyzed. Results were as follows: Median age at diagnosis was 6 years (range, 8 mo. to 19.5 y), and median follow-up was 8.5 years (range, 7 mo. to 24 y). A total of 25 patients presented PM extension. Radiation therapy was part of primary therapy for 78 patients. Five-year event-free survival and overall survival rates were 65.4%±5.2% and 85.6%±3.9%, respectively. On multivariate analysis, initial tumor size was identified as a significant prognostic factor. Event-free survival was similar for PM and NPM tumors (60.3%±10.4% vs. 62.7%±5.9%, P=0.57), whereas there was a trend for overall survival to be better for NPM tumors (90%±3.9% vs. 72.7%±9.6%, P=0.07). Conclusions: Localized ORMS has a favorable outcome despite the current trend toward less aggressive and more limited indications of local therapy. Patients with a favorable pattern of strictly ORMS can be treated without first-line radiation therapy.
VEGF Inhibitors Block Angiogenesis & Spheroid Growth in Synovial Sarcoma
Synovial sarcoma (SS) is a malignant soft-tissue tumor characterized by the recurrent chromosomal translocation SS18–SSX. Vascular endothelial growth factor (VEGF)-targeting anti-angiogenic therapy has been approved for soft-tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, the investigators show that SS18–SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18–SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18–SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C-X-C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18–SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS.
Programmed Cell Death-1 (PD-1) and its Ligands in Pediatric Cancer
Programmed cell death-1 (PD-1) and its ligands, PD-L1 and PD-L2 maintain self-tolerance and modulate physiological immune responses. Recently, targeting the PD-1/PD-L1 pathway with blocking antibodies has emerged as a potentially promising approach to treat advanced cancers in adult patients. Since tumor PD-L1 expression is currently considered the most important predictive biomarker for successful checkpoint blockade, the authors summarize expression data for the most common tumors of childhood. Additionally, they give an introduction into PD-1 function in the immune system to then focus on PD-1 mediated tumor immune escape.
SIRT1 and SIRT2 Inhibition Impairs Pediatric STS Growth
Sirtuins are NAD+ dependent deacetylases and/or ADP-ribosyl transferases active on histone and non-histone substrates. The first sirtuin was discovered as a transcriptional repressor of the mating-type-loci (Silent Information Regulator sir2) in the budding yeast, where it was shown to extend yeast lifespan. Seven mammalian sirtuins (SIRT1-7) have been now identified with distinct subcellular localization, enzymatic activities and substrates. These enzymes regulate cellular processes such as metabolism, cell survival, differentiation, DNA repair and they are implicated in the pathogenesis of solid tumors and leukemias. The purpose of the present study was to investigate the role of sirtuin expression, activity and inhibition in the survival of pediatric sarcoma cell lines. The investigators have analyzed the expression of SIRT1 and SIRT2 in a series of pediatric sarcoma tumor cell lines and normal cells, and they have evaluated the activity of the sirtuin inhibitor and p53 activator tenovin-6 (Tv6) in synovial sarcoma and rhabdomyosarcoma cell lines. They show that SIRT1 is overexpressed in synovial sarcoma biopsies and cell lines in comparison with normal mesenchymal cells. Tv6 induced apoptosis as well as impaired autophagy flux. Using siRNA to knock down SIRT1 and SIRT2, they show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression. The investigators' results show that SIRT1 and SIRT2 expressions are crucial for the survival of synovial sarcomas and rhabdomyosarcomas, and demonstrate that the pharmacological inhibition of sirtuins impairs the autophagy process and induces tumor cell death.
Changes in Nutritional Status in Childhood Cancer Patients
Under and over nutrition are linked to adverse outcomes during and after childhood cancer treatment. Therefore, understanding the timing of weight loss and weight gain and their contributory factors is essential for improving outcomes. The investigators aimed to determine in which period of treatment changes in nutritional status occurred and which factors contributed to these changes. A prospective cohort study of 133 newly diagnosed cancer patients with hematological, solid, and brain malignancies was performed. Anthropometric data and related factors were assessed at 0, 3, 6 and 12 months after diagnosis. Results were as follows: Despite initial weight loss at the beginning of treatment in patients with hematological and solid malignancies, body mass index (BMI) and fat mass (FM) increased within 3 months with 0.13 SDS (P < 0.001) and 0.05 SDS (P = 0.021) respectively. Increase continued during the following months and resulted in a doubling of the number of over nourished patients. Fat free mass (FFM), which was already low at diagnosis, remained low. During the entire study period about 17% of the patients were undernourished on the basis of low FFM. Tube feeding and diminished activity level were related to increases in BMI and %FM respectively. No relationship was found between energy intake or corticosteroids and increase in BMI or %FM. Conclusions: BMI and FM increased during and after the period of intensive treatment, while FFM remained low. Improvement of nutritional status might be accomplished by increasing physical activity from the early phase of treatment.
Insomnia in Adult Survivors of Childhood Cancer
Insomnia is a common problem affecting cancer survivors even years after completion of therapy. Childhood cancer survivors may be at particular risk due to vulnerability to the effects of treatment and medical late effects which impact normal sleep development. Using an indicator of clinically significant insomnia (sleep efficiency), the investigators examined a group of adult survivors of childhood cancer to (1) describe clinical insomnia rates, (2) identify physical and psychological correlates of insomnia, and (3) investigate the frequency with which sleep issues were evaluated during a cancer survivorship medical visit. A total of 122 adult survivors of childhood cancer completed standard measures of sleep, psychological distress, and health-related quality of life. Medical records of the 75 survivors with a survivorship medical visit on the day of self-report measure completion were reviewed for documentation of sleep-related issues. Results were as follows: Twenty-eight percent of participants endorsed sleep efficiency below 85 %, indicating clinically significant insomnia. Insomnia was associated with poor physical health and anxiety but not with demographic or cancer treatment variables. Medical providers failed to document sleep in visit notes for 67 % of patients with self-reported insomnia. Conclusions: A significant proportion of adult survivors of childhood cancer report insomnia, which is associated with physical and psychological health. Few survivors with insomnia discuss this issue with oncology providers during survivorship care. There is a clear need to screen for insomnia in this population. Patients and providers should take greater responsibility for discussing sleep issues and seeking out proper treatment referrals when it is identified.
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