Atlas of Science

Tag: sarcoma

Molecular targeted therapy in alveolar soft part sarcoma

Alveolar soft part sarcoma is a malignant and rare tumor that includes about 1% of all STS (soft tissue sarcoma), and usually occurs in adolescents and young adults. This type of cancer has tendency toward distant metastasis and invasion especially to brain and lungs. Alveolar soft part sarcoma (ASPS) is characterized by unbalanced non-reciprocal translocation between X and 17 chromosomes, t(X; 17) (p11.2; q25) which leads to ASPSCR1-TFE3 fusion gene. TFE3 is a potent regulator of tumor cell growth and metabolism pathways including (mTORC1, c-Met and HIF1α) (Fig. 1).

Fig. 1. Molecular features and targeted therapy of alveolar soft part sarcoma.

Tumor resection is the most effective treatment intervention for operable ASPS and could result in complete remission, but if complete excision of tumor through surgery is not possible, poor prognosis is predictable. Many studies have shown that chemotherapy drugs are not effective in ASPS treatment and response to radiotherapy is controversial, but targeted therapy seems to be a good option for ASPS therapy (Fig. 2).

Fig. 2. Schematic representation of major deregulated oncogenic signaling pathways in ASPS and their inhibition by potential applicable molecular-targeting agents (A). Cancer immunotherapy could be as a salvage therapy approach for ASPS treatment (B). Some of these molecular-targeting agents such as perifosine, sunitinb, cediranib, pazopanib, everolimus and cabozantinib are under clinical trial for ASPS and/or STS treatment. More investigations are needed to better assess the efficacy of these drugs in ASPS treatment. (GF: growth factor, RTK: receptor tyrosine kinases, PI3K: phosphatidylinositol-3 kinase, mTOR: the mammalian target of rapamycin, MEK: mitogen-activated protein kinase kinase, ERK: extracellular signal–regulated kinase, PD-1: programmed cell death protein 1, PD-L: programmed death-ligand 1, CTLA4: cytotoxic T-lymphocyte-associated protein 4).

Transcriptomic analysis of ASPS has revealed upregulation of angiogenic and metastatic targets such as VEGF and c-Met suggesting that angiogenic and metastatic pathways are hallmarks of ASPS and could be used in ASPS therapy. Alveolar soft part sarcoma is a hyper vascular tumor, so use of angiogenesis inhibitors may be a suitable choice in controlling ASPS progression. Use of combined mulitargeted TKI (tyrosine kinase inhibitor) and immunotherapeutic can improve patient outcomes in ASPS; however, more translational and clinical researches are necessary to demonstrate efficacy and safety of these treatment approaches.

Mohammad Hasan Soheilifar ^1,2, Ramezan Ali Taheri ¹, Reza Zolfaghari Emameh ³,
Abdolvahab Moshtaghian ⁴, Hamid Kooshki ¹, Mohammad Reza Motie ⁵
¹Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
²Research Center for Molecular Medicine and Genetics, School of Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
³Department of Energy and Environmental Biotechnology, Division of Industrial & Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
⁴Deputy of Research and Technology, Semnan University of Medical Sciences, Semnan, Iran
⁵Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Publication

Molecular Landscape in Alveolar Soft Part Sarcoma: Implications for Molecular Targeted Therapy.
Soheilifar MH, Taheri RA, Zolfaghari Emameh R, Moshtaghian A, Kooshki H, Motie MR
Biomed Pharmacother. 2018 Jul

July 8, 2019
Can the heart get cancer? Quite rare, but yes

To many, the heart seems as an unusual location for cancer. In fact, most tumors that affect the heart are metastatic in origin (start in other organs and disseminate to the heart). Primary cardiac tumors (tumors that originate from the heart itself) are quite rare and fortunately benign. However, their position in the heart may lead to serious complications, such as heart failure or valve obstruction. Therefore, data on these rare tumors are usually available from autopsy series. However, in a new analysis, authors from Ain Shams University examined the incidence, characteristics, and survival rates of primary cardiac tumors. The authors used data from the SEER (Surveillance, Epidemiology, and End Results) database, a large registry of over 8 million cancer patients in the United States.

Fig. 1. The annual percentage change for the incidence of hemangiosarcoma, showing a non-significant change between 2000 and 2014.

Among the registered patients, only 497 were diagnosed with primary cardiac tumors. Two tumor types were especially prevalent: angiosarcomas (136 patients) and non-Hodgkin’s lymphomas (134 patients). The first (angiosarcoma) originates from blood vessels in the cardiac muscle and sends metastasis early to the lungs. They often develop in the right atrium at a remarkably young age (20 to 50 years old), suggesting that they may have a genetic element or develop in patients, treated with radiotherapy to the chest for childhood cancers. The second (non-Hodgkin’s lymphoma) originate from lymphocytes in the cardiac tissue and usually have a silent presentation until they present with intractable heart failure. They usually develop in immunocompromised patients as those with AIDS or on chemotherapy post-organ transplantation.

The study also analyzed whether the incidence rates of these tumors changes over the period of data collection (between 2000 and 2014). The incidence rate of angiosarcoma did not change significantly over this period (Fig. 1), while the incidence rate of cardiac non-Hodgkin’s lymphomas increased significantly, probably due to the increasing numbers of immunocompromised patients in the past two decades (Fig. 2). However, this statistical increase may be related to the improvement of diagnostic modalities and requires further investigation. Due to the small numbers of patients with other tumor types, their incidence rates trends were not statistically analyzed.

Fig. 2. The annual percentage change for the incidence of non-Hodgkin’s lymphoma, showing a significant increase between 2000 and 2014.

Further, the authors analyzed the survival of these tumors and found that non-Hodgkin’s lymphoma patients have better overall survival than angiosarcoma patients (medians 34 vs. 9 months, respectively). Using other statistical methods, they showed that the survival of these patients is not dependent on their age, sex, or race. However, surgical treatment significantly increases the survival of such cases. Therefore, surgery may be an effective approach for these rare tumors. This study analyzed a relatively large number of patients considering the rarity of the studied event. However, further research is required to establish these findings and determine the best therapeutic modality for these tumors.

Abdelrahman Ibrahim Abushouk, Anas Saad, Muneer J. Al-Husseini
Faculty of Medicine, Ain Shams University, Cairo, Egypt

Publication

Characteristics, survival and incidence rates and trends of primary cardiac malignancies in the United States.
Saad AM, Abushouk AI, Al-Husseini MJ, Salahia S, Alrefai A, Afifi AM, Abdel-Daim MM
Cardiovasc Pathol. 2018 Mar – Apr

June 4, 2019
Chemotherapy and radiotherapy in abdominal sarcoma

Soft tissue sarcomas (STS) are a rare group of cancers that arise in connective tissues such as muscles, fat and blood vessels. STS can occur almost anywhere in the body but are most commonly found in the extremities and less often in the retroperitoneum (the back of the abdomen), neck and thorax. STS encompass a wide range of tumours with different histology, natural history and size. Their response to treatment is dependent on these features as well as their anatomical location and tumour grade. In retroperitoneal sarcoma (RPS) extended surgery is the mainstay of treatment, however, neoadjuvant (before surgery) and/or adjuvant (after surgery) strategies may be utilised to decrease the risk of both local and distant disease recurrence. In this summary we discuss the current role of chemotherapy and radiotherapy in the treatment of RPS and highlight important on-going international clinical trials of neoadjuvant radiotherapy and chemotherapy.

Fig. 1. Coronal CT images showing a left retroperitoneal dedifferentiated liposarcoma before (left) and after (right) neoadjuvant chemotherapy with anthracycline plus ifosfamide (three cycles). The size of the tumour is unchanged, but there is evidence of a pathological response, with cystic degeneration of the dedifferentiated component. This implies there are less viable tumour cells following the course of chemotherapy.

Radiotherapy is a treatment that uses radiation to destroy cancer cells. Neoadjuvant radiotherapy (NRT) aims to sterilise the margins of the tumour with the aim of minimising the likelihood of viable tumour cells being left behind following surgery. Currently NRT is used selectively in RPS. It is considered in patients with tumours abutting vital structures such as major blood vessels or pelvic bones where the possibility for wide circumferential surgical resection is limited.

Although there are no published randomised controlled trials comparing NRT plus surgery to surgery alone in RPS, an ongoing international collaborative study (STRASS trial) has now finished recruiting and the results are eagerly anticipated.

The use of radiotherapy to the tumour margins after surgical resection, termed adjuvant radiotherapy, is not recommended in RPS due to the significant risk of damage to other essential internal organs such as the intestines which fall into the void left by the tumour after surgery.

Chemotherapy is the destruction of cancer cells using medication. Chemotherapy regimens in STS have changed little in the past 40 years as highly effective, targeted therapies remain elusive. In the majority of RPS, chemotherapy is reserved as a palliative strategy and has no proven role as an adjunct to surgery, either in a neoadjuvant or adjuvant setting. There are some notable exceptions: rhabdomyosarcoma, extra-skeletal Ewings sarcoma and synovial sarcoma are all relatively chemosensitive and in these tumours neoadjuvant chemotherapy (NCT) has become standard practice. However, in the majority of RPS subtypes there is no convincing evidence to support the use of NCT and instead clinicians prefer to avoid the delay to surgery and risk of complications associated with chemotherapy use.

The very poor outcomes following surgery in patients with high-grade (highly aggressive) tumours has, however, led to a recent re-evaluation of the role of NCT in these particularly high-risk tumours. Effective NCT could potentially downstage tumours to reduce the complexity of subsequent surgery and could also destroy micrometastases (invisible tumour deposits) to prevent recurrence at distant sites. A new study, currently in development, called STRASS 2 will aim to compare outcomes in patients with high- and intermediate-grade tumours treated with NCT and surgery versus surgery alone. This international multi-centre randomised controlled trial is due to start recruiting patients in 2020.

A collaborative effort is critical to improving outcomes and advancing treatment strategies in RPS. The Transatlantic Retroperitoneal Sarcoma Working Group acts as an international forum for discussion of RPS treatments and for facilitation of global trials, which are essential in this rare disease. However, major improvements in outcomes will only come from development of novel treatments through research and innovation, and continuous engagement between clinicians and basic scientists is essential to achieving this goal.

Ahmad R, Desai A, Ford S, Almond LM
Department of Sarcoma and General Surgery, Midlands Abdominal and Retroperitoneal Sarcoma Unit,
University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom

Publication

Neoadjuvant and adjuvant strategies in retroperitoneal sarcoma.
Almond LM, Gronchi A, Strauss D, Jafri M, Ford S, Desai A.
Eur J Surg Oncol. 2018 May

April 1, 2019