Neoadjuvant ifosfamide and epirubicin in the treatment of malignant peripheral nerve sheath tumors

Background and Objectives. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with poor overall survival. Response to chemotherapy has been debated for these tumors. Methods. We performed a retrospective analysis of the patients at our institution with a biopsy-proven diagnosis of MPNST that underwent neoadjuvant chemotherapy prior to surgery. Results. We retrospectively identified five patients who received neoadjuvant chemotherapy with epirubicin and ifosfamide that demonstrated a 30% reduction in tumor growth and a 60% response rate by RECIST criteria. Additionally, a metabolic response was observed in all three patients who received serial PET scans during neoadjuvant treatment. The clinical benefit rate, which includes stable disease, was 100%. Conclusions. Our data suggest that MPNSTs do respond to epirubicin and ifosfamide based chemotherapy and prospective studies are warranted to further define the clinical benefit

SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production

Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b+ myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT

Cardiac Atrophy Due to Cancer: Characterization, Mechanisms, and Sex Differences

Approximately one-third of cancer deaths are caused by cachexia, a severe form of skeletal muscle and adipose tissue wasting that affects men more than women. The heart also undergoes atrophy in cancer patients but the extent, functional consequences, mechanisms and sex differences have not been elucidated. In a mouse colon-adenocarcinoma model, cancer causes a loss of cardiac mass due to a decrease in cardiac myocyte size that is associated with reduced levels of all sarcomeric proteins. I provide evidence that published reports showing a selective decrease in myosin heavy chain (MyHC) during cancer cachexia are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. I show that MyHC decreases in parallel with other myofibrillar proteins in cachectic cardiac and skeletal muscle. Unlike skeletal muscle, atrophic hearts do not upregulate the ubiquitin-proteasome system (UPS) or its activity but increase autophagy. Thus, cancer causes cardiac atrophy by a mechanism distinct from that in skeletal muscle. This murine model recapitulates the sexual dimorphism associated with cachexia in human patients. I demonstrate that male tumor-bearing mice have a more severe phenotype than females, including greater cardiac mass loss and mortality. In females, estrogen protects against cancer-induced cardiac atrophy and body weight loss by signaling through its receptor. I also examined the effect of dietary phytoestrogens on cancer cachexia. A soy diet worsens cachexia in both sexes, while a casein-based diet decreases the extent of skeletal and cardiac muscle mass loss in males yet increases cancer mortality in both sexes. Finally, I established an in vitro model of cardiac atrophy. Interferon-γ (IFN), a pro-inflammatory cytokine commonly increased in the serum of cancer patients and in the myocardium of patients suffering from Chagas\u27 disease, causes cardiac myocyte atrophy, but unlike the mechanism in vivo, IFN activates the UPS and causes the specific degradation of MyHC in a proteasome-dependent manner. Together, these studies provide mechanistic insight into cardiac atrophy due to cancer and inflammatory cytokines, and demonstrate that cardiac and skeletal muscle cachexia are modulated by both sex and diet

Patient Derived Models to Study Head and Neck Cancer Radiation Response

Patient-derived model systems are important tools for studying novel anti-cancer therapies. Patient-derived xenografts (PDXs) have gained favor over the last 10 years as newer mouse strains have improved the success rate of establishing PDXs from patient biopsies. PDXs can be engrafted from head and neck cancer (HNC) samples across a wide range of cancer stages, retain the genetic features of their human source, and can be treated with both chemotherapy and radiation, allowing for clinically relevant studies. Not only do PDXs allow for the study of patient tissues in an in vivo model, they can also provide a renewable source of cancer cells for organoid cultures. Herein, we review the uses of HNC patient-derived models for radiation research, including approaches to establishing both orthotopic and heterotopic PDXs, approaches and potential pitfalls to delivering chemotherapy and radiation to these animal models, biological advantages and limitations, and alternatives to animal studies that still use patient-derived tissues

Intensity modulated radiation therapy and surgery for Management of Retroperitoneal Sarcomas: a single-institution experience

Abstract Background Peri-operative radiation of retroperitoneal sarcomas (RPS) is an important component of multidisciplinary treatment. All retrospective series thus far included patients treated with older radiation therapy (RT) techniques including 2D and 3DRT. Intensity modulated radiation therapy (IMRT) allows for selective dose escalation while sparing adjacent organs. We therefore report the first series of patients with RPS treated solely with IMRT, surgery and chemotherapy. We hypothesized that IMRT would permit safe dose escalation and superior rates of local control (LC) in this high-risk patient population. Methods Thirty patients with RPS treated with curative intent between 2006 and 2015 were included in this retrospective study. RT was administered either pre- or post-operatively and IMRT was used in all patients. Statistical comparisons, LC, distant metastasis (DM), and overall survival (OS) were calculated by Kaplan-Meier analysis and univariate Cox regression. Results Median follow-up time after completion of RT was 36 months (range 1.4-112). Median tumor size was 14 cm (range 3.6 - 28 cm). The most prevalent histologies were liposarcoma in 10 (33%) patients and leiomyosarcoma in 10 (33%) with 21 patients (70%) having high-grade disease. Twenty-eight (93%) patients had surgical resection with 47% having positive margins. Chemotherapy was administered in 9 (30%) patients. RT was delivered pre-operatively in 11 (37%) patients, and post-operatively in 19 (63%) with 60% of patients receiving a simultaneous integrated boost. Pre-operative median RT dose to the high-risk area was 55 Gy (range, 43–66 Gy) while median post-operative dose was 60.4 Gy (range, 45-66.6 Gy). There was one acute grade 3 and one late grade 3 toxicity and no grade 4 or 5 toxicities. Three year actuarial LC, freedom from DM, and OS rates were 84%, 64%, and 68% respectively. Positive surgical margins were associated with a higher risk of local recurrence (p = 0.02) and decreased OS (p = 0.04). Pre-operative RT was associated with improved LC (p = 0.1) with a 5-year actuarial LC of 100%. Administration of chemotherapy, timing of RT, histology or grade was not predictive of OS. Conclusions Patients with RPS treated with peri-operative IMRT at our institution had excellent local control and low incidences of toxicity