Detection of Ferritin Expression in Soft Tissue Sarcomas With MRI: Potential Implications for Iron Metabolic Therapy.

Background: Cancer cells often have altered iron metabolism relative to non-malignant cells with increased transferrin receptor and ferritin expression. Targeting iron regulatory proteins as part of a cancer therapy regimen is currently being investigated in various malignancies. Anti-cancer therapies that exploit the differences in iron metabolism between malignant and non-malignant cells (e.g. pharmacological ascorbate and iron chelation therapy) have shown promise in various cancers, including glioblastoma, lung, and pancreas cancers. Non-invasive techniques that probe tissue iron metabolism may provide valuable information for the personalization of iron-based cancer therapies. T2* mapping is a clinically available MRI technique that assesses tissue iron content in the heart and liver. We aimed to investigate the capacity of T2* mapping to detect iron stores in soft tissue sarcomas (STS). Methods: In this study, we evaluated T2* relaxation times ex vivo in five STS samples from subjects enrolled on a phase Ib/IIa clinical trial combining pharmacological ascorbate with neoadjuvant radiation therapy. Iron protein expression levels (ferritin, transferrin receptor, iron response protein 2) were evaluated by Western blot analysis. Bioinformatic data relating clinical outcomes in STS patients and iron protein expression levels were evaluated using the KMplotter database. Results: There was a high level of inter-subject variability in the expression of iron protein and T2* relaxation times. We identified that T2* relaxation time is capable of accurately detecting ferritin-heavy chain expression (r = -0.96) in these samples. Bioinformatic data acquired from the KMplot database revealed that transferrin receptor and iron-responsive protein 2 may be negative prognostic markers while ferritin expression may be a positive prognostic marker in the management of STS. Conclusion: These data suggest that targeting iron regulatory proteins may provide a therapeutic approach to enhance STS management. Additionally, T2* mapping has the potential to be used a clinically accessible, non-invasive marker of STS iron regulatory protein expression and influence cancer therapy decisions that warrants further investigation. Level of Evidence: IV.

A Retrospective Analysis of Clinical Trial Accrual of Patients Presented in a Multidisciplinary Tumor Board at a Tertiary Health Care Center and Associated Barriers.

INTRODUCTION: Cancer clinical trial accruals have been historically low and are affected by several factors. Multidisciplinary Tumor Board Meetings (MTBM) are conducted regularly and immensely help to devise a comprehensive care plan including discussions about clinical trial availability and eligibility. OBJECTIVES: To evaluate whether patient discussion at MTBM was associated with a higher consent rate for clinical trials at a single tertiary care center. METHODS: Institutional electronic medical records (EMR) and clinical trials management system (OnCore) were queried to identify all new patient visits in oncology clinics, consents to clinical trials, and MTBM notes between January 1, 2011 and December 31, 2015. The association between MTBM discussion and subsequent clinical trial enrollment within 16 weeks of the new patient visit was evaluated using a χ2 test. RESULTS: Between January 1, 2011 and December 31, 2015, 11,794 new patients were seen in oncology clinics, and 2,225 patients (18.9%) were discussed at MTBMs. MTBM discussion conferred a higher rate of subsequent clinical trial consent within 16 weeks following the patient's first consultation in an oncology clinic: 4.1% for those who were discussed at a MTBM compared to 2.8% for those not discussed (p < 0.01). CONCLUSIONS: This study provides evidence that MTBMs may be effective in identifying patients eligible for available clinical trials by reviewing eligibility criteria during MTBM discussions. We recommend discussion of all new patients in MTBM to improve the quality of care provided to those with cancer and enhanced clinical trial accrual.

Durable Clinical Benefit in Patients with Advanced Cutaneous Melanoma after Discontinuation of Anti-PD-1 Therapies Due to Immune-Related Adverse Events.

INTRODUCTION: Anti-PD-1 therapies, pembrolizumab and nivolumab, are currently the standard of care for treatment of patients with metastatic melanoma. Treatment is usually continued until toxicity or disease progression. Though these therapies are well tolerated, some patients discontinue them due to immune-related adverse events (irAE). Discontinuation of therapy brings challenges to their management due to limited treatment options and lack of long-term prognostic information for these patients. Herein, we reviewed patients at our institution to analyze their clinical outcomes. MATERIALS AND METHODS: Charts of 1264 consecutive patients enrolled between 8/1/2012 and 7/31/2017 at Melanoma Skin & Ocular Tissue Repositories at Holden Comprehensive Cancer Center at the University of Iowa Hospitals and Clinic were reviewed. Eligible patients were those who received single-agent anti-PD-1 therapy and subsequently discontinued it due to irAE. Reviewed data included patient demographics, prior medical history, baseline disease parameters, and outcomes. Kaplan-Meier survival analysis was done to determine progression-free survival (PFS) and overall survival (OS). RESULTS: Overall 169 patients with advanced, unresectable, or metastatic cutaneous melanoma received anti-PD-1 therapy of which 16 (9.5%) white, non-Hispanic patients with median age of 64.5 (range 35 to 81 years) discontinued treatment due to irAE. Fifteen patients received pembrolizumab and one received nivolumab. The median duration of treatment was 4.7 (range 0.7 to 11.5) months. Median follow-up was 30.3 (range 4.6 to 49.4) months. Median PFS was 24.6 months and median OS was not reached. Durable clinical benefit (time to progression or next treatment of more than 6 months from last treatment) was observed in 13 (81.2%) patients. At the time of analysis, 8 patients had progressed and 4 patients died (all-cause). DISCUSSION: Our results suggest that advanced melanoma patients discontinuing anti-PD-1 therapy due to irAE usually experience durable clinical benefit. However, caution is needed with these agents in patients with underlying autoimmune diseases.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models.

Soft tissue sarcomas are a histologically heterogeneous group of rare mesenchymal cancers for which treatment options leading to increased overall survival have not improved in over two decades. The current study shows that pharmacological ascorbate (systemic high dose vitamin C achieving ≥ 20mM plasma levels) is a potentially efficacious and easily integrable addition to current standard of care treatment strategies in preclinical models of fibrosarcoma and liposarcoma both in vitro and in vivo. Furthermore, enhanced ascorbate-mediated toxicity and DNA damage in these sarcoma models were found to be dependent upon H2O2 and intracellular labile iron. Together, these data support the hypothesis that pharmacological ascorbate may represent an easily implementable and non-toxic addition to conventional sarcoma therapies based on taking advantage of fundamental differences in cancer cell oxidative metabolism.

Ipilimumab: from preclinical development to future clinical perspectives in melanoma.

The arsenal for the treatment of metastatic melanoma is limited. A new approach to therapy using checkpoint blockade has improved overall survival in this patient population. Ipilimumab a CTLA-4 monoclonal antibody is a first in class drug that has pioneered this revolution. In this review, the authors provide an account of the different stages that led to the development of ipilimumab, its approval in the clinical setting for the treatment of advanced melanoma and ongoing investigations of combinatorial immune therapy.

Jordan palliative care initiative: a WHO Demonstration Project.

A model for pain relief and palliative care for the Middle East has been established in Jordan. King Hussein Cancer Centre (KHCC) in Amman is now a truly comprehensive cancer center as it includes palliative care for inpatients, outpatients, and patients at home. This is especially important in a country and a region where over 75% of the cancer patients are incurable when diagnosed. To support effective palliative care delivery, there have been many significant changes in Jordan between 2001 and 2006. Regulations governing opioid prescribing have been changed to facilitate effective pain management. The national opioid quota has been increased. Cost-effective, generic, immediate-release morphine tablets are being produced in Jordan. Intensive, interactive bedside training courses for doctors, nurses, and clinical pharmacologists have started to overcome opiophobia and motivate health care professionals to take up palliative care as a profession. "Champions" for palliative care have emerged who are leading the development of palliative care in Jordan's health care systems and starting to support neighboring countries to develop pain relief and palliative care. While before 2003, fewer than 250 patients per year received palliative care, by 2006 more than 800 patients per year were receiving pain relief and palliative care through the KHCC and Al Basheer Hospital. The achieved changes and the unusually rapid and effective institutionalization of palliative care serve as a model for other countries in the Middle East region as to what should be done and how.