Local and regional therapy for primary and locally recurrent melanoma.

In the vast majority of cases, cutaneous melanoma presents as localized disease and is treated with wide excision and sentinel lymph node biopsy, with shared decision making regarding completion lymph node dissection and adjuvant systemic therapy. The treatment of recurrent and in-transit disease is more complex, with further options for regional and systemic therapies and multiple variables to be factored into decisions. Rates of overall and complete response to regional therapies can be quite high in carefully chosen patients, which limits the need for systemic therapies and their inherent side effects. Ongoing trials aim to assess the efficacy of combination regional and systemic therapies and assist in deciding among these options. This review discusses the treatment of primary melanoma and regional nodal disease and offers an in-depth discussion of options for the treatment of recurrent melanoma and in-transit melanoma.

Developments in therapy for brain metastases in melanoma patients.

Introduction: Cutaneous melanoma brain metastases (MBM) are a major cause of morbidity and mortality. While cytotoxic agents, interferon, or interleukin-2, have been used with some success in extracranial disease, limited efficacy is demonstrated in MBM. The rare patient with long-term survival presented with limited intracranial disease amenable to surgery or radiation therapy. However, the development of targeted therapy and immunotherapy over the last decade has significantly improved overall survival in this formerly devastating presentation of metastatic melanoma.Areas covered: This article reviews the mechanism of brain metastasis, challenges with treating the central nervous system, historical treatment of MBM, and outcomes in clinical trials with targeted therapy and immunotherapy.Expert opinion: The MBM patient population now, more than ever, requires a multidisciplinary approach with surgery, radiation therapy, and the use of newer systemic therapies such as immunotherapy agents and targeted therapy agents. MBM has traditionally been excluded from clinical trials for systemic therapy due to poor survival. However, recent data show overall survival rates have significantly improved, supporting the need for inclusion of MBM patients in systemic therapy clinical trials. Understanding the mechanisms of therapeutic activity in the brain, resistance  mechanisms, and the appropriate multi-modality treatment approach requires further investigation. Nevertheless, these therapies continue to give some hope to patients with historically poor survival.

Frailty Cost: Economic Impact of Frailty in the Elective Surgical Patient.

BACKGROUND: Frailty in the surgical patient has been associated with increased morbidity, mortality, and failure to rescue. However, there is little understanding of the economic impact of frailty. STUDY DESIGN: A prospective database of elective surgery patients at an academic medical center was used to create a modified version of the Risk Analysis Index (RAI), a validated frailty index. This included 10,257 patients undergoing elective operations from 2016 to 2017. Patients were classified as not frail (RAI = 0), somewhat frail (RAI = 1 to 10), or significantly frail (RAI > 10). Cost, revenue, and income data were procured from the finance department. Univariate and multivariate analyses were performed. RESULTS: Frail patients were more likely to be older (65 years vs 50 years; p < 0.001) and inpatient (19% vs 36%; p < 0.001). General surgical, gynecologic, urologic, and cardiothoracic services operated on a higher percentage of significantly frail patients compared with orthopaedic, neurosurgical, and vascular (p < 0.001). On univariate analysis, frail patients were more likely to die (0% vs 0.4%; p < 0.001) and have increased length of stay (0.8 vs 2.1 days; p < 0.001), higher total cost ($6,934 vs $13,319), and lower net hospital income ($5,447 vs $3,129) (p < 0.001). On multivariate analysis, frailty was independently associated with increased direct cost (odds ratio [OR] 2.2; p < 0.001), indirect cost (OR 1.9; p < 0.001), total cost (OR 2.2; p < 0.001), and net income (OR 0.8; p < 0.001). Stratified by service line and inpatient vs outpatient status, frailty continued to be associated with increased direct cost, indirect cost, total cost, and decreased hospital income. CONCLUSIONS: Although a significant number of data exist on the impact of frailty in the surgical patient, the economic impacts have only limited description in the literature. Here we demonstrate that frailty, independent of age, has a detrimental financial impact on cost and hospital income in elective surgery.

Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer.

Pharmacologic ascorbate (P-AscH-) is emerging as a promising adjuvant for advanced pancreatic cancer. P-AscH- generates hydrogen peroxide (H2O2), leading to selective cancer cell cytotoxicity. Catalytic manganoporphyrins, such as MnT4MPyP, can increase the rate of oxidation of P-AscH-, thereby increasing the flux of H2O2, resulting in increased cytotoxicity. We hypothesized that a multimodal treatment approach, utilizing a combination of P-AscH-, ionizing radiation and MnT4MPyP, would result in significant flux of H2O2 and pancreatic cancer cytotoxicity. P-AscH- with MnT4MPyP increased the rate of oxidation of P-AscH- and produced radiosensitization in all pancreatic cancer cell lines tested. Three-dimensional (3D) cell cultures demonstrated resistance to P-AscH-, radiation or MnT4MPyP treatments alone; however, combined treatment with P-AscH- and MnT4MPyP resulted in the inhibition of tumor growth, particularly when also combined with radiation. In vivo experiments using a murine model demonstrated an increased rate of ascorbate oxidation when combinations of P-AscH- with MnT4MPyP were given, thus acting as a radiosensitizer. The translational potential was demonstrated by measuring increased ascorbate oxidation ex vivo, whereby MnT4MPyP was added exogenously to plasma samples from patients treated with P-AscH- and radiation. Combination treatment utilizing P-AscH-, manganoporphyrin and radiation results in significant cytotoxicity secondary to enhanced ascorbate oxidation and an increased flux of H2O2. This multimodal approach has the potential to be an effective treatment for pancreatic ductal adenocarcinoma.

Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma.

HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P-AscH- suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer.

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Superoxide Dismutases in Pancreatic Cancer.

The incidence of pancreatic cancer is increasing as the population ages but treatment advancements continue to lag far behind. The majority of pancreatic cancer patients have a K-ras oncogene mutation causing a shift in the redox state of the cell, favoring malignant proliferation. This mutation is believed to lead to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and superoxide overproduction, generating tumorigenic behavior. Superoxide dismutases (SODs) have been studied for their ability to manage the oxidative state of the cell by dismuting superoxide and inhibiting signals for pancreatic cancer growth. In particular, manganese superoxide dismutase has clearly shown importance in cell cycle regulation and has been found to be abnormally low in pancreatic cancer cells as well as the surrounding stromal tissue. Likewise, extracellular superoxide dismutase expression seems to favor suppression of pancreatic cancer growth. With an increased understanding of the redox behavior of pancreatic cancer and key regulators, new treatments are being developed with specific targets in mind. This review summarizes what is known about superoxide dismutases in pancreatic cancer and the most current treatment strategies to be advanced from this knowledge.

Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy.

Ascorbate (AscH-) functions as a versatile reducing agent. At pharmacological doses (P-AscH-; [plasma AscH-] ≥≈20mM), achievable through intravenous delivery, oxidation of P-AscH- can produce a high flux of H2O2 in tumors. Catalase is the major enzyme for detoxifying high concentrations of H2O2. We hypothesize that sensitivity of tumor cells to P-AscH- compared to normal cells is due to their lower capacity to metabolize H2O2. Rate constants for removal of H2O2 (kcell) and catalase activities were determined for 15 tumor and 10 normal cell lines of various tissue types. A differential in the capacity of cells to remove H2O2 was revealed, with the average kcell for normal cells being twice that of tumor cells. The ED50 (50% clonogenic survival) of P-AscH- correlated directly with kcell and catalase activity. Catalase activity could present a promising indicator of which tumors may respond to P-AscH-.