Phase 1b/2a trial of the superoxide dismutase mimetic GC4419 to reduce chemoradiotherapy-induced oral mucositis in patients with oral cavity or oropharyngeal carcinoma

PURPOSE: To assess the safety of the superoxide dismutase mimetic GC4419 in combination with radiation and concurrent cisplatin for patients with oral cavity or oropharyngeal cancer (OCC) and to assess the potential of GC4419 to reduce severe oral mucositis (OM). PATIENTS AND METHODS: Patients with locally advanced OCC treated with definitive or postoperative intensity modulated radiation therapy (IMRT) plus cisplatin received GC4419 by 60-minute intravenous infusion, ending \u3c60 minutes before IMRT, Monday through Friday for 3 to 7 weeks, in a dose and duration escalation study. Oral mucositis was assessed twice weekly during and weekly after IMRT. RESULTS: A total of 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15 to 112 mg/d over 3 weeks (n=20), duration escalation in 3 cohorts receiving 112 mg/d over 4 to 6 weeks (n=12), and then 3 additional cohorts receiving 30 or 90 mg/d over 6 to 7 weeks (n=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of 2 separate cohorts at 112 mg. Nausea/vomiting and facial paresthesia during infusion seemed to be GC4419 dose-related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6 to 7 weeks, with median duration of only 2.5 days. CONCLUSIONS: The safety of GC4419 concurrently with chemoradiation for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM seemed less frequent and briefer than expected

The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect

Management of choroidal/ciliary body metastasis in the era of targeted cancer therapy

IntroductionChoroidal metastases from systemic malignancies are the most common intraocular malignancies in adults. External beam radiation (EBR) has historically been first-line therapy for metastatic tumors to the choroid. However, good responses have been described with newer targeted biologics. The optimal management strategy for patients with choroidal metastatic tumors in the era of targeted cancer therapy is not known. We aim to describe management of these tumors in a “real-world” setting using both radiation and systemic therapy.MethodsWe conducted a retrospective review of patients with choroidal/ciliary body metastases managed by the ocular oncology service at our institution over a five-year period. Demographic data, tumor type, treatment, visual outcomes, and mortality data were recorded.Results26 patients (33 eyes) with choroidal/ciliary body metastasis were identified. Primary malignancies included lung (8) breast (8), renal (3), esophageal (3), carcinoid (2), squamous cell carcinoma of the tonsil (1), and testicular cancer (1). Average time from diagnosis of ocular metastasis to death was 8 months (1-34). 20 eyes were treated with EBR and 13 eyes were treated with other modalities. Final logMAR visual acuity for eyes treated with radiation was 0.11 (0-3). Final visual acuity for eyes treated with other modalities was 0.18 (0-.70), with local tumor control in 20/23 eyes that had follow up after treatment. The difference between final visual acuity in these groups was not visually significant p=0.48.ConclusionPatients with choroidal/ciliary body metastasis treated with either EBR or systemic therapy can have good visual outcomes. More work needs to be conducted to determine the optimal first-line treatment of ocular metastasis for specific tumor subtypes

Effective fisheries management instrumental in improving fish stock status

Marine fish stocks are an important part of the world food system and are particularly important for many of the poorest people of the world. Most existing analyses suggest overfishing is increasing, and there is widespread concern that fish stocks are decreasing throughout most of the world. We assembled trends in abundance and harvest rate of stocks that are scientifically assessed, constituting half of the reported globalmarine fish catch. For these stocks, on average, abundance is increasing and is at proposed target levels. Compared with regions that are intensively managed, regions with less-developed fisheries management have, on average, 3-fold greater harvest rates and half the abundance as assessed stocks. Available evidence suggests that the regions without assessments of abundance have little fisheries management, and stocks are in poor shape. Increased application of area-appropriate fisheries science recommendations and management tools are still needed for sustaining fisheries in places where they are lacking.Fil: Hilborn, Ray. University of Washington; Estados UnidosFil: Amoroso, Ricardo Oscar. University of Washington; Estados UnidosFil: Anderson, Christopher M.. University of Washington; Estados UnidosFil: Baum, Julia K.. University of Victoria; CanadáFil: Branch, Trevor A.. University of Washington; Estados UnidosFil: Costello, Christopher. University of California at Santa Barbara; Estados UnidosFil: de Moor, Carryn L.. University of Cape Town; SudáfricaFil: Faraj, Abdelmalek. Einstitut National de Recherche Halieutique; MarruecosFil: Hively, Daniel. University of Washington; Estados UnidosFil: Jensen, Olaf P.. Rutgers University; Estados UnidosFil: Kurota, Hiroyuki. Japan Fisheries Research and Education Agency; JapónFil: Little, L. Richard. Csiro Oceans and Atmosphere; AustraliaFil: Mace, Pamela. Ministry for Primary Industries; Nueva ZelandaFil: McClanahan, Tim. Wildlife Conservation Society; Estados UnidosFil: Melnychuk, Michael C.. University of Washington; Estados UnidosFil: Minto, Cóilín. Galway-Mayo Institute of Technology; IrlandaFil: Osio, Giacomo Chato. Joint Research Centre (JRC); Italia. DG Maritime Affairs and Fisheries, European Commission; BélgicaFil: Pons, Maite. University of Washington; Estados UnidosFil: Parma, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; ArgentinaFil: Segurado, Susana. Sustainable Fisheries Partnership; Estados UnidosFil: Szuwalski, Cody S.. University of California at Santa Barbara; Estados UnidosFil: Wilson, Jono R.. University of California at Santa Barbara; Estados Unidos. The Nature Conservancy; Estados UnidosFil: Ye, Yimin. Food and Agriculture Organization of the United Nations; Itali

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety

Definitive IMRT for Stage III Thymic Carcinoma: A Brief Report and Literature Review

IntroductionThymic carcinoma is a rare malignancy often presenting at an advanced stage. Radiosurgery and chemotherapy are often the only treatment options available to physicians.MethodsA 70-year old man presented with an unresectable Stage III thymic tumor and was treated with 45Gy in 12 fractions followed by a boost of 21.6 Gy in 12 fractions. He was also treated with bortezomib for multiple myeloma unrelated to his primary malignancy.ResultsThe patient made a full recovery following the radiation regimen and remained disease free four years after treatmentConclusionExclusive treatment with IMRT provides a viable treatment option for patients presenting with advanced stage thymic carcinoma