Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Phase II Trial of Acai Juice Product in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Plant derivatives have been studied as therapies for prostate cancer based on their purported anti-inflammatory and antioxidant properties and low toxicities. The acai berry is an example of a plant rich in phytochemicals, which may slow the growth of prostate cancer. METHODS: This was a phase II, Simon 2-stage clinical trial in patients with biochemically recurrent prostate cancer with a primary endpoint of prostate-specific antigen (PSA) response. Patients were asymptomatic, with a rising PSA of at least 0.2 ng/mL, and were treated with twice daily intake of Acai Juice Product until PSA progression, with a primary endpoint of PSA response. RESULTS: Twenty-one patients were enrolled in the first stage of the trial. One of those patients had a PSA response within the study time period. The PSA doubling time was lengthened in 71% of patients (95% confidence interval = 48% to 89%) on the trial, and in a small number of responders, this was sustained over an extended time. CONCLUSIONS: This study did not meet its primary endpoint of 50% PSA response. Nevertheless, the overall tolerability and effects on PSA stabilization warrant further exploration in a biochemically recurrent population.

Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior tyrosine kinase inhibitor therapy in patients with advanced renal cell carcinoma.

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

A neoadjuvant biochemotherapy approach to stage III melanoma: analysis of surgical outcomes.

AIMS: Completion lymph node dissection (CLND) and adjuvant therapy are recommended for node-positive melanoma patients. We sought to analyze our institution's experience with neoadjuvant biochemotherapy in stage III patients. METHODS: Clinical information was extracted from a retrospective database on stage III melanoma patients. Eligible patients received two cycles of biochemotherapy prior to their CLND. RESULTS: There were 153 patients available for analysis. The average tumor depth was 2.5 mm. More than half of all patients presented with sentinel lymph node-positive disease. Surgical complications occurred in 23% of patients. Patients who experienced an adverse event during their neoadjuvant therapy had a worse overall survival when compared with those who did not (p = 0.005). CONCLUSION: Our data suggest that aggressive neoadjuvant treatment prior to CLND does not impact surgical complications. Our surgical outcomes are similar to the current literature when adjuvant therapy is used in stage III melanoma. The inability to tolerate neoadjuvant therapy in stage III melanoma is a negative prognostic indicator.

Creative arts therapy improves quality of life for pediatric brain tumor patients receiving outpatient chemotherapy.

This mixed methods pilot study evaluated the effects of the creative arts therapy (CAT) on the quality of life (QOL) of children receiving chemotherapy. A 2-group, repeated measures randomized design compared CAT with a volunteer's attention (n = 16). Statistical analysis of the randomized controlled phase of the study suggested an improvement in the following areas after the CAT: parent report of child's hurt (P = .03) and parent report of child's nausea (P = .0061). A nonrandomized phase, using a different instrument showed improved mood with statistical significance on the Faces Scale (P < .01), and patients were more excited (P < .05), happier (P < .02), and less nervous (P < .02). Provider focus groups revealed positive experiences. Case studies are included to exemplify the therapeutic process. With heightened interest in complementary therapy for children with cancer, future research with a larger sample size is needed to document the impact of incorporating creative arts into the healing process.

A randomized controlled trial comparing a fascia iliaca compartment nerve block to a traditional systemic analgesic for femur fractures in a pediatric emergency department.

STUDY OBJECTIVE: We determine whether a fascia iliaca compartment nerve block can provide superior pain management compared with intravenous morphine sulfate for the initial pain management of femur fracture patients presenting to a pediatric emergency department. The primary outcome measured is pain scores; a difference of 15% in scores assessed at 30 minutes from the study's baseline pain management is considered clinically meaningful. Secondary outcomes include the duration of analgesia, the need for additional medications, adverse events, nerve block complications, and satisfaction scores. METHODS: This was a prospective, randomized, unblinded, controlled trial conducted on children aged 15 months to 18 years with acute femur fractures, presenting to a free-standing, tertiary care children's hospital. Patients were randomized to receive intravenous morphine sulfate or a fascia iliaca compartment nerve block using ropivacaine (Naropin). Pain scores (Children's Hospital of Eastern Ontario Pain Scale [CHEOPS]; Face, Legs, Activity, Cry and Consolability Pain Scale; Faces Pain Scale) were recorded at initial analgesic administration (baseline), at 5, 10, 15, 30, and 60 minutes, and then hourly up to 6 hours from baseline by trained nursing observers and research assistants. RESULTS: Fifty-five patients, 26 in the fascia iliaca compartment nerve block group and 29 in the morphine sulfate group, ranged in age from 16 months to 15 years (median 5.7 years). Baseline mean CHEOPS scores were similar: 9.4 fascia iliaca compartment nerve block and 9.5 morphine sulfate. Mean CHEOPS scores at 30 minutes after initial treatment were 5.87 for fascia iliaca compartment nerve block and 7.54 for morphine sulfate, with a difference of 1.67, which corresponds to an 18% (95% confidence interval [CI] 8% to 27%) difference in pain reduction between the 2 groups, according to the average baseline score of 9.45. Similar lower pain scores were observed in the fascia iliaca compartment nerve block group as early as 10 minutes from baseline and throughout the 6-hour duration of the study. In comparing the entire 6-hour CHEOPS pain scores, patients who received a fascia iliaca compartment nerve block showed lower scores by approximately 15% (95% CI 6% to 24%) compared to patients who received morphine sulfate. Median duration of analgesia was longer in the fascia iliaca compartment nerve block group compared with that in the morphine sulfate group (313 minutes [95% CI 154 to 360 minutes] versus 60 minutes [95% CI 10 to 255 minutes]). Fewer additional medications were given to patients who received the fascia iliaca compartment nerve block. No complications from the nerve block occurred. Satisfaction scores were higher with the fascia iliaca compartment nerve block among the medical staff. CONCLUSION: Fascia iliaca compartment nerve block provided clinically superior pain management compared with intravenous morphine sulfate at 30 minutes from baseline and throughout the initial 6 hours of medical treatment of children 16 months to 15 years who had isolated acute femur fractures. The results of this study, however, may be inflated by the nonblinding of the pain observers. Despite this potential bias, the fascia iliaca compartment nerve block should be considered as a valuable procedure in managing the pain commonly observed in these injured children.

Clinical and in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic stem cell transplant recipients.

Post-hematopoietic stem cell transplantation (HSCT) adenovirus infections were identified in 31 of 204 consecutive pediatric HSCT patients, 18 of whom had severe manifestations of infection. Cidofovir treatment led to clinical improvement in 8 of 10 patients with severe infection and to virologic clearance in 9 patients. In vitro susceptibility to cidofovir was demonstrated in 12 clinical adenovirus isolates. Cidofovir is a promising treatment option for this population.