Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

BACKGROUND: The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. METHODS: The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20 years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. RESULTS: Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. CONCLUSIONS: The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. TRIAL REGISTRATION: JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Feasibility and Safety of Super Energy-dense Oral Nutritional Supplementation in Postoperative Gastric Cancer Patients.

BACKGROUND/AIM: Ensuring that postoperative gastric cancer patients receive sufficient oral nutritional supplementation (ONS) to prevent body weight loss (BWL) is a serious challenge. The present pilot study evaluated the feasibility and safety of small, frequent sip feeds (SIP) with super energy-dense ONS (SED ONS; 4 kcal/ml) in postoperative gastric cancer patients. PATIENTS AND METHODS: Patients received 400 kcal/day of SED ONS in four, daily, 25 ml SIP for 12 weeks after gastrectomy. The primary outcome was the percentage of postoperative weight change. The expected mean weight change was 90% (10% standard deviation). A sample population of 14 patients, sufficient for a 95% confidence interval with a 10% margin of error, was enrolled. RESULTS: The mean weight change for patients receiving SIP with SED ONS was 93.8%. The mean SED ONS intake was 348 kcal/day. Thirteen patients consumed more than 200 kcal/day of SED ONS. One patient with a mean intake of 114 kcal/day had undergone total gastrectomy followed by adjuvant chemotherapy. CONCLUSION: Small, frequent SIP with SED ONS was found to be feasible and safe in postoperative gastric cancer patients. A multicenter randomized controlled trial is warranted to determine whether SIP with SED ONS is effective in preventing BWL.

Analgesic efficacy of continuous wound infiltration compared with continuous intravenous fentanyl after gynaecological surgery: a non-inferiority, randomised controlled trial.

OBJECTIVE: The present trial aimed to prove the non-inferiority of the analgesic efficacy of continuous wound infiltration (CWI) to that of continuous intravenous fentanyl (IV) and to compare the safety of the two methods. METHODS: This trial was a prospective, single-centre, two-arm, non-inferiority, randomised controlled trial. Patients participating in the trial were randomised to a CWI group or an IV group. The VAS (visual analogue scale), additional analgesic usage and side effects were then compared between the groups. RESULTS: In total, 61 patients were enrolled; two in CWI were excluded, leaving 59 (30 in the CWI group and 29 in the IV group) for analysis. The difference in the VAS score at 24 h (CWI group - IV group) was -3.2 (95% confidence interval [CI] -14.7 to 8.2), which was less than the non-inferiority margin of 15. The mean amount of total fentanyl use at postoperative hour 48 was 1395 (95% CI 886-1903) µg in the CWI group and 3186 (95% CI 2716-3658) µg in the IV group. The amount of other analgesics and the incidence of adverse effects did not differ significantly between the groups. CONCLUSION: CWI was non-inferior to IV in terms of its analgesic effect, and has an opioid sparing effect in open gynaecological surgery.

Impact of super energy-dense oral nutritional supplementation (SED ONS) on glycemic variability and food intake postoperatively in gastric cancer patients.

PURPOSE: Adherence to oral nutritional supplements (ONS) to prevent weight loss after gastrectomy is problematic. The present study evaluated the impact of super energy-dense ONS (SED ONS; 4 kcal/mL) on glycemic change and energy intake after gastrectomy. METHODS: Gastrectomy patients were placed on continuous glucose monitoring for a 3-day observation period after food intake had been stabilized postoperatively. In addition, they were given 0, 200, and 400 kcal/day of SED ONS on Days 1, 2, and 3, respectively. The primary outcome was the area under the curve < glucose 70 mg/dL (AUC < 70). The secondary outcomes were other indices of glucose fluctuation and the amount of food and SED ONS intake. RESULTS: Seventeen patients were enrolled. The AUC < 70 did not differ significantly with or without SED ONS over the observation period. SED ONS did not cause postprandial hypoglycemia and prevented nocturnal hypoglycemia. The mean dietary intake did not change significantly during the observation period, and the total energy intake increased significantly according to the amount of SED ONS provided. CONCLUSION: SED ONS after gastrectomy increased the total energy intake without dietary reduction and it did not result in hypoglycemia.

Prognosis of ultrasonographic low-grade pediatric appendicitis treated with supportive care.

BACKGROUND: A previous report proposed ultrasonography-based classification as a promising means of predicting pediatric spontaneously resolving appendicitis. The present study investigated the long-term prognosis of supportive care for low-grade appendicitis identified by ultrasonography, defined as an appendix with a smooth submucosal layer irrespective of blood flow or an appendix with an irregular layer and increased blood flow. METHODS: The present, retrospective cohort study enrolled patients under 16 years of age with acute appendicitis at a children's hospital between October 2010 and September 2016. The inclusion criteria were ultrasonography findings showing an appendix with (1) full visualization, (2) a diameter ≥6 mm, (3) a smooth submucosal layer or an irregular layer with increased blood flow, and (4) no appendiceal mass, abscess, or perforation. The exclusion criteria were: (1) a history of acute appendicitis, (2) antibiotic administration within 72 hours before diagnosis, and (3) antibiotic administration or surgery before supportive care. The primary outcome was the event-free duration, defined as a period of supportive care alone with no additional intervention or recurrence of appendicitis. RESULTS: One hundred and eighty-two patients were enrolled. The median Alvarado score was 7 (interquartile range, 6-8), and the median follow-up duration in event-free cases was 1,922 days (interquartile range, 1,347-2,614 days). The event-free rate was 75.0%, 67.0%, and 62.5%, at 1, 2, and 5 years, respectively. CONCLUSION: The long-term, event-free rate exceeded 60% in patients with low-grade appendicitis defined by ultrasonography who received neither surgery nor antibiotic treatment. Most recurrences occurred within 2 years of the initial diagnosis.

Tumor-Treating Fields Therapy for Pediatric Brain Tumors.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: A protocol for a randomized phase 2 trial.

Although cisplatin is one of the most effective agents against various pediatric cancers, it is sometimes difficult to manage due to its dose-limiting nephrotoxicity. Magnesium sulfate (Mg) showed a kidney-protective effect against cisplatin-induced nephrotoxicity (CIN) by regulating renal platinum accumulation both in vitro and in vivo, and the body of clinical data demonstrating the efficacy of this drug in adult cancer patients is increasing.In this open, multicenter, phase-2, randomized trial, patients under age 18 years who are scheduled to receive cisplatin-containing chemotherapy will be enrolled and randomly allocated either to an Mg supplementation arm in even-numbered chemotherapy courses (arm AB) or to another arm in odd-numbered courses (arm BA), with a 1:1 allocation. Analysis objects will be reconstructed into two groups depending on whether the chemotherapy course has Mg supplementation (group B) or not (group A). The primary endpoint is the proportion of chemotherapy courses resulting in elevated serum creatinine equal to or greater than 50% of the prechemotherapy value. For the secondary endpoints, various parameters for measuring kidney function, such as serum cystatin-C, B2M, L-FABP, NGAL, and urinary NAG in the two groups will be compared. A sample size based on alpha = 5% and 80% power requires at least 40 samples per group (ideally, 60 samples per group).If Mg demonstrates efficacy, a phase-3 study to confirm the prophylactic effect of Mg supplementation in both acute and chronic CIN will be developed using novel and better biomarkers. TRIAL REGISTRATION: UMIN-CTR (http://www.umin.ac.jp/icdr/index.html) Identifier UMIN000029215.

Kidney-protective Effect of Magnesium Supplementation in Cisplatin-containing Chemotherapy for Pediatric Cancer: A Retrospective Study.

In total, 158 chemotherapy courses containing cisplatin for 37 pediatric cases of newly diagnosed cancer were divided into 2 groups depending on whether magnesium (Mg) supplementation was administered (Mg+: 92 courses) or not (Mg-: 66 courses). Renal impairment was defined as grade 2 or higher creatinine elevation (CE) after each chemotherapy course. The incidence of CE in the Mg+ was significantly lower than in the Mg- (9.8% vs. 22.7%; P=0.025). Multivariate analysis revealed that Mg supplementation significantly reduced the incidence of CE (odds ratio, 0.36; confidence interval, 0.13-0.99). In pediatric patients, Mg supplementation during cisplatin-containing chemotherapy was associated with less cisplatin-induced nephrotoxicity to prevent cisplatin-induced nephrotoxicity.

The North Wind and the Sun: Pediatric Antimicrobial Stewardship Program Combining Restrictive and Persuasive Approaches in Hematology-Oncology Ward and Hematopoietic Stem Cell Transplant Unit.

BACKGROUND: The Japanese government's goal for the reduction of antimicrobial consumption is two-thirds of the 2013 rate by 2020. While the antimicrobial stewardship programs (ASPs) are essential in health care facilities, ASP data on pediatric hematology-oncology and hematopoietic stem cell transplant (HSCT) patients are limited. Our aim was to evaluate the impact of restrictive and persuasive ASP on immunocompromised children. METHODS: The ASP for hematology-oncology and HSCT patients at Tokyo Metropolitan Children's Medical Center was assessed. Phase 1 was a postprescriptive review of carbapenem conducted between April 2010 and September 2011. Phase 2 consisted of the preauthorization of carbapenem, prospective audit with feedback, a weekly luncheon meeting among physicians, consensus on febrile neutropenia management, and implementation of viral molecular diagnostics between October 2011 and September 2015. Both phases were compared for day-of-therapy per 1,000 patient-days, cost of intravenous antimicrobial agents, average hospitalization duration, all-cause mortality, infection-related mortality at 30 days, and appropriateness of empirical treatment of bacteremia. RESULTS: The ASP did not differ from phase 1 to phase 2 in terms of average hospitalization length, mortality rate, or appropriateness of empirical treatment for bacteremia. Day-of-therapies of cefepime, piperacillin/tazobactam, meropenem, vancomycin, liposomal amphotericin B, and fosfluconazole decreased by 20%, 45%, 57%, 38%, 85% and 44%, respectively (P < 0.05). The total cost of antibiotic and antifungal agents decreased by 27%, for a savings of $59,905 USD annually. CONCLUSION: Restrictive and persuasive ASP in the hematology-oncology ward and the HSCT unit safely decreased the use of antibacterial and antifungal agents.

Randomized Comparison of Subcuticular Sutures Versus Staples for Skin Closure After Open Abdominal Surgery: a Multicenter Open-Label Randomized Controlled Trial.

BACKGROUND: The incisional surgical site infection (SSI) is an extremely common complication following open abdominal surgery and imposes a considerable treatment and cost burden. METHOD: We conducted a multicenter open-label randomized controlled trial at three Tokyo Metropolitan medical institutions. We enrolled adult patients who underwent either an elective or an emergency open laparotomy. Eligible patients were allocated preoperatively to undergo wound closure with either subcuticular sutures or staples. A central Web-based randomization tool was used to assign participants randomly by a permuted block sequence with a 1:1 allocation ratio and a block size of 4 before mass closure to each group. The primary endpoint was the occurrence of a superficial SSI within 30 days after surgery in accordance with the Centers for Disease Control and Prevention criteria. This trial was registered with UMIN-CTR as UMIN 000004836 ( http://www.umin.ac.jp/ctr ). RESULTS: Between September 1, 2010 and August 31, 2015, 401 patients were enrolled and randomly assigned to either group. One hundred and ninety-nine patients were allocated to the subcuticular suture and 202 patients to the staple groups (hereafter the "suture" and "staple" group, respectively). Three hundred and ninety-nine were eligible for the primary endpoint. Superficial SSIs occurred in 25 of 198 suture patients and in 27 of 201 staple patients. Overall, the rate of superficial SSIs did not differ significantly between the suture and staple groups. CONCLUSION: Subcuticular sutures did not increase the occurrence of superficial SSIs following open laparotomies mainly consisting of clean-contaminated surgical procedures. The applicability of the wound closure material and method is likely to depend on individual circumstances of the patient and surgical procedure.