Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

Desmoplastic Small Round Cell Tumor: Long-Term Complications After Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal soft tissue sarcoma affecting adolescents and young adults. Cytoreduction, hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), and adjuvant radiotherapy may improve local control. We review our experience with patients who undergo CRS/HIPEC and adjuvant radiotherapy for DSRCT. METHODS: A retrospective review was performed for patients with DSRCT from 2013 to 2017 who underwent CRS/HIPEC. Clinicopathologic, operative, and outcome data were reviewed. RESULTS: Ten CRS/HIPEC procedures were performed for nine patients (7 males, 6 Caucasian, median age 19 years (range 10-24)). Four patients presented with extra-abdominal disease; five had liver involvement. The median peritoneal cancer index was 16 (range 5-20). All received neoadjuvant chemotherapy. CCR 0/1 resection was possible in nine patients. Major complications occurred in four with no operative mortalities. All received adjuvant chemotherapy, seven received radiation therapy, and three received stem-cell transplant. All but one patient recurred after treatment. The median recurrence-free and overall survival (OS) were 12 and 45 months (95% confidence interval 35.1-54.9) respectively, with a 3-year OS of 55%. Long-term parenteral nutrition was required in eight for a median of 261 days (range 37-997). Clinically significant long-term complications requiring further surgery included gastroparesis (N = 1), small bowel obstruction (N = 3) and hemorrhagic cystitis (N = 2). CONCLUSIONS: Multimodal therapy for DSRCT consisting of multiagent neoadjuvant chemotherapy, CRS/HIPEC, adjuvant chemotherapy, and radiation therapy is associated with potential cumulative toxicity. Recurrence after resection is common. Prolonged parenteral nutrition may be necessary, and late gastrointestinal and genitourinary complications may require additional treatment.

Anesthesia and Pain Management for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Desmoplastic Small Round Cell Tumors in Children, Adolescents, and Young Adults.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival. METHODS: A retrospective review of anesthetic management and postoperative pain control strategies after CRS/HIPEC for DSRCT from 2013 to 2017 was performed. RESULTS: The review analyzed 10 CRS/HIPEC procedures performed for nine DSRCT patients with a median age of 19 years (range 10-24 years). Six of these patients were Caucasian, and seven were men. The median operative duration was 551 min (range 510-725 min), and the median anesthesia duration was 621 min (range 480-820 min). Postoperative mechanical ventilation was necessary in 5 patients for a median duration of 1 day (range 0-2 days). The median intraoperative intravenous fluid administration was 13 ml/kg/h (range 6.3-24.4 ml/kg/h), and the colloid administration was 12 ml/kg (range 0.0-53.0 ml/kg). The median blood loss was 15 ml/kg (range 6.3-77.2 ml/kg). Nine patients received intraoperative transfusion with a median red blood cell transfusion volume of 14 ml/kg (range 10.1-58.5 ml/kg). The median intraoperative urine output was 2 ml/kg/h (range 0.09-8.40 ml/kg/h), and half of the patients received intraoperative diuretics. Cisplatin was used during HIPEC for eight surgeries. Acute kidney injury was observed in two patients, one of whom required short-term dialysis. Epidural infusions were used in eight cases for a median of 4 days (range 3-5 days). Postoperative intravenous opioid use (morphine equivalent) was 0.67 mg/kg/day (range 0.1-9.2 mg/kg/day) administered for a median of 11 days (range 2-35 days). CONCLUSION: Cytoreduction and HIPEC for DSRCT are associated with significant perioperative fluid requirements and potentially challenging pain management. Renal protective strategies should be considered for reduction of cisplatin-associated nephrotoxicity. Further investigation for a more effective, less systemically toxic HIPEC agent is warranted.

The Impact of Ostomy Creation after Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy in a Newly Established Peritoneal Malignancy Program.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has improved outcomes for selected patients with peritoneal carcinomatosis and often requires ostomy creation. We examined the impact of ostomy creation in a newly established peritoneal malignancy program. A retrospective review was performed of CRS-HIPEC procedures from 2011 to 2016. Those who did and did not receive an ostomy were compared. Fifty-eight patients underwent CRS-HIPEC and an ostomy was created in 25.9 per cent. Median peritoneal cancer index (14 vs 16, P = 0.63) and multivisceral resection rates (87.9 vs 100.0%, P = 0.17) were similar between groups. Multivariable analysis revealed that bowel resection (OR 210.65, P = 0.02) was significantly associated with ostomy creation. Advanced age was noted to be inversely associated with stoma formation (OR 0.04, P = 0.04). Progression-free survival was significantly lower in the ostomy group (18 vs 23 months, P = 0.03). Those with an ostomy experienced prolonged length of stay (13.3 ± 7.4 vs 9.5 ± 3.7, P = 0.01). At follow-up, 6/10 temporary ostomies had undergone reversal and three patients experienced morbidity after reversal. Ostomy creation may occur during CRS-HIPEC and carries potential for morbidity. Ostomy creation may contribute to postoperative length of stay. Patients should be counseled preoperatively on the potential impact of ostomy placement during CRS-HIPEC.

Operative and Immediate Postoperative Differences Between Traditional Multiport and Reduced Port Laparoscopic Total Splenectomy in Pediatric Patients.

BACKGROUND: Laparoscopy offers many benefits to splenectomy, such as reduced incisional pain and shortened hospital duration. The purpose of this study is to evaluate procedural and outcome differences between multiport (MP) and reduced port (RP) splenectomy when utilized to treat children. PATIENTS AND METHODS: An institutional review board approved retrospective analysis of all consecutive laparoscopic total splenectomies performed at a single institution between January 2010 and October 2015 was conducted. We evaluated demographics, surgical technique, instance of conversion, operative duration, estimated blood loss, need for intraoperative blood transfusion, postoperative length of stay, time to full feeds, complications, and follow-up duration. RESULTS: Over a 5-year period, 66 patients less than 20 years of age underwent laparoscopic total splenectomy. RP splenectomy was attempted in 14 patients. The remaining 52 were MP operations. Populations were comparable with regard to demographics. Preoperative splenic volumes (mL) were greater in the RP population (median [IQR]: 1377 [747-1508] versus 452 [242-710], P = .039). RP splenectomy demonstrated no difference compared to MP splenectomy in operative time (153 versus 138 minutes, P = .360), estimated blood loss (120 versus 154 mL, P = .634), or percent of cases requiring intraoperative blood transfusion (14 versus 23, P = .716). By the first postoperative day, 57% of RP and 17% of MP patients could be discharged (P = .005). Thirty-day readmission rates were similar, at 7% for RP and 8% for MP operations. Fever was the indication for all readmissions. Mean duration of follow-up is 28 months for MP and 13 months for RP cases. CONCLUSION: A reduced number of ports can be safely utilized for total splenectomy in pediatric patients without increasing procedural duration or need for intraoperative blood transfusion. In addition, rate of discharge on the first postoperative day was significantly higher in the RP splenectomy group.

Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors.

PURPOSE: Antiangiogenic agents show significant antitumor activity against various tumor types. In a study evaluating the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide in children with solid tumors, an unexpectedly high incidence of pneumothorax was observed. We evaluated patient characteristics and risk factors for the development of pneumothorax in patients receiving this therapy. PATIENTS AND METHODS: Demographics, clinical course, and radiographic data of 44 patients treated with sorafenib, bevacizumab and cyclophosphamide were reviewed. Risk factors associated with the development of pneumothorax were analyzed. RESULTS: Pneumothorax likely related to study therapy developed in 11 of 44 (25%) patients of whom 33 had pulmonary abnormalities. Median age of patients was 14.7 years (range, 1.08-24.5). Histologies associated with pneumothorax included rhabdoid tumor, synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and renal cell carcinoma. Cavitation of pulmonary nodules in response to therapy was associated with pneumothorax development (P<0.001). Median time from start of therapy to development of pneumothorax was 5.7 weeks (range, 2.4-31). CONCLUSION: The development of cavitary pulmonary nodules in response to therapy is a risk factor for pneumothorax. As pneumothorax is a potentially life-threatening complication of antiangiogenic therapy in children with solid tumors, its risk needs to be evaluated when considering this therapy.

Imaging analysis of hepatoblastoma resectability across neoadjuvant chemotherapy.

PURPOSE: Hepatoblastomas often require neoadjuvant chemotherapy to facilitate partial hepatectomy, which necessitates freedom of tumor borders from the confluence of hepatic veins (COHV), portal vein bifurcation (PVB), and retrohepatic inferior vena cava (IVC). This study aimed to clarify the effect of incremental neoadjuvant cycles on the AHEP0731 protocol criteria of hepatoblastoma resectability. METHODS: Hepatoblastoma responses to neoadjuvant chemotherapy were analyzed among patients (n=23) treated at two children's hospitals between 1996 and 2010. Using digital imaging data, ellipsoid and point-based models were created to measure tumor volume regression and respective distances from tumor borders nearest to the COHV, PVB, and IVC. RESULTS: Hepatoblastoma volumes regressed with incremental neoadjuvant chemotherapy cycles (p<0.001). Although tumor borders regressed away from the COHV (p=0.008), on average only 1.1mm was gained. No change from tumor borders to the PVB was detected (p=0.102). Distances from tumor borders to the IVC remained stable at one hospital (p=0.612), but increased only 0.15 mm every 10 days of therapy at the other (p=0.002). Neoadjuvant chemotherapy induced slightly more tumors to meet the threshold vascular margin of 1cm (baseline to completion): COHV, 11 (47.8%) to 17 (73.9%; p=0.058); PVB, 11 (47.8%) to 15 (65.2%; p=0.157); and IVC, 4 (17.4%) to 10 (43.5%; p=0.034). No differences were detected in demographic or disease-specific characteristics between patients who did or did not achieve this 1-cm margin after conclusion of chemotherapy. CONCLUSION: Hepatoblastoma volumes regress significantly with increasing neoadjuvant chemotherapy cycles. However, tumors often remain anchored to the major hepatic vasculature, showing marginal improvement in resectability criteria.

Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. EXPERIMENTAL DESIGN: Sorafenib dose was escalated from 90 to 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. RESULTS: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m(2). Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m(2) at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019). CONCLUSION: The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.

Liposome-encapsulated curcumin suppresses neuroblastoma growth through nuclear factor-kappa B inhibition.

BACKGROUND: Nuclear factor-κB (NF-κB) has been implicated in tumor cell proliferation and survival and in tumor angiogenesis. We sought to evaluate the effects of curcumin, an inhibitor of NF-κB, on a xenograft model of disseminated neuroblastoma. METHODS: For in vitro studies, neuroblastoma cell lines NB1691, CHLA-20, and SK-N-AS were treated with various doses of liposomal curcumin. Disseminated neuroblastoma was established in vivo by tail vein injection of NB1691-luc cells into SCID mice, which were then treated with 50 mg/kg/day of liposomal curcumin 5 days/week intraperitoneally. RESULTS: Curcumin suppressed NF-κB activation and proliferation of all neuroblastoma cell lines in vitro. In vivo, curcumin treatment resulted in a significant decrease in disseminated tumor burden. Curcumin-treated tumors had decreased NF-κB activity and an associated significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis, as well as a decrease in tumor vascular endothelial growth factor levels and microvessel density. CONCLUSION: Liposomal curcumin suppressed neuroblastoma growth, with treated tumors showing a decrease in NF-κB activity. Our results suggest that liposomal curcumin may be a viable option for the treatment of neuroblastoma that works via inhibiting the NF-κB pathway.

Self-complementary adeno-associated viral vectors for gene therapy of hemophilia B: progress and challenges.

Therapies currently used for hemophilia involve injection of protein concentrates that are expensive, invasive and associated with side effects such as development of neutralizing antibodies (inhibitors) that diminish therapeutic efficacy. Gene transfer is an attractive alternative to circumvent these issues. However, until now, clinical trials using gene therapy to treat hemophilia have failed to demonstrate sustained efficacy, although a vector based on a self-complementary adeno-associated virus has recently shown promise. This article will briefly outline a novel gene-transfer approach using self-complementary adeno-associated viral vectors using hemophilia B as a target disorder. This approach is currently being evaluated in the clinic. We will provide an overview of the development of self-complementary adeno-associated virus vectors as well as preclinical and clinical data with this vector system.

Continuous delivery of human type I interferons (alpha/beta) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model.

In this study, we focused primarily on the antileukemic activity of interferon-beta (IFN-beta) in a murine xenograft model of acute myeloid leukemia (AML). Bolus administration of recombinant IFN-beta via the subcutaneous or intravenous route failed to show efficacy in mice injected with AML cells despite achieving peak plasma IFN-beta levels of more than 200 IU/mL. In contrast, stable expression of IFN-beta following adeno-associated virus (AAV) vector-mediated gene transfer resulted in significant antileukemic activity against primary AML cells derived from patients with poor prognostic markers. An almost linear relationship was observed with stable plasma levels of IFN-beta and antileukemic activity in mice. Even levels below 10 IU/mL were able to reduce tumor load by 50-fold when compared with control animals. These levels of IFN-beta are likely to be nontoxic in humans. Therefore, approaches capable of maintaining stable plasma levels of IFN-beta merit further clinical evaluation in patients with AML.