Industry Payments Among Appropriate Use Criteria Voting Panels: An Open Payments Analysis.

BACKGROUND: Although multiple studies have consistently demonstrated that orthopaedic surgeons receive greater transfers of value than other specialties, the industry payments of providers who are involved in the formation of practice guidelines have not been thoroughly explored. Therefore, the purpose of our analysis was to evaluate the industry payments of the authors of the Appropriate Use Criteria (AUC) from the American Academy of Orthopaedic Surgeons (AAOS). METHODS: The publicly available AAOS web portal (OrthoGuidelines.org) was queried for all AUCs that had been released between January 1, 2013, and December 31, 2019, regarding the management of musculoskeletal pathologies. A cross-sectional analysis of the Centers for Medicare & Medicaid Services (CMS) Open Payments database was conducted to determine the number and total value of industry payments to AUC voting committee members during the year of voting for the AUC. Industry payments for each orthopaedic surgeon voting member were compared with payments received by orthopaedic surgeons nationwide who received any payment within the same year. The proportion of orthopaedic surgeon voting members who received any industry payment was compared with the proportion of orthopaedic surgeons nationwide who received payments. RESULTS: Our analysis included a total of 18 different AUCs with 216 voting members, 157 of whom were orthopaedic surgeons. Of the orthopaedic surgeon voting members, 105 (67%) received industry payments, a rate roughly comparable with the national average among orthopaedic surgeons (74%). For 7 of 18 AUCs (39%), the median payment per orthopaedic surgeon voting member was above the median among orthopaedic surgeons receiving payments nationwide that year. Qualitatively, orthopaedic surgeon voting members were more likely to receive payments in the form of royalties, licenses, or speaking fees than orthopaedic surgeons nationwide. CONCLUSIONS: AUC voting members receive payments at frequencies and magnitudes that are roughly comparable with orthopaedic surgeons nationwide. Whether voting panel members receiving payments at these rates is ideal or is in the best interest of patients is a policy decision for the AAOS and society at large. Our study confirms that payments are common and, thus, continued vigilance is justified.

Exploring perioperative complications of anterior lumber interbody fusion in patients with a history of prior abdominal surgery: A retrospective cohort study.

BACKGROUND CONTEXT: Anterior lumbar interbody fusion (ALIF) exposes the anterior aspect of the spine through a retroperitoneal approach. Access to the anterior spine requires mobilization of intra-abdominal viscera/vasculature, which can become complicated as scarring and/or adhesions develop from prior abdominal surgical interventions, increasing risk of intraoperative complications. The literature suggests that "significant prior abdominal surgery" is a relative contraindication of ALIF surgery; however, there is no consensus within the literature as to what defines "major/significant" abdominal surgeries. Additionally, the association between the number of prior abdominal surgeries and perioperative complications in ALIF surgery has not been explored within the literature. PURPOSE: This study seeks to explore the association between perioperative complications of ALIF surgery and the type (major and/or minor) and number of prior abdominal surgeries. DESIGN: A retrospective cohort study was performed to examine perioperative complications in ALIF patients with or without prior history of abdominal surgery. PATIENT SAMPLE: All consecutive patients undergoing ALIF with or without a history of prior abdominal surgery from 2008 to 2018 at a single tertiary center were evaluated. Patients under the age of 18, patients with spinal malignancy, or patients who had ALIF above L3 were excluded. OUTCOME MEASURES: Perioperative complications included intraoperative complications during ALIF surgery and postoperative complications within 90 days of ALIF surgery. Intraoperative complications include vascular injury, ureter injury, retroperitoneal hematoma, etc. Postoperative complications include urinary tract infection, revision of abdominal scar, ileus, deep vein thrombosis, pulmonary embolism, etc. Other outcome measures include readmission within 90 days, length of ALIF surgery, and length of hospital stay. METHODS: Electronic medical records of 660 patients who underwent ALIF between 2008 and 2018 were retrospectively reviewed. Patient demographics, Charleston Comorbidity Index (CCI), level of fusion, past abdominal surgical history, use of access surgeon during exposure, intraoperative, and postoperative complications were collected. Predictors of intraoperative and postoperative complications were analyzed using simple and multivariable logistic regression. Statistical analysis was performed using JMP 14.0 (SAS, Cary, NC, USA) software. RESULTS: After controlling for age, length of ALIF, gender, multilevel ALIF, and the use of an access surgeon, there was no significant association between the type of prior abdominal surgery (major and/or minor) and intraoperative complications on multivariable logistic regression analysis (Minor: odds ratio [OR]=1.68; 95% confidence interval [CI]: 0.58-4.86 & Major: OR=1.99; 95% CI: 0.80-4.91). On multivariable logistic regression, the odds of developing an intraoperative complication increases by 52% for each additional prior abdominal surgery after adjusting for age, length of ALIF, gender, multilevel ALIF, and the use of an access surgeon (OR=1.52, 95% CI: 1.10-2.11). Iliac vein laceration was the most common intraoperative complication (n=27, 4%). Neither the type (major and/or minor) nor the number of prior abdominal surgeries were significant predictors of postoperative complications (Minor: OR=1.29; 95% CI: .72-2.31, Major: OR=1.24; 95% CI: 0.77-2.00, & Number: OR=1.03; 95% CI: .84-1.26). CONCLUSION: With each additional prior abdominal surgery, accumulation of scarring and adhesions can likely obscure anatomical landmarks and increase the risk of developing an intraoperative complication. Therefore, the number of prior abdominal surgeries should be taken into consideration during planning and operative exposure of the anterior spine via a retroperitoneal approach.

Outcome differences between young children and adolescents undergoing kidney transplantation.

BACKGROUND/PURPOSE: Although graft loss remains the biggest challenge for all pediatric kidney transplant (KT) recipients, unique challenges exist within different age groups. We aim to evaluate the different characteristics and graft survival outcomes of young children and adolescents undergoing KT. METHODS: Children who underwent isolated KT between 2000 and 2013 at our institution were included in this retrospective analysis. Patient characteristics and outcomes were compared using student's t-test, chi-square test, Kaplan-Meier curve and Cox proportional hazards model. RESULTS: Of 73 children who underwent KT, 31 were <12 (young children), and 42 were ≥ 12 years old (adolescents). Overall patient survival was 100%. The younger group had superior 5-year (100% vs. 75.5%) and 10-year (94.4% vs. 43.8%) graft survival (p=0.008). Factors predictive of poor graft survival on multivariate analysis were older age at transplantation (HR 1.2, CI 1-1.4, p=0.047), female gender (HR 9.0, CI 1.9-43, p=0.006), and acute rejection episodes (HR 13, CI 2-90, p=0.008). The most common causes of graft loss were acute and chronic rejection episodes and immunosuppression nonadherence. CONCLUSION: Adolescents undergoing KT have inferior graft survival compared to younger children. In adjusted modeling, children with older age, female gender, and acute rejection episodes have inferior graft survival.

Factors influencing disease recurrence after ileocolic resection in adult and pediatric onset Crohn's disease.

BACKGROUND: Factors influencing recurrence of ileocecal Crohn's disease (CD) after surgical resection may differ between adolescents and adults. METHODS: CD patients who underwent ileocecectomy were retrospectively divided into pediatric onset (age at diagnosis ≤ 16 years, n = 34) and adult onset (>16, n = 108) patients to evaluate differences in risks of endoscopic and clinical recurrence. RESULTS: In 142 patients, rates of any recurrence, endoscopic recurrence, and clinical recurrence at 5 years were 78%, 88%, and 65%, respectively. Risks of recurrence were similar between groups. Younger patients were more likely to be on immunologics preoperatively and more likely to be started on immunoprophylaxis postoperatively. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in the older group. CONCLUSIONS: Despite increased preoperative and postoperative immunoprophylaxis in younger patients, recurrence rates of CD after ileocecectomy do not differ between these groups. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in patients with adult onset CD.

Pyloric exclusion for treatment of complicated duodenal atresia.

Duodenal atresia (DA) is a well-described congenital anomaly that usually responds well to surgical correction. Associated defects are common, and these confounding variables often influence outcome. The authors present a case of a newborn female with an unusual constellation of problems including DA with annular pancreas, trisomy 21, and coarctation of the aorta. She developed protracted complications postoperatively and was treated with an innovative surgical strategy.

Trauma induced left ventricular apical ballooning syndrome in a 15 year old: a rare case of Tako-tsubo cardiomyopathy.

We present a case of a 15 year old girl who developed transient left ventricular apical ballooning syndrome, Tako-tsubo cardiomyopathy, after a significant motor vehicle accident. On post-trauma day three she developed heart failure with mid-to-apical left ventricular wall dysfunction with an EF of 10%-15%. The patient eventually regained full cardiac function by post-trauma day seven. Here we present the first case report of trauma induced left ventricular apical ballooning syndrome in pediatrics.

Teratomas in infants and children.

PURPOSE OF REVIEW: Teratomas are rare neoplasms composed of tissue elements derived from the germinal layers of the embryo. Although they may originate anywhere along the midline, teratomas are most commonly found in sacrococcygeal, gonadal, mediastinal, retroperitoneal, cervicofacial and intracranial locations. Clinical behavior varies significantly by site and size. The presence of immature or premalignant elements may influence therapy and long-term outcome. This report reviews the current literature with regard to the diagnosis, management and outcome of teratomas in infants and children. RECENT FINDINGS: Recently, large case series have further elucidated the biologic behavior and clinical course of these rare tumors. Emerging evidence indicates that age of diagnosis is an increasingly important prognostic feature independent of tumor location. Advances in imaging are facilitating earlier diagnosis and identification of patients at higher risk of adverse outcome. In select cases, fetal and early neonatal interventions are improving outcome and survival. SUMMARY: Presenting symptoms may vary widely based on location; however, independent of primary location, definitive therapy for teratomas is complete surgical resection. Early diagnosis, timely intervention and meticulous follow-up are critical in the long-term favorable outcome.

The Bianchi procedure: a 20-year single institution experience.

BACKGROUND/PURPOSE: The emergence of improved outcomes for small bowel (SB) transplantation has raised questions regarding the utility of autologous intestinal lengthening for patients with short bowel syndrome (SBS). Chronic immunosuppression, multiple hospitalizations, and posttransplant lymphoproliferative disease are significant adverse factors. The purpose of this study is to evaluate the 20-year single institution experience with the Bianchi procedure and analyze its role in the management of pediatric SBS. METHODS: Medical records for 19 consecutive patients who underwent the Bianchi procedure from 1984 to 2004 were reviewed. Patients were categorized into 3 groups: less than 5 years, 5 to 9.9 years, and 10 years or more after surgery. Various outcome variables were evaluated. Data are presented in tabular format as the number of patients (%) or average (range). RESULTS: Nineteen patients were included in the study. Of 16 patients weaned from total parenteral nutrition (TPN), 7 (44%) responded to Bianchi procedure alone and 9 patients (56%) required SB transplant at an average of 4.09 years (range, 0.7-13.64 years) post-Bianchi. Four patients (21%) died, 1 received SB transplant and died of unrelated causes, and 3 were still on TPN and had not received SB transplantation. CONCLUSION: The Bianchi procedure facilitated weaning from TPN and eliminated the need for supplemental nutrition in select patients. Although the role of surgery is primarily adjunctive in the treatment of SBS, it offers therapeutic benefit in decreasing parenteral nutrition requirements and promoting intestinal adaptation. In particular, the Bianchi procedure has significant potential to improve the prognosis of pediatric patients with SBS.

Neuroblastoma impairs chemokine-mediated dendritic cell migration in vitro.

BACKGROUND/PURPOSE: Chemokine receptor (CCR7 [cysteine chemokine receptor 7]) and ligand (CCL19) interactions trigger dendritic cell (DC) recruitment from sites of antigen uptake to secondary lymphoid organs for T-cell priming and tumor lysis. Inhibition of this interaction may allow some aggressive tumors to evade immune detection. Although we have shown dysfunctional DC migration in murine neuroblastoma (NB) in vivo, the molecular mechanisms of impairment are unknown. We hypothesize that NB-induced aberrant CCR7-CCL19 signaling impairs DC migration. METHODS: Bone marrow-derived DCs were isolated from A/J mice (n = 24), matured, and cocultured with murine NB (TBJ) or media (control) for 7 days. CCR7 and CCL19 protein and RNA expressions by control and NB-exposed DC were measured by flow cytometry, Western blot analysis, and polymerase chain reaction. Migration assays using Transwell plates (Corning Incorporated, Corning, NY, via Fisher Scientific, Pittsburgh, Pa) were performed with matured DC and CCL19. Furthermore, to determine if these changes in DC migration could be overcome, superphysiological concentrations of CCL19 (100 ng/mL) were used. Results are reported as the average percentage +/- SD. RESULTS: No significant differences in CCR7 or CCL19 protein expression between tumor and control were seen at 7 days. However, NB significantly decreased CCL19-induced migration by more than 50%: control (26.48% +/- 1.52%) vs DC cocultured with TBJ (12.7% +/- 0.3%) (P < .05). Superphysiological doses up to 100 ng/mL CCL19 showed no significant upregulation in migration in DC cocultured with tumor cells. CONCLUSIONS: Although in vitro coculture with NB does not induce significant changes in either CCR7 or CCL19 expression, profound functional impairments in CCR7/CCL19-mediated migration occurs. These findings suggest that intracellular signal transduction pathways for these chemokines may be impaired by tumor. Targeting this chemokine-receptor pathway may provide a novel therapeutic strategy.

Murine neuroblastoma attenuates dendritic cell cysteine cysteine receptor 7 (CCR7) expression.

BACKGROUND/PURPOSE: Dendritic cell (DC) migration from tumors to T-cell priming sites is critical in developing antitumor cytotoxicity. Cysteine cysteine receptor 7 (CCR7), a promigratory chemokine receptor, regulates DC recruitment to secondary lymphoid organs. Tumors may inhibit CCR7 expression to evade immunodetection. Previous work implicates impaired DC migration as a critical defect in immunity to neuroblastoma (NB). However, the mechanism has yet to be defined. We hypothesize that NB abrogates DC CCR7 expression and signaling, leading to decreased antitumor immunity. METHODS: A/J mice (N = 36) were injected with saline (control) or murine NB (TBJ) and bone marrow-derived DC were isolated at 7, 14, and 28 days. CCR7 expression was analyzed by polymerase chain reaction, Western blot, and flow cytometry. Cytometry data were analyzed using the paired Student's t test. RESULTS: Dendritic cells isolated from mice with NB had a 60% increase in CCR7 protein expression by flow cytometry compared with control mice at day 7. However, there was a 43% downregulation of CCR7 expression by DC from tumor-bearing mice compared with controls 2 weeks postinoculation (P < .005). These observations were confirmed by polymerase chain reaction and Western blot analysis. CONCLUSION: Neuroblastoma initially upregulates CCR7 expression by DC. However, with tumor progression, this chemokine is downregulated, likely leading to impaired DC migration. Immunotherapeutic strategies to bypass or augment CCR7-dependent DC trafficking may improve survival for patients with aggressive disease.

Neuroblastoma-induced inhibition of dendritic cell IL-12 production via abrogation of CD40 expression.

BACKGROUND/PURPOSE: CD40 expression by dendritic cells (DCs) critically regulates their maturation/antitumor activity. CD40-CD40 ligand (CD40L) signaling stimulates DC-mediated IL-12 production/cytotoxicity. Recent studies suggest that neuroblastoma (NB)-derived gangliosides impair DC maturation, IL-12 secretion, and NK/T-cell activity. Neuroblastoma ganglioside-mediated abrogation of CD40 expression by DC and tumor-induced tolerance has not been studied. The purpose of this study is to determine if NB inhibits DC IL-12 production via CD40. The contributory role of the NB-derived ganglioside GM3 in this process is also examined. METHODS: Dendritic cells were generated from bone marrow of mice injected with saline (control) or murine NB. Control DCs were matured with or without GM3. Dendritic cells were cocultured with NB cells treated with or without a ganglioside synthesis inhibitor. Dendritic cell groups were analyzed for maturation/costimulatory markers. Control and tumor-derived DC were stimulated with CD40L or Staphylococcus aureus and studied for IL-12 expression. RESULTS: CD40 expression on DC generated from NB bearing mice decreased by 64% (P < .001). GM3 down-regulated DC maturation and CD40 expression. Only CD40-dependent IL-12 production was abrogated (60%, P < .01) in DC derived from NB-bearing mice. Dendritic cell capacity to synthesize IL-12 remained intact. CONCLUSIONS: Neuroblastoma-induced inhibition of DC function may result from ganglioside-mediated CD40 signaling deficiency. Strategies to bypass/augment CD40-CD40L signaling may improve current NB immunotherapies.

Results of growth trophic therapy in children with short bowel syndrome.

PURPOSE: In addition to the structural, ultrastructural, and functional changes that occur after extensive enterectomy or in utero bowel loss that results in short bowel syndrome (SBS), a complex array of humoral responses take place that may also affect adaptation of the remaining small intestine as well as nutritional status or growth. These include alterations in the levels of circulating hormones and trophic substances such as growth hormone (GH) and insulinlike growth factors (IGF-1 and IGFBP-3). The purpose of this investigation is to report on the management/treatment of 3 children with SBS (>4 years in duration) and growth failure. METHODS: Serum measures of growth factors and the response to GH stimulation after an arginine insulin tolerance test (AITT) were determined. Weight and height z-scores as well as linear growth velocity were calculated annually pre- and postinitiation of medication therapy. RESULTS: Patient 1 (boy, 8.5 years old, midgut volvulus, 18-cm bowel) was found to be GH deficient, whereas patients 2 (girl, 12.5 years old, gastroschisis, 70-cm bowel) and 3 (boy, 9 years old, jejunal atresia, 21 cm bowel) were found to have limited GH responsiveness. Subsequently, treatment with GH (1) and growth releasing factor (GRF; 2 & 3) was prescribed. Z-scores for both weight and height improved over time. Positive linear growth velocity was observed from initiation of therapy (<0.5 cm/yr for all) to more than 3 years of treatment (mean 1, 4.7 cm/yr; 2, 8.7 cm/yr; 3, 5.0 cm/yr [age adjusted normals >4.5, >8.5, and >4.9 cm/yr, respectively]). All patients received a regular diet with oral supplements, whereas 2 received parenteral nutrition support for about 1 year. CONCLUSIONS: In children with medically refractory SBS, it is not only important to offer trophic factors but also essential that sufficient nutrient substrate be provided to achieve adequate growth.

Neuroblastoma and dendritic cell function.

Neuroblastoma, the most common extracranial solid tumor of childhood, remains a challenge for clinicians and investigators in pediatric surgical oncology. The absence of effective conventional therapies for most patients with neuroblastoma justifies the application of novel, biology-based, experimental approaches to the treatment of this deadly disease. The observation that some aggressive neuroblastomas, particularly in infants, may spontaneously regress suggested that immune-mediated mechanisms may be important in the biology of this disease. Advances in the understanding of the cognate interactions between T cells, antigen-presenting cells and tumors have demonstrated the sentinel role of dendritic cells (DC), the most potent antigen presenting cells, in initiating the cellular immune response to cancer. Until recently the function of DC in pediatric solid tumors, especially neuroblastoma, had not been extensively studied. This review discusses the role of DC in initiating and coordinating the immune response against cancer, the ability of neuroblastoma to induce DC dysregulation at multiple levels by inhibiting DC maturation and function, and the current vaccine strategies being designed to employ the unique ability of DC to promote neuroblastoma regression.

Serum growth factors and growth indices pre- and post-pediatric intestinal transplantation.

BACKGROUND/PURPOSE: Although intestinal transplantation (ITx) has succeeded in liberating children with intestinal failure from total parenteral nutrition (TPN), positive growth has yet to be achieved in the majority of patients. This investigation aims to evaluate levels of serum growth factors as they relate to growth parameters and nutritional outcomes. METHODS: Serum measures of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) that had been obtained before and after transplantation were reviewed (with Institutional Review Board approval) in a subset of pediatric ITx recipients. Z-scores for weight and height were calculated at transplant and biannually thereafter for 2 years. RESULTS: Five children received a small bowel/liver transplant between August 1996 and March 2000 (median age, 1.3 years). Before transplantation, levels of IGF-1 and IGFBP-3 were low in 60% and 67% of patients, respectively. Posttransplant levels of these growth factors were within normal limits or elevated in all but 2 patients (IGFBP-3 only). A positive trend in z-scores was observed in just one of 5 patients for weight and in 2 of 5 for height/length during the follow-up period. Of the 3 patients who experienced negative linear growth velocity over time, 2 had low pretransplant levels of both IGF-1 and IGFBP-3. All patients were weaned from TPN within 3 months after transplant. CONCLUSIONS: Pretransplant levels of growth mediators may be predictive factors in children who will require an intensive regimen of nutritional rehabilitation posttransplant to promote the growth process. Absorption studies may aid in determining the appropriate nutrient substrates for the post-ITx population.

Advanced neuroblastoma impairs dendritic cell function in adoptive immunotherapy.

BACKGROUND/PURPOSE: The authors previously described the complete regression of established neuroblastoma (NB) by the adoptive transfer of syngeneic interleukin-12 transduced dendritic cells (DC) from naive mice. However, some malignancies, like NB, abrogate DC immunostimulation. The authors hypothesize that IL-12 transduction of DC from NB-bearing mice will have the same antitumor properties. METHODS: A/J mice (n = 32) with established NB received peritumoral injection of 1 x 10(6) DC (DC, IL-12 DC, day 7 IL-12 DC or day 14 IL-12 DC) on day 7. Tumor growth, phenotype, and ability to induce NK and T cell activity were measured. RESULTS: Vaccination with naive admIL-12 DC resulted in 100% tumor regression and prolonged survival. Transduced DC induced only partial responses in 75% (day 7) and 25% (day 14) of animals. No differences in phenotype or effector cell activation were noted between admIL-12DC in tumor-bearing or naive mice. CONCLUSIONS: IL-12 DC from tumor-bearing animals have a decreased ability to induce antitumor activity against established murine NB. This decreased capacity appears to be related to the duration of exposure to tumor because day 14 transduced DC had less of an effect than day 7 DC, despite similar phenotypes and ability to activate immune effector cells.

The influence of Down's syndrome on the management and outcome of children with Hirschsprung's disease.

BACKGROUND: Children with Down's syndrome (DS) have a reportedly poorer outcome after treatment of Hirschsprung's disease (HD) compared with control children. Because of overall improvements in their management, the authors hypothesized that the diagnosis of DS would not influence outcome after the management of HD. METHODS: Consecutive children with HD (1995 through 2002) were collected prospectively then divided retrospectively into those with DS and controls (C). Patients who underwent surgery at another institution and those with total colonic aganglionosis were excluded. RESULTS: Of 66 patients, 9 had DS. Mean age at diagnosis, gender, racial distribution, gestational age, and proximity to our center were similar between groups. Presenting symptoms, location of the transition zone, and type of initial operation were similar. Patients with DS had significantly more comorbidities than controls, which generated significantly greater treatment costs and a higher mortality rate. However, with an average of 22 months of follow-up, the overall outcome including postoperative complications, enterocolitis, and constipation was similar. CONCLUSIONS: These data suggest that in contrast to earlier reports, DS has minimal influence on surgical outcome of patients with HD. Although the overall cost of treating patients with DS is greater, this mainly reflects the impact of managing comorbidities.

Synergistic interleukin-18 and low-dose interleukin-2 promote regression of established murine neuroblastoma in vivo.

BACKGROUND/PURPOSE: Severe systemic toxicities have limited the clinical applications of the potent cytokine, interleukin-2 (IL-2). Recent studies have shown that IL-18 synergizes with IL-2 to enhance cytolytic activity in vitro. Combination therapy allows for IL-2 dose reduction, thus, limiting its toxicity while augmenting natural killer cell activity. The authors hypothesize that IL-18 plus low-dose IL-2 may induce a potent and sustained antitumor response in vivo providing effective immunotherapy for neuroblastoma. METHODS: Four groups of A/J mice (n = 28) were inoculated subcutaneously in the right flank with 1 x 10(6) murine neuroblastoma cells (TBJ). On day 7, 5 consecutive daily peritumoral injections were performed with saline (control), human rIL-2 (30,000 IU), murine IL-18 (1 microg), or IL-2 plus IL-18. Tumor growth was monitored, and animals with tumor progression were killed on day 21. Seven weeks after the initial treatment, animals with rejected tumors were rechallenged with 5 x 10(6) cells in the opposite flank. Quantitative data were analyzed by Student's t test. RESULTS: Rapid tumor growth and death was noted in all control animals by 21 days. Complete tumor eradication was seen in 28% of mice treated with IL-2 (P =.03), 42% of mice treated with IL-18 (P <.05), and 57% of mice treated with of IL-2 plus IL-18 (P <.05). Despite the initial response, all animals failed rechallenge and developed new or recurrent tumors within 7 to 10 days. CONCLUSIONS: Coadministration of low-dose IL-2 plus IL-18 induced a potent primary response to murine neuroblastoma likely caused by activation of natural killer cells in the tumor microenvironment. This combined cytokine therapy strategy was unable to induce sustained immunity to rechallenge. However, dendritic cell vaccination combined with IL-2 plus IL-18 cytokine treatment did allow for the establishment of a complete and durable antitumor response.

Cellular mechanisms of interleukin-12-mediated neuroblastoma regression.

BACKGROUND/PURPOSE: Interleukin-12 (IL-12) is a proinflammatory cytokine with potent antitumor effects. Previous studies from the authors laboratory showed regression of established neuroblastoma in mice vaccinated with IL-12 transduced dendritic cells (DC). Although regression was associated with intense T cell infiltration, the precise role of T cells is unknown. The purpose of this work is to study the cellular mechanisms in IL-12-mediated tumor regression. METHODS: Three groups of mice (n = 12) received subcutaneous inoculation with 1 x 10(6) murine neuroblastoma cells (TBJ). Anti-CD4 (T helper), anti-CD8 (T cytotoxic), or antiasialo-GM1 (natural killer) antibodies were injected intravenously at 3-day intervals to deplete various immune effector cell populations. Mice in each depletion group and the control (nondepleted) group were injected intratumorally on day 7 with 1 x 10(6) DC IL-12-transduced DC. Tumors were harvested for morphometry and immunohistochemistry at 21 days. RESULTS: CD4 depletion had no effect on tumor growth in either control or IL-12-vaccinated animals. In contrast, CD8-depleted animals treated with IL-12-transduced DC underwent initial regression followed by progressive tumor growth (P <.01). These tumors were smaller in size at the same time-point. However, NK cell depletion (antiasialo GM1) completely abrogated the antitumor effects of IL-12-transduced DC, leading to progressive tumor growth from the outset. There was no difference between the control and treated animals in this group. CONCLUSIONS: Contrary to our hypothesis that IL-12 DC primarily function to stimulate a T cell-mediated response, these data suggest that NK cells are essential for the initial antitumor response of animals treated with IL-12-transduced DC. CD8+ T cells appear to be necessary effector cells for complete rejection of tumor and possibly memory. NK cells are responsible for the early immune response. Furthermore, CD4+ (T helper) cells did not play any role in IL-12-induced regression. These results imply that for DC to generate an effective antitumor response against neuroblastoma both acquired and innate effector cells are required.