Laparoscopic Thal fundoplication in children: a prospective 10- to 15-year follow-up study.

OBJECTIVE: To study long-term (10-15 years) efficacy of antireflux surgery (ARS) in a prospectively followed cohort of pediatric patients with gastroesophageal reflux disease, using 24-hour pH monitoring and reflux-specific questionnaires. BACKGROUND: Studies on short-term outcome of ARS in pediatric patients with gastroesophageal reflux disease have shown good to excellent results; however, long-term follow-up studies are scarce, retrospective, and have not used objective measurements. METHODS: Between 1993 and 1998, a cohort of 57 pediatric patients (ages 1 month to 18 years; 46% with neurological impairment) underwent laparoscopic anterior partial fundoplication (Thal). Preoperatively and postoperatively (at 3-4 months and at 1-5 and 10-15 years), reflux-specific questionnaires were filled out, and 24-hour pH monitoring was performed. RESULTS: At 3 to 4 months, at 1 to 5 years, and at 10 to 15 years after ARS, 81%, 80%, and 73% of patients, respectively, were completely free of reflux symptoms. Disease-free survival analysis, however, demonstrated that only 57% of patients were symptom free at 10 to 15 years after ARS. Total acid exposure time significantly decreased from 13.4% before ARS to 0.7% (P < 0.001) at 3 to 4 months after ARS; however, at 3 to 4 months after ARS, pH monitoring was still pathological in 18% of patients. At 10 to 15 years after ARS, the number of patients with pathological reflux had even significantly increased to 43% (P = 0.008). No significant differences were found comparing neurologically impaired and normally developed patients. CONCLUSIONS: As gastroesophageal reflux persists or recurs in 43% of children 10 to 15 years after laparoscopic Thal fundoplication, it is crucial to implement routine long-term follow-up after ARS in pediatric patients with gastroesophageal reflux disease.

Unintentional Suture Fistula Between the Proximal and Distal Esophagus in a Preterm Neonate with Type C Esophageal Atresia.

We present the case of a patient with gross type C esophageal atresia in a preterm neonate (gestational age of 31 weeks + 1 day) with a birth weight of 1,470 g. The fistula was released via a thoracotomy, but no primary anastomosis could be made, due to an unexpected long gap. The distal esophagus was closed and approximated to the blind pouch using traction sutures until an adjacent position was reached. A gastrostomy was created for enteral feeding. Although a second attempt to make an anastomosis was unsuccessful, the patient unexpectedly developed a suture fistula 6 weeks after the first procedure, enabling feeding via a nasogastric tube. Over time, six dilations were necessary. Full enteral feeding was achieved at the age of 6 months. Our case confirms sparse reports that deliberately creating a suture fistula may be a solution in esophageal atresia patients when an unexpected long gap prohibits a primary anastomosis.

Intercostal Nerve Cryoablation or Epidural Analgesia for Multimodal Pain Management after the Nuss Procedure: A Cohort Study.

BACKGROUND: Nuss procedure for pectus excavatum is a minimally invasive, but painful procedure. Recently, intercostal nerve cryoablation has been introduced as a pain management technique. MATERIALS AND METHODS: In this cohort study, we compared the efficacy of multimodal pain management strategies in children undergoing a Nuss procedure. The effectiveness of intercostal nerve cryoablation combined with patient-controlled systemic opioid analgesia (PCA) was compared with continuous epidural analgesia (CEA) combined with PCA. The study was conducted between January 2019 and July 2022. Primary outcome was length of stay (LOS), and secondary outcomes were operation room time, postoperative pain, opioid consumption, and gabapentin use. RESULTS: Sixty-six consecutive patients were included, 33 patients in each group. The cryoablation group exhibited lower Numeric Rating Scale (NRS) pain scores on postoperative day 1 and 2 (p = 0.002, p = 0.001) and a shorter LOS (3 vs. 6 days (p < 0.001). Cryoablation resulted in less patients requiring opioids at discharge (30.3 vs. 97.0%; p < 0.001) and 1 week after surgery (6.1 vs. 45.4%; p < 0.001)). In the CEA group, gabapentin use was more prevalent (78.8 vs. 18.2%; p < 0.001) and the operation room time was shorter (119.4 vs. 135.0 minutes; p < .010). No neuropathic pain was reported. CONCLUSIONS: Intercostal nerve cryoablation is a superior analgesic method compared with CEA, with reduced LOS, opioid use, and NRS pain scores. The prophylactic use of gabapentin is redundant.

Dynamic Compression Therapy for Pectus Carinatum in Children and Adolescents: Factors for Success.

BACKGROUND: Pectus carinatum (PC) is a congenital chest wall deformity. In childhood, it is increasingly treated with dynamic compression therapy. Factors for success for dynamic brace therapy are relatively unknown. METHODS: Between 2013 and 2020, 740 patients treated with the Dynamic Compression System (DCS), were studied. This included the effect of age, gender, pectus height, symmetry and pectus rigidity on treatment time and symptoms with linear multiple regression analyses. RESULTS: Carinatum height and high pressure of initial correction at the start of treatment were associated with a prolonged duration of treatment. For each cm increase in carinatum height, the total treatment duration increased with 1.9 months (p-value= 0.002, 95% CI: 0.70-3.13). An initial correction pressure of ≥7.6 pounds per square inch (psi), increased the treatment duration with 3.5 months (p-value 0.006, 95% CI: 1.04-6.01) compared to an initial correction pressure of ≤5.0 psi. A high initial pressure of correction of ≥7.6 psi increased the odds of having somatic symptoms with 1.19 (p-value= 0.012, 95% CI: 1.04-1.45) and psychosocial symptoms with 1.13 (p-value= 0.04, 95% CI: 1.01-1.27) compared to a low initial pressure of correction of ≤5.0 psi. An initial pressure of correction of 5.1-7.5 psi increased the odds of having somatic symptoms with 1.14 (p-value 0.046, 95% CI: 1.00-1.29) compared to an initial pressure of correction of ≤5.0 psi. Patients with asymmetric chests were more likely to abandon therapy CONCLUSIONS: High carinatum height and high initial pressure of correction are associated with prolonged bracing treatment and a higher failure rate. LEVEL OF EVIDENCE: III.

Graft dilatation and Barrett's esophagus in adults after gastric pull-up and jejunal interposition for long-gap esophageal atresia.

BACKGROUND: Esophageal replacement (ER) with gastric pull-up (GPU) or jejunal interposition (JI) used to be the standard treatment for long-gap esophageal atresia (LGEA). Changes of the ER grafts on a macro- and microscopic level however, are unknown. AIM: To evaluate long-term clinical symptoms and anatomical and mucosal changes in adolescents and adults after ER for LGEA. METHODS: A cohort study was conducted including all LGEA patients ≥ 16 years who had undergone GPU or JI between 1985-2003 at two tertiary referral centers in the Netherlands. Patients underwent clinical assessment, contrast study and endoscopy with biopsy. Data was collected prospectively. Group differences between JI and GPU patients, and associations between different outcome measures were assessed using the Fisher's exact test for bivariate variables and the Mann-Whitney U-test for continuous variables. Differences with a P-value < 0.05 were considered statistically significant. RESULTS: Nine GPU patients and eleven JI patients were included. Median age at follow-up was 21.5 years and 24.4 years, respectively. Reflux was reported in six GPU patients (67%) vs four JI patients (36%) (P = 0.37). Dysphagia symptoms were reported in 64% of JI patients, compared to 22% of GPU patients (P = 0.09). Contrast studies showed dilatation of the jejunal graft in six patients (55%) and graft lengthening in four of these six patients. Endoscopy revealed columnar-lined esophagus in three GPU patients (33%) and intestinal metaplasia was histologically confirmed in two patients (22%). No association was found between reflux symptoms and macroscopic anomalies or intestinal metaplasia. Three GPU patients (33%) experienced severe feeding problems vs none in the JI group. The median body mass index of JI patients was 20.9 kg/m2 vs 19.5 kg/m2 in GPU patients (P = 0.08). CONCLUSION: The majority of GPU patients had reflux and intestinal metaplasia in 22%. The majority of JI patients had dysphagia and a dilated graft. Follow-up after ER for LGEA is essential.

Learning curve of thoracoscopic repair of esophageal atresia.

BACKGROUND: Thoracoscopic repair of esophageal atresia is considered to be one of the more advanced pediatric surgical procedures, and it undoubtedly has a learning curve. This is a single-center study that was designed to determine the learning curve of thoracoscopic repair of esophageal atresia. METHODS: The study involved comparison of the first and second five-year outcomes of thoracoscopic esophageal atresia repair. RESULTS: The demographics of the two groups were comparable. There was a remarkable reduction of postoperative leakage or stenosis, and recurrence of fistulae, in spite of the fact that nowadays the procedure is mainly performed by young staff members and fellows. CONCLUSIONS: There is a considerable learning curve for thoracoscopic repair of esophageal atresia. Centers with the ambition to start up a program for thoracoscopic repair of esophageal atresia should do so with the guidance of experienced centers.

Ravitch Surgery or Dynamic Compression Bracing for Pectus Carinatum: A Retrospective Cohort Study.

BACKGROUND: Pectus carinatum is a pediatric condition that can be treated by dynamic compression system (DCS) bracing or surgery. Several publications on DCS bracing or surgery are available; however, they do not compare both treatments. METHODS: Over a 10-year period, 738 patients with pectus carinatum were treated at the Amsterdam Pectus Center (Amsterdam, The Netherlands). This study describes this 10-year experience and the results of both treatments. RESULTS: Of the 631 patients who underwent DCS bracing treatment, 553 finished treatment, and 78 patients are still under treatment. A total of 73.8% (n = 408) of these patients finished treatment successfully, 13.6% (n = 75) experienced treatment failure, and 12.7% (n = 70) were lost to follow-up. The success rate decreased with an increasing pressure of initial compression (84.2%-67.3%). Marfan syndrome and Poland syndrome were associated with unfavorable results. Ravitch surgery was performed in 105 patients, with a success rate of 92.4%. Complications occurred in 32.4% of patients, and 6.7% of patients had complications for which surgery was needed. No relationship was found between osteotomy or sternal fixation and outcomes or complications. The Abramson procedure was performed in 2 patients. CONCLUSIONS: DCS bracing should be the treatment of choice in patients with pectus carinatum because of its noninvasiveness, good results, and lower complication rate compared with surgery. Besides pressure of initial correction, motivation is an important factor influencing outcomes, and compliance remains a major challenge in treating pectus carinatum using DCS bracing. Bracing patients before their growth spurt should be discouraged. Patients with a higher pressure of initial compression (>8.0-8.5 psi) and Marfan syndrome or Poland syndrome have poorer outcomes. In those patients, surgery may be considered.

[Dynamic compression brace for pectus carinatum: 5 years on]. / Dynamische-compressiebrace bij pectus carinatum.

Pectus carinatum is a congenital chest-wall deformity with a prevalence of 0.3-0.7%. This chest-wall deformity can lead to functional, cosmetic and psychosocial problems. For many years, the only available treatment was an invasive surgical procedure. A less-invasive treatment, namely external compression of the sternum with a brace, showed disappointing results due to discomfort, a high percentage of skin complications and low compliance. The introduction of the dynamic compression brace has meant that the pressure of sternal compression can be measured and adjusted, which has improved comfort and compliance and resulted in an increased success rate of 92% and a decrease in the percentage of skin complications to just 8%. Despite the fact that wearing a compression brace for a longer period of time is not an easy undertaking for an adolescent, the use of the dynamic compression brace results in a high success rate, and is a safe and an efficient treatment.

Respiratory function after esophageal replacement in children.

BACKGROUND: Children born with esophageal atresia require an anastomosis between the proximal and distal esophagus. When this distance is too wide (long gap esophageal atresia, LGEA) esophageal replacement strategies have to be deployed. The aim of this study was to assess long-term respiratory morbidity and lung function after esophageal replacement with either stomach (gastric pull-up, GPU) or jejunum (jejunal interposition, JI) for LGEA. METHODS: Retrospective cohort study. Patients operated with GPU and JI for LGEA (1985-2007) underwent a semi-structured interview and lung function testing (LFT). RESULTS: Seven GPU-patients and eight JI-patients were included. Median age was 12years. One patient per group could not perform LFT. Respiratory symptoms were reported by 13/15 patients (7/7 GPU-patients vs 6/8 JI-patients). All LFT items were lower than reference values; 6/13 patients showed restriction and 6/13 obstruction. All six GPU-patients had abnormal TLC and/or FEV1/FVC vs 3/7 after JI. Restriction was noted in 4/6 GPU-patients vs 2/7 JI-patients. CONCLUSION: After esophageal replacement for LGEA many children have impaired lung function and respiratory symptoms are common. Lung volumes seem decreased after GPU compared to JI. This may be caused by the intrathoracic stomach which may limit normal lung growth. Respiratory follow-up in adult life is important after esophageal replacement. LEVEL OF EVIDENCE: III.

Treatment of postparotidectomy fistulae with fibrin glue.

Although fistulae resulting from superficial parotidectomy represent a serious problem, there is still little consensus on the optimal treatment. Some suggest management by applying dressings, while others advise surgery. In recent years several other strategies have been proposed. In this manuscript, we present two cases of postparotidectomy fistulae treated by injection with fibrin tissue glue (Tissucol Duo 500, Baxter AG, Vienna, Austria). Furthermore, a review of the literature is presented. In both patients the fistulae completely healed within months without complications. A literature search revealed that this is the first time postparotidectomy fistulae were treated this way. We conclude that postparotidectomy fistulae can be effectively treated with fibrin glue. Moreover, this treatment is simple, safe and has no side effects.

Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells.

Overexpression of p53 is found in approximately 50% of human cancers, making it an attractive target antigen for immunotherapy of cancer. Research in this area has thus far primarily focused on p53-specific CTLs. Although these CTLs were shown to be highly effective against p53-overexpressing tumors in vivo, immunological tolerance seems to strongly restrict the spectrum of the p53-specific CTL repertoire in p53(+/+) subjects. In view of the emerging role of CD4(+) Th (Th) cells in the antitumor response, we investigated the specificity and antitumor efficacy of the p53-specific Th response in mice. Our data show that high affinity Th cells against the naturally processed epitope p53(108-122) can be elicited in both p53(-/-) and p53(+/+) mice, indicating that the p53-specific T-cell response is not affected by tolerance at the Th level. Furthermore, p53(108-122)-specific Th cells were effective in enabling p53-specific CTLs to control the growth of p53-overexpressing tumors in vivo. Therefore, exploitation of the p53-specific Th response appears to be a highly useful aspect of immunotherapeutic strategies against cancers.

Quality of Life and Anxiety in Parents of Children with an Anorectal Malformation or Hirschsprung Disease: The First Year after Diagnosis.

INTRODUCTION: In 2012, we started the KLANKbord-study. A quality of life (QoL) study that follows patients with an anorectal malformation (ARM) or Hirschsprung disease (HD) and their parents from diagnosis till the age of 18 years. We hypothesized that the diagnosis of ARM or HD initially has a negative influence on QoL and anxiety levels of parents, but that this influence will diminish over time. The aim of this study is to see whether QoL and anxiety levels of parents change within the first year after the diagnosis. METHODS: Parents of all children born with ARM or HD, were eligible for this study. Within 3 months after the diagnosis ARM or HD, parents received a set of validated QoL questionnaires (measurement 1). Measurement 2 was 12 months after the first questionnaire. MAIN RESULTS: During measurement 1 mothers (n = 20) scored significantly higher on the social (p value, 0.01; 95% confidence interval [CI], 0.3946-3.1528) and environmental domain (p value, 0.01; 95% CI, 0.4449-2.2851) of the World Health Organization Quality of Life-BREF (WHOQOL-BREF) compared with the known reference values. Fathers (n = 19) scored significantly higher on the physical (p value, 0.01; 95% CI, 0.2964-1.8072), psychological (p value, 0.001; 95% CI, 0.7697-2.4757), and environmental domain (p value, 0.003; 95% CI, 0.5586-2.4214) than the reference values. Comparison of all domains of the WHOQOL-BREF for mothers and fathers between measurements did not show a significant difference. Anxiety levels of mothers were lower during measurement 2 compared with measurement 1. Anxiety levels of fathers were higher during measurement 2 compared with measurement 1. These differences are not significant. Anxiety levels of mothers were significantly higher than anxiety levels of fathers during measurement 1 (p value, 0.002; 95% CI, 0.808-2,956). During measurement 2 this difference in anxiety of mothers versus fathers did not exist (p value, 0.373; 95% CI, -1.157 to 2.922). CONCLUSION: A negative influence on the QoL of parents having a child with ARM or HD, compared with the reference population was not seen in this population. QoL did not change significantly during the first year for both fathers and mothers. Anxiety levels of mothers did decline during this first year. The number of parents included in this study is still small, which might influence our results. Therefore, we will continue the KLANKbord-study indefinitely.

A two-center comparative study of gastric pull-up and jejunal interposition for long gap esophageal atresia.

PURPOSE: When restoration of the anatomical continuity in case of long gap esophageal atresia (LGEA) is not feasible, esophageal replacement surgery becomes mandatory. The aim of this paper is to critically compare the experience of two tertiary referral centers in The Netherlands performing either gastric pull-up (GPU) or jejunal interposition (JI). METHODS: Retrospective chart review of all the patients with LGEA who underwent GPU in the University Medical Center Groningen and JI in the University Medical Center Utrecht. Main endpoints were short term morbidity, mortality and long term functional outcome (digestive functioning and growth). Descriptive analyses conducted using Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables. RESULTS: Nine children underwent GPU and 15 JI. Median age (years) at last follow up was fourteen (GPU) and eight (JI). One patient died, 10 years after JI. No grafts were lost. Perioperative anastomotic complications were reported more often after JI (73% vs. 22%, p=0.03). However reintervention rate was the same in both groups (33%). Among long term outcomes, functional obstruction was not registered after GPU, while it was recorded in 46% after JI (p=0.02). No other significant differences were found apart from some tendencies concerning full oral nutrition and gastroesophageal reflux (GPU>JI). CONCLUSION: Comparative data from this study reveal no mortality but significant morbidity in both groups. No graft was lost. Although not statistically different as a result of small patient numbers, clinically important differences regarding gastrointestinal system were noted. Growth should be monitored closely in both groups.

Immunotherapy of cancer through targeting of the p53 tumor antigen.

The expression of the p53 tumor suppressor protein is frequently increased in a great variety of human cancers, making this antigen an attractive candidate for targeting therapeutic T cell immunity. However, potential complications as a result of immunological tolerance or autoimmune pathology must be taken into account when exploiting this ubiquitously expressed auto-antigen for the immunotherapy of cancer.

Anxiety and quality of life of parents with children diagnosed with an anorectal malformation or Hirschsprung disease.

AIM: The aim of this study was to investigate the difference in anxiety and quality of life (QOL) between mothers and fathers of children with anorectal malformations (ARM) or Hirschsprung disease (HD). In addition, anxiety of parents of newborns was compared with parents of children in the age-group of 10 to 13 years. METHODS: Parents of 44 patients with ARM or HD completed the World Health Organization Quality of Life (WHOQOL)-BREF (26 items) and the Spielberger State-Trait Anxiety Inventory (STAI-trait 10 items, STAI-state 6 items). They were divided into two groups according to their children's age (0-4 years and 10-13 years). RESULTS: Overall mothers scored significantly worse than fathers on state anxiety (p = 0.005). Trait anxiety was not significantly different between mothers and fathers. The psychological domain of the WHOQOL-BREF was significantly different between parents (p = 0.016), with mothers scoring worse. Dividing the group in newborns and school going children mothers of newborns showed significantly more state anxiety compared with fathers of newborns (p = 0.016). In the group of older children, both anxiety and QOL were not significantly different between fathers and mothers. Comparing mothers of newborns with mothers of older children, the first group scored higher on state anxiety, but this difference was not significant (p = 0.138; 95% confidence interval, 0.535-3.717). CONCLUSIONS: Mothers of newborns have a higher level of anxiety than fathers of newborns with ARM or HD. When children with ARM or HD become older, this difference in anxiety between parents is not significant anymore. This may be explained by coping strategies.

Long-gap esophageal atresia: a meta-analysis of jejunal interposition, colon interposition, and gastric pull-up.

AIM: There is still no consensus about the optimal surgical approach for esophageal replacement in the case of long-gap esophageal atresia (LGEA) or extensive corrosive strictures. The aim of this article was to perform a meta-analysis comparing the most widely used techniques for esophageal replacement in children: jejunal interposition (JI), colon interposition (CI), and gastric pull-up (GPU). METHODS: Review of the English-language literature published in the past 5 years about esophageal replacement in children was done. The focus was on postoperative survival rate, morbidity (gastrointestinal complications such as anastomotic stenosis/leakage and respiratory complications such as pneumothorax, pneumonia, and atelectasis), and long-term follow-up when available. Among long-term gastrointestinal outcomes were dysphagia, reflux, and dumping; among long-term respiratory outcomes were recurrent pneumonia and recurrent aspiration leading to chronic lung disease. Data were computed by Comprehensive Meta-Analysis software (Version 2.2.064). MAIN RESULTS: A total of 15 studies (4 comparative retrospective, 8 retrospective, and 3 prospective) including 470 patients (264 LGEA) were identified; 344 (73%) patients underwent CI, 99 (21%) GPU, and 27 (6%) JI. Among these 15 studies, 9 provided data about long-term follow-up. CONCLUSION: Proper prospective comparative studies are lacking. GPU and CI appear comparable regarding postoperative mortality, anastomotic complications, and graft loss. On the long-term, GPU seems to be associated with a higher respiratory morbidity but fewer gastrointestinal complications than CI. Based on this article only two series provide data about JI, and they show highly divergent results. JI appears to be a valid replacement technique when performed by experienced centers; however larger numbers are needed to assess the outcomes of this procedure.

The effects and efficacy of antireflux surgery in children with gastroesophageal reflux disease: a systematic review.

BACKGROUND: Antireflux surgery (ARS) for gastroesophageal reflux disease (GERD) is one of the most frequently performed major operations in children. Many studies have described the results of ARS in children, however, with a wide difference in outcome. This study aims to systematically review the efficacy of pediatric ARS and its effects on gastroesophageal function, as measured by gastroesophageal function tests. This is the first systematic review comprising only prospective, longitudinal studies, minimizing the risk of bias. METHODS: Three electronic databases (Medline, Embase, and the Cochrane Library) were searched for prospective studies reporting on ARS in children with GERD. RESULTS: In total, 17 eligible studies were identified, reporting on a total of 1,280 children. The median success rate after ARS was 86% (57-100%). The success rate in neurologically impaired children was worse in one study, but similar in another study compared to normally developed children. Different surgical techniques (total versus partial fundoplication, or laparoscopic versus open approach) showed similar reflux recurrence rates. However, less postoperative dysphagia was observed after partial fundoplication and laparoscopic ARS was associated with less pain medication and a shorter hospital stay. Complications of ARS varied from minimal postoperative complications to severe dysphagia and gas bloating. The reflux index (RI), obtained by 24-h pH monitoring (n = 8) decreased after ARS. Manometry, as done in three studies, showed no increase in lower esophageal sphincter pressure after ARS. Gastric emptying (n = 3) was reported either unchanged or accelerated after ARS. No studies reported on barium swallow x-ray, endoscopy, or multichannel intraluminal impedance monitoring before and after ARS. CONCLUSION: ARS in children shows a good overall success rate (median 86%) in terms of complete relief of symptoms. Efficacy of ARS in neurologically impaired children may be similar to normally developed children. The outcome of ARS does not seem to be influenced by different surgical techniques, although postoperative dysphagia may occur less after partial fundoplication. However, these conclusions are bound by the lack of high-quality prospective studies on pediatric ARS. Similar studies on the effects of pediatric ARS on gastroesophageal function are also very limited. We recommend consistent use of standardized assessment tests to clarify the effects of ARS on gastroesophageal function and to identify possible risk factors for failure of ARS in children.

Self-tolerance does not restrict the CD4+ T-helper response against the p53 tumor antigen.

Tumorigenesis is frequently associated with mutation and overexpression of p53, which makes it an attractive target antigen for T cell-mediated immunotherapy of cancer. However, the magnitude and breadth of the p53-specific T-cell repertoire may be restricted due to the ubiquitous expression of wild-type p53 in normal somatic tissues. In view of the importance of the CD4+ T-helper cell responses in effective antitumor immunity, we have analyzed and compared the p53-specific reactivity of this T cell subset in p53+/+ and p53-/- C57Bl/6 mice. This response was found to be directed against the same three immunodominant epitopes in both mouse types. Fine-specificity, magnitude, and avidity were not affected by self-tolerance. Immunization of p53-/- and p53+/+ mice with synthetic peptide vaccines comprising the identified epitopes induced equal levels of Th1 immunity. Our findings imply that the p53-specific CD4+ T-cell repertoire is not restricted by self-tolerance and is fully available for the targeting of cancer.

Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides.

Peptide-based vaccines aimed at the induction of effective T cell responses against established cancers have so far only met with limited clinical success and clearly need to be improved. In a preclinical model of human papillomavirus (HPV)16-induced cervical cancer we show that prime-boost vaccinations with the HPV16-derived 35 amino-acid long peptide E7(43-77), containing both a CTL epitope and a Th epitope, resulted in the induction of far more robust E7-specific CD8(+) T cell responses than vaccinations with the minimal CTL epitope only. We demonstrate that two distinct mechanisms are responsible for this effect. First, vaccinations with the long peptide lead to the generation of E7-specific CD4(+) Th cells. The level of the induced E7-specific CD8(+) T cell response proved to be dependent on the interactions of these Th cells with professional APC. Second, we demonstrate that vaccination with the long peptide and dendritic cell-activating agents resulted in a superior induction of E7-specific CD8(+) T cells, even when T cell help was excluded. This suggests that, due to its size, the long peptide was preferably endocytosed, processed, and presented by professional APCs. Moreover, the efficacy of this superior HPV-specific T cell induction was demonstrated in therapeutic prime-boost vaccinations in which the long peptide admixed with the dendritic cell-activating adjuvant oligodeoxynucleotide-CpG resulted in the eradication of large, established HPV16-expressing tumors. Because the vaccine types used in this study are easy to prepare under good manufacturing practice conditions and are safe to administer to humans, these data provide important information for future clinical trials.