A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Outcomes of nonrejection in weakly fluorescent intestine detected by indocyanine green fluorescence angiography: a case series of infants.

BACKGROUND: Indocyanine green fluorescence angiography, a validated noninvasive imaging technique, is used to assess tissue vascularization. Here, we report three infant patients who underwent intraoperative indocyanine green fluorescence angiography and suffered from postoperative complications caused by the lack of weak fluorescent intestinal resection and assessed residual intestinal perfusion. CASE PRESENTATION: We observed the clinical characteristics and operative findings of patients treated from January 2022 to December 2022. Indocyanine green (0.5 mg/kg) was intravenously injected. The first patient was a 29-day-old girl with surgical necrotizing enterocolitis who underwent intraoperative indocyanine green fluorescence angiography at the first- and second-look operations. The proximal jejunum was difficult to diagnose to detect blood flow during the second-look operation. The second patient was a 32-day-old boy with surgical necrotizing enterocolitis. A part of the antimesenteric mucosa of the patient that exhibited weak fluorescence was preserved; however, it formed postoperative hematomas. The third patient was a 30-day-old boy with midgut volvulus. Weak fluorescence in the intestinal wall was observed 5 cm of the small intestine from the ileocecal valve was preserved, but it formed a stricture, and the patient underwent ileocecal resection after 30 days. CONCLUSIONS: Weak fluorescence in the intestine in infants by performing indocyanine green fluorescence angiography is associated with a high risk of non-recovering ischemic lesions and postoperative complications.

Comparison of Postoperative Respiratory Function Between Patients After Thoracoscopic and Open Lobectomy.

Purpose: This study aimed to compare respiratory functions of patients after thoracoscopic lobectomy (TS) with those after thoracotomy (TR). Methods: This retrospective study was conducted in two centers, one of which adapted TS as a standard procedure in 2009 and the other performs it via TR. Data on patients who underwent lobectomy for congenital lung disease between 2009 and 2021 and underwent pulmonary function test (spirometry) were collected. Results: Ten patients underwent TS and 36 underwent TR. Distribution based on sex, prenatal diagnosis, pathological diagnosis, and resected lobe were similar between the two groups. The median [interquartile range] age at procedure in the TR group was significantly smaller than that in the TS group (13 [11-18] months versus 38 [13-79] months, P = .03). The procedure duration in the TR group was significantly shorter than that in the TS group (230 [171-264] minutes versus 264 [226-420] minutes, P = .02). Pulmonary function test was conducted at the age of eight in both groups, but the interval between the procedure, and the test was significantly shorter in the TS group (TR: 7 [5-8] years versus TS: 5 [2-7] years, P = .03). The ratio of forced vital capacity compared to predicted one (TR: 86.6 [76.6-95.3] versus TS: 88.7 [86.8-89.1], P = .58) and the ratio of forced expiratory volume in 1 second against that predicted (TR: 84.0 [80.5-88.7] versus TS: 88.7 [86.8-89.1], P = .08) were not significantly different between the two groups. Conclusions: Although TR was performed earlier than TS, respiratory function was similar between the two groups.

Cancer incidence and type of treatment hospital among children, adolescents, and young adults in Japan, 2016-2018.

Cancer in children, adolescents, and young adults (AYAs) although rare, is the leading disease-specific cause of death in Japan. This study aims to investigate cancer incidence and type of treatment hospital among children and AYAs in Japan. Cancer incidence data (2016-2018) for those aged 0-39 years were obtained from the Japanese population-based National Cancer Registry. Cancer types were classified according to the 2017 update of the International Classification of Childhood Cancer (Third Edition), and AYA Site Recode 2020 Revision. Cases were also categorized into three groups: those treated at core hospitals for pediatric cancer treatment (pediatric cancer hospitals [PCHs]), those treated at designated cancer care hospitals, and those treated at nondesignated hospitals. The age-standardized incidence rate was 166.6 (per million-person years) for children (age 0-14 years) and 579.0 for AYAs (age 15-39 years) (including all cancers and benign or uncertain-behavior central nervous system [CNS] tumors). The type of cancer varied with age: hematological malignancies, blastomas, and CNS tumors were common in children under 10 years, malignant bone tumors and soft tissue sarcomas were relatively common in teenagers, and in young adults over 20 years, carcinomas in thyroid, testis, gastrointestinal, female cervix, and breast were common. The proportion of cases treated at PCHs ranged from 20% to 30% for children, 10% or less for AYAs, and differed according to age group and cancer type. Based on this information, the optimal system of cancer care should be discussed.

Safety and efficacy of multiple tyrosine kinase inhibitors in pediatric/adolescent and young adult patients with relapsed or refractory osteosarcomas: A single-institution retrospective analysis.

BACKGROUND: The prognosis of relapsed or refractory osteosarcoma remains poor. Recent reports have stated that molecular targeting agents, including multiple tyrosine kinase inhibitors (MTKIs), are effective against adult osteosarcoma. To determine the safety and efficacy of MTKI therapy in children, adolescents and young adults (AYAs), we conducted a retrospective study on adverse events and treatment outcomes. METHODS: We retrospectively reviewed the medical records of patients with relapsed or refractory osteosarcoma who received MTKI therapy at the Department of Pediatric Oncology, National Cancer Center Hospital, from December 2013 to May 2021. RESULTS: The study included 31 patients (15 males and 16 females) who received MTKIs, including sorafenib monotherapy (seven patients), sorafenib and everolimus (14 patients), and regorafenib monotherapy (10 patients). Their median age was 17 years (range: 11-22 years). The incidence of treatment-related grade 3 nonhematological adverse events was 14.3% in the sorafenib monotherapy group, 21.4% in the sorafenib with everolimus group, and 20.0% in the regorafenib monotherapy group. No grade 4 nonhematological adverse events were observed. The median progression-free survival (PFS) was 51 days in the sorafenib monotherapy group, 101 days in the sorafenib with everolimus group, and 167 days in the regorafenib monotherapy group. CONCLUSION: The safety profile of MTKI therapies in pediatric and AYA patients was comparable to that in adult patients. MTKI therapies, particularly regorafenib, against pediatric relapsed osteosarcoma can suppress tumor growth and prolong PFS with tolerable adverse events.

Role of surgery in neuroblastoma.

Neuroblastoma is the most common malignant solid tumor handled by pediatric surgeons. It is well-known that neuroblastoma shows variable biological and clinical behaviors. In this review article, surgical strategy in neuroblastoma was described by risk stratification. Also, strategy of biopsy and clinical conditions that require special considerations such as neuroblastoma detected by mass screening, relapsed neuroblastoma, patients with stage MS and dumbbell type tumors was mentioned. As multimodal systemic treatments have been expanding, the role of surgery in neuroblastoma has become relatively less significant but requisite. We surgeons should decide therapeutic strategy based on the correct understanding of biology of neuroblastoma thinking of the better future of children.

Strategy for hepatoblastoma with major vascular involvement: A guide for surgical decision-making.

BACKGROUND: Surgical management of tumor thrombus extending to the major vascular system for children with hepatoblastoma is challenging and insufficiently discussed. METHODS: We conducted a retrospective review of hepatoblastoma with tumor thrombus extending to the major vascular system (inferior vena cava, 3 hepatic veins, and portal vein trunk) treated at our center between May 2010 and June 2021. We describe our preoperative assessment, surgical strategies, and outcomes. RESULTS: We identified 9 patients (median age at the diagnosis: 3.4 years). All patients received chemotherapy before liver surgery. At the time of the diagnosis, tumor thrombus extended to the portal vein trunk (n = 6), inferior vena cava (n = 3), and 3 hepatic veins (n = 2). Among the 9 patients, 4 underwent liver resection. Liver transplantation was performed in 5 patients. The inferior vena cava wall was circumferentially resected for tumor removal in 1 patient and partially resected in 2 patients. One patient underwent liver transplantation using veno-venous bypass. Patients with tumor thrombus extending to the portal vein trunk were more likely to be managed by liver transplantation in comparison to those with tumor thrombus spreading to the inferior vena cava. The median follow-up period was 5.5 years. One patient underwent transhepatic balloon dilatation for biliary stricture after liver resection. Tumor recurrence was seen in 3 patients (33.3%; lung, n = 2; lymph node and liver, n = 1). No patients died during the follow-up period. CONCLUSION: Surgical intervention for pediatric hepatoblastoma with tumor thrombus extending into the major vascular system is safe, feasible, and achieves excellent outcomes.

Infantile Kaposiform hemangioendothelioma in a female patient complicated with severe obstructed jaundice: a case report.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare locally aggressive vascular neoplasm that occurs mainly in the pediatric population. KHE usually originates just underneath the skin and affects deeper tissues through infiltrative growth; however, visceral tissue involvement is quite rare. CASE PRESENTATION: An 8-month-old girl with jaundice and acholic stool was referred to our hospital for further evaluation of a hepatoduodenal ligament tumor. A blood examination revealed high bilirubin and liver enzyme levels, but no signs of coagulopathy. The first attempt at a diagnostic surgical procedure did not provide sufficient diagnostic information. However, the histopathological diagnosis of the cystic duct excised in the second surgery indicated KHE. Therefore, in our case, KHE was considered a cause of obstructive jaundice. Sirolimus (rapamycin) was initiated, and the patient was discharged 7 months after admission. CONCLUSIONS: In cases of atypical hypervascular lesions in the abdominal cavity, especially in the pediatric population, it is important to consider the possibility of KHE, and surgical intervention with proper strategies is required for diagnosis, followed sequentially by promising treatments.

Vaginal yolk sac tumor resected by a novel laparo/endoscope-assisted posterior sagittal approach: a case report.

BACKGROUND: Yolk sac tumor (YST) is a germ cell tumor that is generally associated with good prognosis in children. It has been recently reported that vaginal YSTs can be cured using chemotherapy alone. Thus, minimal invasiveness and function preservation are pre-requisites for surgical approaches. Herein, we report a case of vaginal YST that was resected in a function-preserving manner using a unique combination of surgical approaches. CASE PRESENTATION: In a 9-month-old Asian female infant, a vaginal tumor was detected while investigating for vaginal bleeding. The patient was referred to our hospital, and the tumor was diagnosed as a YST after incisional biopsy. Six courses of carboplatin-based chemotherapy were administered. Contrary to the findings in previous reports, the tumor was chemo-resistant and surgical resection was required for the residual tumor. During surgery, we utilized laparoscopic and endoscopic procedures to ensure tumor-free surgical margins at the cervix, rectum, and lateral wall of the vagina. Additionally, the posterior sagittal approach was used to easily resect the tumor, and the vagina was reconstructed leaving only inconspicuous scars in the intergluteal cleft. No complications occurred postoperatively. Pathological examination of the surgical specimen revealed tumor-free surgical margins. The patient received four cycles of intensified chemotherapy before and after the surgery. The patient has been disease-free for 6 months now. CONCLUSIONS: Our combination of laparo/endoscopic and posterior sagittal approach ensured a tumor-free macroscopic surgical margin with easier, cosmetically pleasing vaginal reconstruction, while preserving the anorectal and urinary functions. We believe that this approach could be utilized not only for vaginal YST, but also for any vaginal tumor, especially those arising from the posterior or lateral wall.

Quantitative assessment of copy number alterations by liquid biopsy for neuroblastoma.

Liquid biopsy, a method of detecting genomic alterations using blood specimens, has recently attracted attention as a noninvasive alternative to surgical tissue biopsy. We attempted quantitative analysis to detect amplification of MYCN (MYCNamp) and loss of heterozygosity at 11q (11qLOH), which are clinical requisites as prognostic factors of neuroblastoma (NB). In this study, cell-free DNA (cfDNA) was extracted from plasma samples from 24 NB patients at diagnosis. Copy numbers of MYCN and NAGK genes were quantitatively analyzed by droplet digital PCR (ddPCR). 11qLOH was also assessed by detecting allelic imbalances of heterozygous single nucleotide polymorphisms in the 11q region. The results obtained were compared to those of specimens from tumor tissues. The correlation coefficient of MYCN copy number of cfDNA and tumor DNA was 0.88 (p < 0.00001). 11qLOH was also accurately detected from cfDNA, except for one case with localized NB. Given the high accuracy of liquid biopsy, to investigate components of cfDNA, the proportion of tumor-derived DNA was estimated by examining the variant allele frequency of tumor-specific mutations in cfDNA. The proportion of tumor-derived DNA in cfDNA was 42.5% (range, 16.9%-55.9%), suggesting sufficient sensitivity of liquid biopsy for NB. In conclusion, MYCN copy number and 11qLOH could be quantitatively analyzed in plasma cfDNA by ddPCR assay. These results suggest that plasma cfDNA can be substituted for tumor DNA and can also be applied for comprehensive genomic profiling analysis.

Factors Associated With Adverse Outcomes Following Duodenal Atresia Surgery in Neonates: A Retrospective Study.

Objectives There is limited evidence on the infants' postoperative complications who have undergone surgical repair of duodenal atresia and stenosis. This study aimed to identify the factors associated with poor surgical outcomes after the initial repair. Methods We retrospectively reviewed the data of 82 patients who underwent surgery for duodenal atresia and stenosis between January 1994 and December 2013 at our institution. Gestational age, birth weight, fetal growth, and other associated anomalies were recorded. Multivariate regression analyses were used to identify the factors associated with surgical outcomes, including postoperative complications and time to full oral intake. Results The median gestational age was 37.6 weeks, with 30 (37%) preterm (<37 weeks) and 11 (13%) early preterm (<34 weeks) infants. The median birth weight was 2531 g, with 27 (33%) patients < 2000 g and 10 (12%) patients < 1500 g. Postoperative surgical complications were identified in 18 (22%) cases, of which 12 (15%) required additional operations. Multivariate regression analysis revealed that a combination of very low birth weight (<1500 g) and early preterm was significantly associated with both surgical and non-surgical postoperative complications (p = 0.0028 and 0.021, respectively) and a prolonged time to full oral intake postoperatively (p = 0.013). Conclusion Very low birth weight and early preterm were significantly associated with postoperative complications and a prolonged time to full oral intake.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Laparoscopic approach for abdominal neuroblastoma in Japan: results from nationwide multicenter survey.

BACKGROUND: Some neuroblastoma (NB) cases are suitable for minimally invasive surgery (MIS), but indication and technical issue are unclear. We assessed the current status of MIS for abdominal NB after mass screening period in Japan. METHODS: Preliminary questionnaires requesting the numbers of NB cases that underwent MIS from 2004 to 2016 were sent to 159 Japanese institutes of pediatric surgery. The secondary questionnaires were then sent to the institutions that reported MIS cases of NB in order to collect detailed data. RESULTS: One hundred and thirty-four (84.2%) institutions responded to the preliminary questionnaires, and 83 (52.2%) reported managing operative cases. The total number of operative cases was 1496. MIS was performed for 175 (11.6%) cases, of which the completed forms of 140 patients were returned, including 100 abdominal NB cases. The male/female ratio was 51/49. Forty-seven cases underwent a laparoscopic biopsy, and 2 (4.3%) cases were converted to laparotomy due to bleeding. Sixty-five cases underwent MIS for radical resection, and 7 (10.8%) were converted to laparotomy. The reasons for open conversion were bleeding and severe adhesion. Regarding open conversion, there were no significant relationships between conversion and neo-adjuvant chemotherapy, biopsies, stage, size, or MYCN amplification. We found no relationship between resectability and vascular encasement in this study. There was relationship between the resected tumor size and the patients' height, which was expressed using the following formula: [Formula: see text] (x, patients height, y, tumor size; p = 0.004219, SE: 1.55566). Postoperative complications after radical resection were recognized in 7 (10.8%) cases. CONCLUSIONS: MIS was performed in limited cases of abdominal NB. A laparoscopic biopsy with careful attention to bleeding is feasible. The resected tumor size was shown to correlate with the patients' height. Tumor size within 6 cm of maximum diameter can be resected safely.

Results of mass screening for neuroblastoma in 18-month-old infants in Osaka area, Japan.

PURPOSE: In 2004, the Japanese government halted nationwide mass screening for neuroblastoma in 6-month-old infants as it led to overdiagnosis of localized tumors with favorable prognoses and failed to reduce neuroblastoma-related mortality. However, a new mass screening program for neuroblastoma in 18-month-old infants (18MS) was conducted in the Osaka prefecture. We assessed the efficacy of the 18MS in screening unfavorable cases. METHODS: Public health centers in Osaka prefecture, excluding the Osaka city area, provided test kits to the guardians of infants who received a check-up at 18 months of age between 2004 and 2017. For patients whose standardized urinary levels of vanillylmandelic acid or homovanillic acid exceeded the threshold, they were further examined and treated in two specific hospitals Osaka University Hospital and Osaka Women's and Children's Hospital. Screening-positive patients with and without neuroblastoma were retrospectively reviewed. RESULTS: Among 142,423 children screened during the 18MS, 85 tested positive, and 14 were diagnosed with neuroblastoma. Twelve patients were classified as very low risk, while 2 were classified as high risk, based on the International Neuroblastoma Risk Group risk classification. CONCLUSION: The 18MS did not screen unfavorable cases with neuroblastoma efficiently, although few participants benefited from it.

Current thoracoscopic approach for mediastinal neuroblastoma in Japan-results from nationwide multicenter survey.

BACKGROUND: Minimally invasive surgery (MIS) is appropriate for the treatment of some neuroblastomas (NBs); however, the indications and technical issues are unclear. This study aimed to clarify the current status of MIS for mediastinal NB in Japan. METHODS: Preliminary questionnaires requesting the numbers of neuroblastoma cases in which MIS was performed from 2004 to 2016 were sent to 159 Japanese institutes of pediatric surgery. Secondary questionnaires were sent to institutions with MIS cases to collect detailed data. RESULTS: One hundred thirty-four (84.2%) institutions returned the preliminary questionnaire and 83 institutions (52.2%) reported a total of 1496 operative cases. MIS was performed for 175 (11.6%) cases. Among the 175 cases, completed forms of 140 patients were returned and 40 (male, n = 28; female, n = 12) cases had mediastinal NB. Fourteen patients received thoracoscopic biopsy, none were converted to thoracotomy. Twenty-eight patients received MIS for radical resection, none were converted to thoracotomy. Perioperative complications (Horner's syndrome) were recognized after radical resection in one (2.5%) case. CONCLUSIONS: MIS was performed in a limited number of mediastinal NB cases. A thoracoscopic approach would be feasible for mediastinal NB.