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.

KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Impact of a Cancer History on Cardiovascular Events Among Patients With Myocardial Infarction Who Received Revascularization.

BACKGROUND: It remains controversial whether a cancer history increases the risk of cardiovascular (CV) events among patients with myocardial infarction (MI) who undergo revascularization.Methods and Results: Patients who were confirmed as type 1 acute MI (AMI) by coronary angiography were retrospectively analyzed. Patients who died in hospital or those not undergoing revascularization were excluded. Patients with a cancer history were compared with those without it. A cancer history was examined in the in-hospital cancer registry. The primary outcome was a composite of cardiac death, recurrent type 1 MI, post-discharge coronary revascularization, heart failure hospitalization, and stroke. Among 551 AMI patients, 55 had a cancer history (cancer group) and 496 did not (non-cancer group). Cox proportional hazards model revealed that the risk of composite endpoint was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.13-2.82). Among the cancer group, patients who were diagnosed as AMI within 6 months after the cancer diagnosis had a higher risk of the composite endpoint than those who were diagnosed as AMI 6 months or later after the cancer diagnosis (adjusted HR: 5.43; 95% CI: 1.55-19.07). CONCLUSIONS: A cancer history increased the risk of CV events after discharge among AMI patients after revascularization.

Development of adolescent childhood cancer survivors' psychosocial issues scale.

BACKGROUND: Follow-up care for adolescent childhood cancer survivors (ACCS) after they return to school requires an understanding of their psychosocial issues. Therefore, this study developed the adolescent childhood cancer survivors' psychosocial issues scale (ACCSPIS) and evaluated its reliability and validity. METHODS: In the development phase, pediatric oncology clinical professionals created the 24 item questionnaire of ACCS's psychosocial issues. In the feasibility phase, a survey was administered to 165 ACCS aged 12-18 years after discharge from hospital in Japan, and 57 completed questionnaires were analyzed. The survey items were psychosocial issues, attributes, K6 scale, and impact of event scale-revised (IES-R) scale. Factor analysis was conducted for psychosocial issues. Regarding reliability, Cronbach's α coefficients and item-total correlation coefficients were calculated. Regarding validity, Spearman's rank correlation coefficients between ACCSPIS and K6 and IES-R were calculated, and confirmatory factor analysis was conducted. RESULTS: Four factors comprising 15 items were extracted: "appearance changes due to treatment effects," "anxiety about marriage and the future," "change in appearance due to treatment", and "psychological distress due to interpersonal relationships and information about the disease." The model fit was good, with a total ACCSPIS α coefficient of 0.901 and α coefficients for the subscales ranging from 0.651 to 0.914. The K6 and IES-R were significantly associated with the total ACCSPIS, and item-total correlations were satisfactory. CONCLUSIONS: The reliability and validity of ACCSPIS were generally confirmed. This scale could be useful to measure psychosocial issues in ACCS aged 12-18 years after their return to school.

Nelarabine, intensive L-asparaginase, and protracted intrathecal therapy for newly diagnosed T-cell acute lymphoblastic leukaemia in children and young adults (ALL-T11): a nationwide, multicenter, phase 2 trial including randomisation in the very high-risk group.

BACKGROUND: T-cell acute lymphoblastic leukaemia has distinct biological characteristics and a poorer prognosis than B-cell precursor acute lymphoblastic leukaemia. This trial aimed to reduce the rate of radiation and haematopoietic stem-cell transplantation (HSCT) while improving outcomes by adding nelarabine, intensified L-asparaginase, and protracted intrathecal therapy in the Berlin-Frankfurt-Münster (BFM)-type treatment. METHODS: In this nationwide, multicenter, phase 2 trial, we enrolled patients with newly diagnosed T-cell acute lymphoblastic leukaemia (age <25 years at diagnosis) conducted by Japan Children's Cancer Group and Japan Adult Leukemia Study Group. Patients were stratified into standard-risk, high-risk, and very-high-risk groups according to prednisolone response, CNS status, and end-of-consolidation minimal residual disease. We used the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)-BFM-ALL 2000-backbone chemotherapy. Nelarabine (650 mg/m2 per day for 5 days) was given to high-risk and very high-risk patients. All patients received, until the measurement of end-of-consolidation minimal residual disease, an identical therapy schedule, which included the prednisolone pre-phase remission induction therapy with dexamethasone (10 mg/m2 per day, for 3 weeks [for patients <10 years] or for 2 weeks including a 7-day off interval [for patients ≥10 years]) instead of prednisolone, and consolidation therapy added with Escherichia coli-derived L-asparaginase. On the basis of the stratification, patients received different intensities of treatment; L-asparaginase-intensified standard BFM-type therapy for standard risk and nelarabine-added high risk BFM-type therapy for high risk. In the very high-risk group, patients were randomly assigned (1:1) to group A (BFM-based block therapy) and group B (another block therapy, including high-dose dexamethasone) stratified by hospital, age (≥18 years or <18 years), and end-of-induction bone marrow blast percentage of M1 (<5%) or M2 (≥5%, <25%)+M3 (≥25%). Cranial radiotherapy was limited to patients with overt CNS disease at diagnosis (CNS3; >5 white blood cells per µL with blasts) and patients with no evidence of CNS disease received protracted triple intrathecal therapy. Only very high-risk patients were scheduled to receive HSCT. The primary endpoint was 3-year event-free survival for the entire cohort and the proportion of patients with disappearance of minimal residual disease between randomly assigned groups A and B in the very high-risk group. Secondary endpoints were overall survival, remission induction rate, and occurrence of adverse events. 3 years after the completion of patient accrual, a primary efficacy analysis was performed in the full analysis set and the per-protocol set. This study is registered with the Japan Registry of Clinical Trials, jRCTs041180145. FINDINGS: Between Dec 1, 2011, and Nov 30, 2017, of 349 eligible patients (median age 9 years [IQR 6-13]), 238 (68%) were male, and 28 (8%) patients had CNS3 status. 168 (48%) patients were stratified as standard risk, 103 (30%) as high risk, 39 (11%) as very high risk, and 39 (11%) as no risk (patients who had off protocol treatment before risk assessment. The composite complete remission (complete remission plus complete remission in suppression) rate after remission induction therapy was 89% (298 of 335 patients). HSCT was performed in 35 (10%) of 333 patients. With a median follow-up of 5·2 years (IQR 3·6-6·7), 3-year event-free survival was 86·4% (95% CI 82·3-89·7%) and 3-year overall survival was 91·3% (87·7-93·8%). The proportion of minimal residual disease disappearance was 0·86 (12 of 14 patients; 95% CI 0·57-0·98) in group A and 0·50 (6 of 12 patients, 0·21-0·79) in group B. Grade 3 peripheral motor neuropathy was seen in 11 (3%) of 349 patients and sensory neuropathy was seen in 6 (2%) patients. The most common grade 3 or worse adverse event was febrile neutropenia (294 [84%] of 349 patients). Treatment-related death occurred in three patients due to sepsis, gastric perforation, or intracranial haemorrhage during remission induction. INTERPRETATION: The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use. FUNDING: Ministry of Health, Labor and Welfare of Japan, and Japan Agency for Medical Research and Development. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Rare Case of BCOR::CCNB3 Sarcoma of Bone.

BACKGROUND BCOR: CCNB3 sarcoma is a rare mesenchymal tumor that was formerly included in the undifferentiated/unclassified sarcoma group and was recently reclassified as one of undifferentiated small round cell sarcomas with a genetically distinct subtype in the WHO 2020 classification. Because of its rarity, still not much is known, especially about its clinical features. CASE REPORT A 15-year-old boy presented with almost 1-year intermittent thigh pain. On the first visit, a pathologic fracture of the femur and a big mass expanding through the femoral cortex with lobular shape and homogenous appearance were recognized on radiography and magnetic resonance imaging. Plain radiography, which was taken 6 months before at a local clinic, showed an expansion and thickening of the right proximal femoral shaft. Biopsy specimen of the lesion revealed a proliferation of round to spindle tumor cells with diffuse and strong immunohistochemical nuclear positivity for BCOR and CCNB3. Under the diagnosis of BCOR::CCNB3 sarcoma of the femur, a chemotherapy based on a protocol of Ewing sarcoma, followed by a wide resection and total femoral replacement surgery, were conducted. The effect of chemotherapy was favorable, showing no microscopic residual tumor. Although postoperative chemotherapy was not completed because of a minor infection detected on the surgical site, the patient was doing well, without any recurrence, for 26 months. CONCLUSIONS BCOR: CCNB3 sarcoma of the bone is a quite rare tumor with much lower incidence than Ewing sarcoma. Notable clinical characteristics of the current case were a 1-year-long symptomatic period and homogenous appearance on MRI.

Feasibility and safety of platinum-doublet therapy in patients with small-cell lung cancer in the third-line setting: A multi-institutional retrospective study.

Small-cell lung cancer (SCLC) is a highly malignant tumor, and no standard third-line therapy has been established. The present study retrospectively analyzed the efficacy and safety of platinum-based regimens in patients with third-line SCLC who received third-line chemotherapy. The association of regimen type with overall survival (OS) or time to treatment failure (TTF) was evaluated using the Cox hazard proportional method, including well-known covariates affecting the prognosis of SCLC. TTF and OS analyses were conducted using the Kaplan-Meier method. The data cutoff date was June 30, 2020. As a result, from January 2015 to August 2019, 111 patients were diagnosed with SCLC, and 37 received third-line chemotherapy. Subsequently, 15 patients received a platinum-doublet regimen, and 22 patients received a single-agent regimen. Only the type of regimen was significantly associated with TTF in univariate analysis (odds ratio, 0.44; 95% confidence interval, 0.20-0.95; P=0.03). There were no significant factors associated with OS. The median TTF of patients receiving a platinum-doublet regimen and those receiving a single-agent regimen were 3.9 and 2.3 months, respectively (P=0.03). The overall response rates of the platinum-doublet and single-agent regimens were 20.0 and 4.5%, respectively. Similarly, the disease control rates were 73.3 and 36.4% for platinum-doublet and single-agent regimens, respectively. There was a tendency for adverse events (AEs) with any grade to occur more often in platinum-based regimens compared with in single-agent regimens. Severe AEs of grade 3 or higher were observed more often in the platinum-based regimen, especially in myelosuppression. In conclusion, the present study demonstrated the feasibility and safety of platinum-doublet regimens in patients with SCLC in a third-line setting (Registration no. 2020-048. Date of registration, June 5, 2020).

Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis.

INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Diabetic ketoacidosis shortly after COVID-19 vaccination in a non-small-cell lung cancer patient receiving combination of PD-1 and CTLA-4 inhibitors: A case report.

We describe a case of diabetic ketoacidosis (DKA) shortly after the SARS-CoV-2 (COVID-19) vaccination in a 65-year-old woman with non-small-cell lung cancer under a combination treatment of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. She had no history of diabetic mellitus. A few days after the second shot of COVID-19 vaccination, she developed DKA. We speculate that the immune-related adverse event and immunogenicity of vaccination synergistically induced DKA.

Long-term outcomes following surgical repair of coronary artery fistula in adults.

BACKGROUND AND AIM OF THE STUDY: Coronary artery fistula (CAF) is a relatively rare cardiac anomaly. We investigated long-term outcomes following surgical repair of CAF in adults. METHODS: We retrospectively investigated 13 consecutive patients undergoing surgical repair of CAF in our institution between 2008 and 2019 (67.3 ± 10.4 years old, 38% male). CAF types were coronary artery-pulmonary artery fistula (77%), coronary artery-coronary sinus fistula (15%), and both (8%). CAFs originated from the left coronary artery (38%), right coronary artery (8%), and bilateral coronary arteries (38%). Pulmonary and systemic flow (Qp/Qs) was measured in seven patients (54%), with a mean value of 1.52. Seven patients underwent surgery for CAFs alone, and others simultaneously underwent surgery for comorbid cardiac diseases. RESULTS: All procedures were conducted under cardiopulmonary bypass. Surgical procedures were direct epicardial ligation of fistula (92%), direct closure of CAF through pulmonary artery incision (38%), direct closure of CAF through coronary sinus incision (8%), or patch closure of CAF through coronary artery incision (8%). Myocardial perfusion scintigraphy showed asymptomatic myocardial ischemia in the right coronary area after surgery in one patient. There were no deaths perioperatively or during follow-up (mean: 66.6 months). There were no coronary or other CAF-related events. CONCLUSIONS: Several anatomical variations in CAF were observed which coexist with cardiac disease. Long-term outcomes following surgical repair were satisfactory, and the concurrent intervention of CAFs during surgery for comorbid cardiac disease is useful to prevent future complications related CAFs in adults.

Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma.

BACKGROUND: The optimal treatment for rhabdomyosarcoma (RMS) requires multidisciplinary treatment with chemotherapy, surgery, and radiotherapy. Surgery and radiotherapy are integral to the local control (LC) of RMS. However, postsurgical and radiotherapy-related complications could develop according to the local therapy and tumor location. In this study, we conducted a single-center analysis of the outcomes and toxicity of multidisciplinary treatment using proton beam therapy (PBT) for pediatric RMS. MATERIALS AND METHODS: RMS patients aged younger than 20 years whose RMS was newly diagnosed and who underwent PBT at University of Tsukuba Hospital (UTH) during the period from 2009 to 2019 were enrolled in this study. The patients' clinical information was collected by retrospective medical record review. RESULTS: Forty-eight patients were included. The 3-year progression-free survival (PFS) and overall survival (OS) rates of all the patients were 68.8% and 94.2%, respectively. The 3-year PFS rates achieved with radical resection, conservative resection, and biopsy only were 65.3%, 83.3%, and 67.6%, respectively (p = 0.721). The 3-year LC rates achieved with radical resection, conservative resection, and biopsy only were 90.9%, 83.3%, and 72.9%, respectively (p = 0.548). Grade 3 or higher mucositis/dermatitis occurred in 14 patients. Although the days of opioid use due to mucositis/dermatitis during the chemotherapy with PBT were longer than those during the chemotherapy without PBT [6.1 and 1.6 (mean), respectively, p = 0.001], the frequencies of fever and elevation of C-reactive protein were equivalent. CONCLUSIONS: Multidisciplinary therapy containing PBT was feasible and provided a relatively fair 3-year PFS, even in children with newly diagnosed RMS without severe toxicity.

Lethal macrophage-related complications of juvenile myelomonocytic leukemia with a blastic crisis: an autopsy case report.

For hematopoietic stem cell transplantation to be successful, complications must be managed. Graft-versus-host disease is particularly important, but various other complications, treatment side effects, and relapse of primary disease may also occur. We report an autopsy case of juvenile myelomonocytic leukemia with a blastic crisis, in which activated and recovered autologous macrophage-related complications after cord blood transplantation caused the patient's death. Pathological analysis of autopsy specimens revealed diffuse infiltration of mature macrophages into the skin but scarce lymphocytes. These macrophages were found in the bone marrow interspersed with a small number of blasts that had previously occupied about 60% of the bone marrow before death. The direct cause of death was an opportunistic airway infection due to bone marrow and immune failures triggered by overactivation and proliferation of macrophages. Genetic analysis showed the activated macrophages were autologous. Together these findings indicate that the patient died from macrophage-mediated complications, but not from a blastic crisis or conventional graft-versus-host disease. When macrophage activation persists after hematopoietic stem cell transplantation, macrophage-mediated complications should be considered as a differential diagnosis. To manage this complication, pathology specimens should be examined to check for the presence of effector cells at an early stage.

Impact of dialysis in patients undergoing bioprosthetic aortic valve replacement.

OBJECTIVES: To determine the incidence of bioprosthetic structural valve deterioration in dialysis patients undergoing aortic valve replacement compared to that in patients without dialysis. METHODS: This single-centre retrospective observational study included 1159 patients who underwent aortic valve replacement using bioprosthetic valves for aortic stenosis and/or regurgitation at our institution between 2007 and 2017 [patients with dialysis (group D, n = 134, 12%) or without dialysis (group N, n = 1025, 88%)]. To adjust for potential differences between groups in terms of initial preoperative characteristics or selection bias, a propensity score analysis was conducted. The final sample that was used in the comparison included 258 patients, as follows: 129 patients with dialysis (group D) and 129 patients without dialysis (group N). The cumulative incidences of all-cause death, cardiac death and moderate or severe structural valve deterioration were estimated using the Kaplan-Meier method. RESULTS: Operative mortality was significantly higher in group D than group N (9% vs 0%, P = 0.001). Kaplan-Meier analysis revealed that in group D, the incidence was significantly higher for all-cause death (P < 0.001, 50% vs 18% at 5 years), cardiac death (P = 0.001, 18% vs 5% at 5 years) and moderate or severe structural valve deterioration (P < 0.001, 29% vs 5% at 5 years) compared with group N. CONCLUSIONS: The incidence of structural valve deterioration in dialysis patients undergoing aortic valve replacement was higher than that in patients without dialysis. Bioprosthetic valves should be carefully selected in dialysis patients undergoing aortic valve replacement.

Proton beam therapy for children and adolescents and young adults (AYAs): JASTRO and JSPHO Guidelines.

Children and adolescents and young adults (AYAs) with cancer are often treated with a multidisciplinary approach. This includes use of radiotherapy, which is important for local control, but may also cause adverse events in the long term, including second cancer. The risks for limited growth and development, endocrine dysfunction, reduced fertility and second cancer in children and AYAs are reduced by proton beam therapy (PBT), which has a dose distribution that decreases irradiation of normal organs while still targeting the tumor. To define the outcomes and characteristics of PBT in cancer treatment in pediatric and AYA patients, this document was developed by the Japanese Society for Radiation Oncology (JASTRO) and the Japanese Society of Pediatric Hematology/Oncology (JSPHO).

Soft tissue sarcoma in adolescent and young adult patients: a retrospective study using a nationwide bone and soft tissue tumor registry in Japan.

OBJECTIVE: The relationship between the adolescent and young adult age groups and poor overall survival in soft tissue sarcoma and the risk factors for poor outcomes in adolescent and young adult patients with soft tissue sarcoma were analyzed. METHODS: The medical records of 7759 Japanese patients diagnosed with soft tissue sarcoma from 2006-13 were accessed from the Bone and Soft Tissue Tumor registry. The epidemiological features of adolescent and young adult patients were compared with those of other age groups. The cancer survival rates were calculated using the Kaplan-Meier method. The prognostic factors for cancer survival were analyzed with the Cox proportional hazards models. The primary endpoint for prognosis was tumor-related death. RESULTS: There were 210 children, 1467 adolescent and young adults, 2771 adults and 3311 elderly among the 7759 patients identified with soft tissue sarcoma. Compared with other age groups, the proportions of myxoid/round cell liposarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, primitive neuroectodermal tumor and rhabdomyosarcoma in adolescent and young adult patients were the highest, but none was significantly more prevalent in adolescent and young adult patients. On multivariate analysis, age was not a prognostic factor for poor cancer survival among adolescent and young adult patients with soft tissue sarcoma. The cancer survival rates of adolescent and young adult patients with malignant peripheral nerve sheath tumor were poorer than those of the other age groups; however, adolescent and young adult age was not a prognostic factor on multivariate analysis in malignant peripheral nerve sheath tumor patients. CONCLUSIONS: Our study is the first to investigate soft tissue sarcoma in adolescent and young adult patients using the nationwide Bone and Soft Tissue Tumor registry. Adolescent and young adult age is not a prognostic factor for poor cancer survival among those with soft tissue sarcoma in Japan.

Prognostic factors and impact of surgery in patients with metastatic soft tissue sarcoma at diagnosis: A population-based cohort study.

BACKGROUND: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear. METHODS: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors. RESULTS: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival. CONCLUSIONS: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery.

Retrospective Analysis of INRG Clinical and Genomic Factors for 605 Neuroblastomas in Japan: A Report from the Japan Children's Cancer Group Neuroblastoma Committee (JCCG-JNBSG).

Neuroblastomas (NBs) exhibit broad and divergent clinical behaviors and tumor risk classification at diagnosis is crucial for the selection of an appropriate therapeutic strategy for each patient. The present study aimed to validate the clinical relevance of International Neuroblastoma Risk Group (INRG) prognostic and genomic markers in a Japanese NB cohort using a retrospective analysis. Follow-up data based on 30 common INRG queries in 605 NB cases diagnosed in Japan between 1990 and 2014 were collected and the genome signature of each tumor sample was integrated. As previously indicated, age, tumor stage, MYCN, DNA ploidy, the adrenals as the primary tumor site, serum ferritin and lactate dehydrogenase (LDH) levels, segmental chromosome aberrations, and the number of chromosome breakpoints (BP) correlated with lower survival rates, while the thorax as the primary tumor site and numerical chromosome aberrations correlated with a favorable prognosis. In the patient group with stage 4, MYCN non-amplified tumors (n = 225), one of the challenging subsets for risk stratification, age ≥ 18 months, LDH ≥ 1400 U/L, and BP ≥ 7 correlated with lower overall and event-free survival rates (p < 0.05). The genome subgroup GG-P2s (partial chromosome gain/loss type with 1p/11q losses and 17q gain, n = 30) was strongly associated with a lower overall survival rate (5-year survival rate: 34%, p < 0.05). Therefore, the combination of the tumor genomic pattern (GG-P2s and BP ≥ 7) with age at diagnosis and LDH will be a promising predictor for MYCN-non-amplified high-risk NBs in patient subsets, in accordance with previous findings from the INRG project.

Surgical resection of the primary lesion for osteosarcoma patients with metastasis at initial diagnosis.

BACKGROUND: Approximately 10-20% of osteosarcoma patients present with metastasis on diagnosis. Completely resecting the lesion is associated with better prognosis. However, evidence regarding optimal surgical strategies for patients with unresectable metastasis is limited. METHODS: This retrospective analysis was based on the Japanese Nationwide Bone and Soft Tissue Tumor registry. In total, 335 patients diagnosed with osteosarcoma with metastasis were included. Factors affecting overall survival were identified using multivariate analysis. Kaplan-Meier method was used to compare the overall survival by the status of surgical intervention. Two hundred and four patients who did not undergo surgery for metastasis were divided into two groups, depending on whether they underwent surgery for the primary lesion. The background differences between these two groups were adjusted with propensity score matching, with 43 patients per group. The overall survival was calculated using the Kaplan-Meier method and compared with a log-rank test. RESULTS: Factors positively impacting overall survival were age <40, female sex, extremity origin, surgery for the primary lesions, surgery for metastasis and radiotherapy without surgery. For patients with unresectable metastasis, after propensity score matching, the survival rate was higher in the group that underwent primary lesion surgery than the group without surgery. Their median survival was 19 (95% confidence interval: 11.7-26.3) and 11 months (95% confidence interval: 4.5-17.5) (P = 0.02), respectively. CONCLUSIONS: Surgical resection of the primary osteosarcoma lesion did not worsen prognosis, even in patients with unresectable metastasis. Further study is needed to identify which patient group will benefit from primary lesion resection.