A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy.

Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the BamHI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10-8 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy (n = 10) and those who did not (n = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10-8 per base pair while the latter had 9.0 ± 4.5 × 10-8 per base pair (P < 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.

Cross-individual cancer transmission to children during the gestational and perinatal periods.

Cancer transmission may rarely occur between individuals. Besides through allogenic transplantation, cancer transmission via the hemochorial placenta, which is permissive for cell traffic, has been described in a few reports. Three etiologies of transplacental cancer transmission include (1) maternofetal transmission of maternal cancer cells, (2) transmission of gestational choriocarcinoma to the fetus, and (3) transfer of preleukemic cells from one monozygotic twin to the other. Additionally, we recently reported two pediatric cases of lung tumors in which the lung-only distribution of tumors and genomic profiling of both the child's and mother's tumor samples suggested the airway/transbronchial transmission of maternal cervical cancer cells to the child by aspiration at birth. The immune system coordinates the hemostatic balance between effector and regulatory immunity, especially during fetal development. The immunoregulatory properties are shared in both physiological pregnancy-related and pathological cancer-related conditions. Mechanistically, the survival and colonization of transmitted cancer cells within a child are likely attributed to a combination of the child's immune tolerance and the cancer's immune escape. In this review, we summarize the current understanding of gestational/perinatal cancer transmission and discuss the possible mechanism-based immunotherapy for this rare form of pediatric cancer.

Identification of barriers to implementation of precision oncology in patients with rare cancers.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

Statistics of bone sarcoma in Japan: report from the population-based cancer registry in Japan.

BACKGROUND: No previous reports have characterized national bone sarcoma profiles overall. We examined the nationwide statistics for bone sarcoma in Japan using data from the National Cancer Registry (NCR), a population-based cancer registry. METHODS: We identified 3,755 patients with bone sarcomas entered in the NCR during 2016-2019 using International Classification of Diseases-Oncology, Third Edition codes for cancer topography and morphology. We extracted data on patient demographics, tumor details (reason for diagnosis, tumor location, histology, extent of disease), hospital volume/type, treatment, and prognosis for each patient. RESULTS: Bone sarcoma showed a slight male preponderance. The age distribution peaked at ages 10-20 and 60-80; approximately 44% of patients were aged over 60 years. Chordoma, chondrosarcoma, and malignant fibrous histiocytoma of bone peaked in the elderly, and Ewing's sarcoma peaked in children. Osteosarcoma had two peaks in Japan as well as in Western countries. The most frequent tumor locations were the limb (45%) and the pelvis (21%). Extent of disease was categorized as: "localized" (39%), "regional" (27%), and "distant" (11%). We found significant associations between overall survival and age, tumor location, facility type, hospital volume, histologic subtype, reason for diagnosis, and extent of disease. The latter had the poorest survival. CONCLUSIONS: This is the first study to outline the epidemiology, clinical features, treatment, prognosis, and significant factors affecting prognosis of bone sarcoma in Japan using the NCR. Documenting our data regarding elderly patients' outcomes is essential so other countries showing similar population-aging trends can learn from our experiences. LEVEL OF EVIDENCE: Prognostic studies, Level III.

[Experience with an international study on standard-risk relapsed childhood acute lymphoblastic leukemia (IntReALL SR 2010 study) in Japan].

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma.

Sarcomas with BCOR genetic alterations (BCOR-associated sarcomas) represent a recently recognized family of soft tissue and bone tumors characterized by BCOR fusion, BCOR internal tandem duplication, or YWHAE::NUTM2B fusion. Histologically, the tumors demonstrate oval to spindle cell proliferation in a variably vascular stroma and overexpression of BCOR and SATB2. Herein, we describe 3 soft tissue sarcomas with KDM2B fusions that phenotypically and epigenetically match BCOR-associated sarcomas. The cases included 1 infant, 1 adolescent, and 1 older patient. All tumors showed histologic findings indistinguishable from those of BCOR-associated sarcomas and were originally diagnosed as such based on the phenotype. However, none of the tumors had BCOR or YWHAE genetic alterations. Instead, targeted RNA sequencing identified in-frame KDM2B::NUTM2B, KDM2B::CREBBP, and KDM2B::DUX4 fusions. KDM2B fusions were validated using reverse-transcription PCR, Sanger sequencing, and in situ hybridization assays. Genome-wide DNA methylation analysis matched all 3 tumors with BCOR-associated sarcomas using the Deutsches Krebsforschungszentrum (DKFZ) classifier and t-distributed stochastic neighbor embedding analysis. One localized tumor showed a flat genome-wide copy number profile, and the patient remained disease-free after treatment. The other tumors showed multiple copy number alterations, including MDM2/CDK4 amplification and/or CDKN2A/B loss, and both tumors metastasized, leading to the patient's death in one of the cases. When tested using KDM2B immunohistochemistry, all 3 KDM2B-rearranged sarcomas showed diffuse strong staining, and all 13 sarcomas with BCOR genetic alterations also demonstrated diffuse, strong, or weak staining. By contrast, among 72 mimicking tumors, only a subset of synovial sarcomas showed focal or diffuse weak KDM2B expression. In conclusion, our study suggests that KDM2B-rearranged soft tissue sarcomas belong to the BCOR-associated sarcoma family and expand its molecular spectrum. This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.

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.

Clinical characteristics of primary cutaneous and subcutaneous Ewing sarcoma.

OBJECTIVE: Given the rarity of cutaneous/subcutaneous Ewing sarcoma, their clinical characteristics remain poorly understood. In this study, we aimed to analyse the clinical characteristics of patients with cutaneous/subcutaneous Ewing sarcoma and review the treatment strategy. METHODS: We reviewed the clinical data of 154 patients with Ewing sarcoma who were treated at our hospital between 2005 and 2019. Amongst these patients, 21 patients with cutaneous/subcutaneous Ewing sarcoma were analysed. As a basic strategy, patients with localized disease received intensive chemotherapy (vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide), followed by definitive surgery with or without radiotherapy. In total, 15 patients underwent pre-diagnostic resection with macroscopic residue (seven patients) or non-macroscopic residue (eight patients) before intensive chemotherapy. RESULTS: The median tumour length of the measurable lesions was 3.2 cm, and the ratio of metastasis was significantly lower than the Ewing sarcoma of other anatomical sites (10% vs. 37%, P = 0.013). Despite the pre-diagnostic resection, local recurrence after additional resection and/or adjuvant radiotherapy did not occur in any of the patients with localized disease. Overall survival was significantly higher in patients with cutaneous/subcutaneous Ewing sarcoma than in patients with Ewing sarcoma of other anatomical sites (hazard ratio = 0.33, P = 0.013). The event-free survival rate of cutaneous/subcutaneous Ewing sarcoma was also superior to that of Ewing sarcoma of other anatomical sites (hazard ratio = 0.35, P = 0.01). CONCLUSIONS: Patients with cutaneous/subcutaneous Ewing sarcoma may have better prognosis than those with Ewing sarcoma at other anatomical sites. Although pre-diagnostic resection without appropriate investigations is not recommended, local control may be recovered by using a combination of additional resection, chemotherapy and radiotherapy.

The first Japanese biobank of patient-derived pediatric acute lymphoblastic leukemia xenograft models.

A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscid ll2rgtm1Sug /ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies.

Clinical utility of comprehensive genomic profiling tests for advanced or metastatic solid tumor in clinical practice.

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers.

Feasibility and clinical utility of comprehensive genomic profiling of hematological malignancies.

Identification of genetic alterations through next-generation sequencing (NGS) can guide treatment decision-making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS-based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0-55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer-cell lymphoma. These results suggest the clinical utility of NGS-based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Safety and Efficacy of Blinatumomab in Japanese Adult and Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Final Results from an Expansion Cohort.

INTRODUCTION: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Globally recommended blinatumomab doses were administered to adult (9-28 µg/day) and pediatric (5-15 µg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. RESULTS: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response. CONCLUSION: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.

Use of Pegfilgrastim in Japanese Pediatric Patients With Solid Tumors: A Retrospective Analysis.

There are no detailed analyses of regarding pegfilgrastim usage in Japanese pediatric solid tumor patients. The approved dose of pegfilgrastim in Japan is 3.6 mg. We retrospectively evaluated the incidence of dose delays and dose reductions due to neutropenia in pediatric patients with solid tumors receiving chemotherapy with pegfilgrastim between 2015 and 2018. The effects of the timing of pegfilgrastim administration were evaluated. In chemotherapies administered every 2 and 3 weeks, prolongation of chemotherapy cycles was analyzed. Fifty-nine patients received chemotherapy with prophylactic pegfilgrastim for a total 247 cycles. No significant incidence of dose delays was observed with pegfilgrastim administration during the first 1 to 3 days after chemotherapy. When 77 cycles in 2-week regimens were compared with 166 cycles in 3-week regimens, mean cycle durations were 15.19±2.06 and 21.97±2.88 days, respectively (P<0.001). A total of 77 chemotherapy cycles administered every 14 days were subdivided. The incidence of dose delays in pediatric patients receiving chemotherapy for 5 consecutive days was similar to that for 1 day and 2 consecutive days. Pegfilgrastim prophylaxis could be of use for Japanese pediatric patients with solid tumors receiving chemotherapy, including administration every 2 weeks. Its use aids in maintaining the chemotherapy schedule.

Surgical Treatment for Pneumothorax and Tumor-bronchial Fistula Secondary to Pulmonary Metastasis of Osteosarcoma in Pediatric and Adolescent Patients.

BACKGROUND: Pneumothorax and tumor-bronchial fistula are rare complications of pulmonary metastasis of osteosarcoma. OBSERVATIONS: We herein report the cases of 3 pediatric and adolescent patients who developed pneumothorax or tumor-bronchial fistula during treatment of pulmonary metastasis of osteosarcoma with chemotherapeutics or antiangiogenic agents. Two patients developed pneumothorax, and the other patient developed tumor-bronchial fistula. All of the patients finally underwent the surgery to treat their complications. CONCLUSIONS: Although it is not a curative surgery, surgery for pneumothorax and tumor-bronchial fistula is acceptable. The operative procedure should be considered on the basis of the predicted prognosis of the patient.

Feasibility and usefulness of recommended screenings at long-term follow-up clinics for hematopoietic cell transplant survivors.

PURPOSE: Advances in allogeneic hematopoietic cell transplantation (allo-HCT) have resulted in a growing number of transplant survivors; however, long-term survivors are at risk of developing late complications, and published guidelines recommend screening of this population. We conducted a single-center prospective study to evaluate the adherence to and usefulness of recommended screenings at a long-term follow-up (LTFU) clinic. METHODS: We included consecutive patients who received allo-HCT at our center from 2014, as well as post-HCT patients visiting our outpatient clinic. Visits and screenings were planned at 3 months, 6 months, and 1 year after allo-HCT, and annually thereafter. Outcomes were reported by physicians including the incidence of findings at each screening that led to interventions. RESULTS: Among the 216 participants, 95% visited the LTFU clinic, and 94% completed planned screenings. However, the rate of secondary cancer screenings targeting high-risk subjects was lower (38% to 68%). The overall percentage of screening results leading to interventions was 4.5%, with higher percentages (> 10%) for bone density testing, ophthalmological examinations, dental assessment, upper gastrointestinal endoscopy, and colonoscopy, with two patients diagnosed with secondary cancers. CONCLUSIONS: Although the overall screening rate was high, it should be possible to improve the detection rate of late complications by decreasing screening failures, especially the screening for secondary cancers limited for high-risk survivors. A nationwide effort to educate HCT survivors and health practitioners using standardized nationwide LTFU tools may be effective, along with the development of institutional, local, and nationwide networks to maintain effective follow-up systems.

[Successful treatment of very severe late-onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin, steroids, and control of intra-abdominal pressure].

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).

Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study.

Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).

Association of CD204+ macrophages with poor outcomes of malignant lymphomas not in remission treated by allogeneic HCT.

OBJECTIVE: CD204+ tumor-associated macrophages are associated with adverse outcomes of various malignancies. We performed a study to elucidate the role of CD204+ macrophages in allogeneic hematopoietic cell transplantation (allogeneic HCT). METHODS: In a total of 81 patients who received allogeneic HCT for non-remission malignant lymphoma, immunohistochemical staining of CD204 using specimens preserved before allogeneic HCT was performed. According to the average number of CD204+ macrophages in a high-power field, patients were categorized into three groups: low (<25th percentile), intermediate (≥25th percentile and <50th percentile), and high (≥50th percentile). RESULTS: The B-cell lymphoma proportion was higher in the low group, while T-cell lymphoma and adult T-cell leukemia proportions were higher in the high group. The 3-year overall survival (OS) was poorest in the high group; low vs intermediate vs high = 83.3% vs 43.7% vs 20.2% (P < .01). The 3-year cumulative incidences of relapse were significantly higher in the high group than the intermediate and low groups: 67.0% vs 38.1% vs 18.2% (P < .01). In multivariate analyses, the numbers of CD204+ macrophages were independent risk factors of poorer OS and cumulative incidences of relapse. CONCLUSIONS: CD204+ macrophages might be associated with poorer prognosis in allogeneic HCT for malignant lymphomas.