Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia.

Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphologic MDS/AML in 33 patients, including refractory cytopenia in 16, refractory anemia with excess blasts (RAEB) in 7, and AML in 10. The major mutated FA genes observed in this study were FANCA (n = 52) and FANCG (n = 23). The distribution of the ALDH2 variant alleles did not differ significantly between patients with mutations in FANCA and FANCG. However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations. In FANCA, patients with the c.2546delC mutation (n = 24) related to poorer MDS/AML-free survival and a younger age at HSCT than those without this mutation. All patients with RAEB/AML had an abnormal karyotype and poorer prognosis after HSCT; specifically, the presence of a structurally complex karyotype with a monosomy (n = 6) was associated with dismal prognosis. In conclusion, the best practice for a clinician may be to integrate the morphological, cytogenetic, and genetic data to optimize HSCT timing in Japanese FA patients.

Prone "computed tomography hernia study" for the diagnosis of inguinal hernia.

PURPOSE: To improve diagnostic accuracy in cases of a suspected inguinal hernia, we perform a "CT hernia study," with the patient lying prone to allow decompression of the structures in the inguinal region. METHODS: We reviewed the records of 914 patients with a suspected inguinal hernia who underwent prone non-contrast lower abdominal CT with two rolled-up towels, 20 cm in diameter, placed transversely beneath them, at the umbilicus and hips, respectively. RESULTS: The CT hernia study yielded a diagnosis of inguinal hernia in 861 (94.2%) patients and a condition other than inguinal hernia in 43 (4.7%) patients. Hernia was not detected preoperatively but found intraoperatively in 10 patients (1.1%). Surgery was performed for a collective total of 1029 hernias in 873 patients, and the CT hernia study-based hernia detection rate was 98.3%. We compared the preoperative diagnoses of various types of hernia (Japanese Hernia Society Types I-V) against the intraoperative diagnoses and found that the CT hernia study yielded 95.8% accuracy. CONCLUSION: The CT hernia study appears to provide a high detection rate and makes differentiating the various types of inguinal hernia possible. We believe our CT hernia study adds a level of objectivity that is diagnostically beneficial.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

The phenotype and clinical course of Japanese Fanconi Anaemia infants is influenced by patient, but not maternal ALDH2 genotype.

Studies using Fanconi anaemia (FA) mutant mouse models suggested that the combination of a defective FA pathway and aldehyde dehydrogenase-2 (ALDH2) dysfunction could provoke bone marrow failure, leukaemia and developmental defects, and that both maternal and fetal aldehyde detoxification are crucial to protect the developing embryo from DNA damage. We studied the ALDH2 genotypes of 35 Japanese FA patients and their mothers. We found that a normal maternal ALDH2 allele was not essential for fetal development of ALDH2-deficient patients, and none of the post-natal clinical parameters were clearly affected by the maternal ALDH2 genotype in these patients.

Hemophagocytic lymphohistiocytosis caused by systemic herpes simplex virus type 1 infection: Successful treatment with dexamethasone palmitate.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition resulting from an uncontrolled and ineffective immune response. Here, we report a case of HLH caused by disseminated herpes simplex virus (HSV)-1 infection. The patient was initially treated with prednisolone and high-dose acyclovir. Although liver enzymes, coagulation abnormalities, and inflammatory markers were remarkably improved, the platelet count remained low. Prednisolone was therefore switched to dexamethasone palmitate. Thereafter, the platelet count normalized. Inflammatory markers normalized 30 days after admission and serum HSV-DNA became undetectable on day 41. The patient was discharged on day 91 and no developmental delay was evident at 7 months of age. These findings suggest that dexamethasone palmitate is effective for neonatal HLH.

Successful acute lymphoblastic leukemia-type therapy in two children with mixed-phenotype acute leukemia.

Mixed-phenotype acute leukemia (MPAL) is a rare type of leukemia expressing both myeloid and lymphoid markers. There is limited information, especially on pediatric cases. Therefore, the optimal therapeutic approach to pediatric MPAL has not been defined. Here, we report two pediatric cases of MPAL. According to the 2008 World Health Organization (WHO) classification and European Group for the Immunological Characterization of Leukemias (EGIL) criteria, patient 1 was diagnosed with overt MPAL positive for the myeloid marker myeloperoxidase (MPO), and B-lymphoid markers. Patient 2 was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) using EGIL criteria. According to the 2008 WHO classification, however, patient 2 was diagnosed with overt MPAL positive for CD3, T-lymphoid markers and MPO. We chose an ALL-type therapy consisting of both lymphoid- and myeloid-directed agents; these patients have maintained complete remission following treatment. Further information on pediatric MPAL is needed to establish an appropriate therapeutic strategy including stem cell transplantation for this rare condition.

Small renal cell carcinoma accompanied by extensive inferior vena cava tumor thrombus diagnosed by percutaneous transvenous biopsy.

Introduction: Up to 10% of patients with renal cell carcinoma present with tumor thrombus in the inferior vena cava. We report that a case of small renal cell carcinoma with tumor thrombus extending above the diaphragm for which transvenous biopsy was performed for diagnosis. Case presentation: A 79-year-old man performed computed tomography to evaluate hepatic dysfunction, which revealed intravenous tumor extending above the diaphragm and a 15-mm-sized exophytic tumor in right kidney. Imaging suggested that the renal tumor was renal cell carcinoma. As this tumor was small and exophytic, confirmation of the intravenous tumor being tumor thrombus associated with renal cell carcinoma was difficult. We simultaneously performed transvenous biopsy on the intravenous tumor and percutaneous biopsy on the renal tumor for obtaining histologic diagnoses. The final diagnosis was small renal cell carcinoma accompanied by tumor thrombus above the diaphragm. Conclusion: Transvenous biopsy may be useful for the definitive diagnosis of inferior vena cava-tumor thrombus in cases of small renal cell carcinoma.

Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.

Internal hernia through the foramen of Winslow: the "narrowed portal vein" sign on abdominal CT.

We report a case of ileal internal hernia through the foramen of Winslow into the lesser sac. Preoperative computed tomography (CT) demonstrated that the herniated ileum, which showed a closed-loop obstruction, was located behind the portal vein, and the vein was subsequently compressed and narrowed by the herniated ileum. We found that similar cases in the literature of Winslow's foramen hernias that caused portal vein compression; however, portal vein narrowing has not been described as a characteristic CT finding. The narrowed portal vein sign could be useful in diagnosing the hernia through the foramen of Winslow.

High incidence of radiation-induced cavernous hemangioma in long-term survivors who underwent hematopoietic stem cell transplantation with radiation therapy during childhood or adolescence.

Radiation-induced cavernous hemangioma (RICH) is a late complication of cerebral radiation therapy. Long-term survivors of hematopoietic stem cell transplantation (HSCT) who underwent radiation therapy could be at increased risk for RICH. We investigated records of 68 patients who underwent HSCT during childhood or adolescence and were assessed by magnetic resonance imaging (MRI), including T2*-weighted imaging of the brain, annually for 5 years over a range of 6 to 29 years after HSCT. We developed a scoring and grading system for RICH to monitor the process and the progress of radiologic changes. Among the 68 patients investigated, 28 (41.2%) were diagnosed with CH. All 28 patients had received total body irradiation as a conditioning treatment for HSCT and/or cranial radiation therapy before HSCT as part of the treatment of their primary disease. RICH was diagnosed in none of the patients who did not receive radiation (n = 19), in 46.2% of those who received 6 to 12 Gy (n = 39), and in all of those who received 18 to 36 Gy (n = 10). Total RICH scores were correlated with higher radiation doses. Careful and long-term evaluation with MRI, including T2*-weighted imaging, is necessary for HSCT recipients who received radiation therapy before and/or during HSCT.

Decreased serum testosterone levels in long-term adult survivors with fatty liver after childhood stem cell transplantation.

Fatty liver and male gonadal dysfunction are potential late effects of therapy in adult survivors treated with stem cell transplantation (SCT) in childhood. Obesity and metabolic syndrome also are associated with low serum testosterone levels in the general population. However, the relationship between the degree of fatty liver and changes in serum testosterone levels in adult survivors has not been fully studied. We reviewed the clinical records of 34 male patients who received allogeneic SCT in childhood or adolescence. The median age at SCT was 10.0 years, and the median follow-up after SCT was 15.9 years. All but one patient showed no tendency toward overweight/obesity during the follow-up period. Fatty liver was diagnosed by ultrasound in 15 patients at 4 to 20 years after SCT. Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. Moreover, fatty liver was statistically associated with decreased serum testosterone levels, whereas nonfatty liver was not (median, 527 ng/dL [range, 168-944 ng/dL] versus 302 ng/dL [165-698 ng/dL]; P < .0001). Changes in testosterone levels after SCT are affected not only by primary gonadal dysfunction but also by subsequent development or exacerbation of fatty liver.

Matched sibling donor stem cell transplantation for Fanconi anemia patients with T-cell somatic mosaicism.

SCT from HLA-identical sibling donors is generally associated with an excellent survival in FA patients if performed prior to the development of MDS or leukemia. However, the optimal conditioning regimen has not been defined. We report here our experience with 15 Japanese FA patients who underwent HLA-matched sibling donor SCT. The aim of this study is to compare radiation-based conditioning to Flu-based conditioning for FA patients in a Japanese population where the T-cell somatic mosaicism is higher than in the Caucasian population. Eight patients (a-group) received a radiation-based conditioning (500-600 cGy of thoracoabdominal/TBI) with CY dose modification (20-120 mg/kg), and ATG; two patients exhibited rejection. Seven patients (b-group) received CY (40 mg/kg), 150-180 mg/m(2) of Flu, and ATG. Durable engraftment was demonstrated in all patients. In FA patients, Flu-based conditioning may allow stable engraftment in matched sibling donor transplantation without radiation, even in patients with T-cell somatic mosaicism.

Precursor-T lymphoblastic lymphoma after unrelated bone marrow transplantation in a patient with Fanconi anemia.

Lymphoid malignancies are rare in patients with Fanconi anemia (FA), particularly after bone marrow transplantation. A boy, who was diagnosed with FA at the age of 5; underwent successful bone marrow transplantation at the age of 11. One year later, he presented with fever and dry cough, and was found to have an anterior mediastinal tumor. Biopsy of the tumor revealed precursor-T cell lymphoblastic lymphoma. Human leukocyte antigen analysis confirmed that the tumor cells were derived from the patient's own cells. He received mild chemotherapy for lymphoma, but his condition deteriorated rapidly and he died from excessive chemotherapy-related toxicity. The literature contains no reports of successful chemotherapy for lymphoid tumors in patients with FA, and therefore, alternatives to chemotherapy should be considered in the treatment of such patients.

Computed tomographic colonography with a reduced dose of laxative using a novel barium sulfate contrast agent in Japan.

PURPOSE: To test the tagging efficacy, patient acceptability, and accuracy of computed tomographic colonography (CTC) with a reduced dose of laxative using a novel barium sulfate (BaSO4) contrast agent. MATERIALS AND METHODS: CTC followed by optical colonoscopy (OC) was performed on 73 patients with positive results in fecal occult blood tests. They were administrated a BaSO4 suspension and a magnesium citrate solution for bowel preparation. Patients completed a questionnaire about the acceptability of bowel preparation. Tagging efficacy was estimated using a novel categorization system, which classified all segments into 8 categories. The accuracy of detecting protruded lesions ≥ 6 mm was calculated from the comparison of CTC and OC results, using the latter as a reference standard. RESULTS: Tagging efficacy was good in 77.3% of colonic segments where residue was observed. The acceptability of bowel preparation for CTC was significantly higher than that for OC. The sensitivity, specificity, and positive and negative predictive values were 0.778, 0.945, 0.824, and 0.929, respectively. All lesions ≥ 7 mm were successfully detected by CTC. CONCLUSION: CTC with a reduced dose of laxative using a novel BaSO4 contrast agent has a favorable tagging efficacy, patient acceptability, and accuracy.

Nodal status of malignant lymphoma in pelvic and retroperitoneal lymphatic pathways: comparison of integrated PET/CT with or without contrast enhancement.

AIM: To determine the diagnostic accuracy of integrated contrast-enhanced positron emission tomography (PET) and computed tomography (CT), as compared with non-contrasted PET/CT, in evaluating nodal status of malignant lymphoma in pelvic and retroperitoneal lymphatic pathways. MATERIALS AND METHODS: Sixty-six patients (33 men and 33 women) with malignant lymphoma underwent staging with integrated CT and fluorine-18-fluorodeoxyglucose ((18)FDG) PET. Tumor types were diffuse large B-cell lymphoma (n=26, 39%), follicular lymphoma (n=20, 30%), Hodgkin disease (n=16, 24%), and marginal zone B-cell lymphoma (n=4, 6%). Both non-contrasted PET/CT and contrast-enhanced PET/CT images were examined separately by two different qualified physicians for each imaging modality, and nodal status of pelvic and retroperitoneal lymphatic pathways was evaluated. Reference standard included follow-up with clinical, laboratory, and conventional CT findings. We compared diagnostic accuracy retrospectively on basis of per-patient and per-lesion analyses between two modalities using McNemar test, respectively. RESULTS: Nodal status of pelvic and retroperitoneal lymphatic pathways was more accurately determined on contrast-enhanced PET/CT (n=52, 79%) compared with non-contrasted PET/CT (n=47, 71%). Difference in the accuracy of nodal staging between non-contrasted PET/CT and contrast-enhanced PET/CT was significant (p=0.048). On basis of per-lesion analysis, contrast-enhanced PET/CT determined more accurately the status of external iliac lymph node (p=0.002), internal iliac lymph node (p<0.0001), and common iliac lymph node (p=0.002) compared with non-contrasted PET/CT. Diagnostic accuracies of paraaortic lymph node, aortocaval lymph node, and paracaval lymph node were similar by either non-contrasted PET/CT or contrast-enhanced PET/CT. CONCLUSION: Integrated contrast-enhanced PET/CT improves the diagnostic accuracy in evaluating nodal status of pelvic and retroperitoneal lymphatic pathways in patients with malignant lymphoma.

Computer-aided detection in computed tomography colonography: current status and problems with detection of early colorectal cancer.

PURPOSE: The aim of this study was to evaluate the usefulness of computer-aided detection (CAD) in diagnosing early colorectal cancer using computed tomography colonography (CTC). MATERIALS AND METHODS: A total of 30 CTC data sets for 30 early colorectal cancers in 30 patients were retrospectively reviewed by three radiologists. After primary evaluation, a second reading was performed using CAD findings. The readers evaluated each colorectal segment for the presence or absence of colorectal cancer using five confidence rating levels. To compare the assessment results, the sensitivity and specificity with and without CAD were calculated on the basis of the confidence rating, and differences in these variables were analyzed by receiver operating characteristic (ROC) analysis. RESULTS: The average sensitivities for the detection without and with CAD for the three readers were 81.6% and 75.6%, respectively. Among the three readers, only one reader improved sensitivity with CAD compared to that without. CAD decreased specificity in all three readers. CAD detected 100% of protruding lesions but only 69.2% of flat lesions. On ROC analysis, the diagnostic performance of all three readers was decreased by use of CAD. CONCLUSION: Currently available CAD with CTC does not improve diagnostic performance for detecting early colorectal cancer. An improved CAD algorithm is required for detecting flat lesions and reducing the false-positive rate.

Factors associated with pericolic fat stranding of colon cancer on computed tomography colonography.

BACKGROUND: Pericolic fat stranding on computed tomography (CT) scans has been an important feature for staging colon cancer. However, the factors associated with pericolic fat stranding have not been elucidated to date. PURPOSE: To determine factors associated with pericolic fat stranding of colon cancer on CT colonography (CTC). MATERIAL AND METHODS: Overall, 150 patients with 155 colon cancer lesions were retrospectively assessed by two radiologists for pericolic fat stranding on CTC. Circumferential proportion of the tumor (CPtumor; <50%, 50-75%, and ≥75%), longitudinal length, depth of invasion (≤T2, T3, T4), lymph node and distant metastasis, and lymphovascular invasion were recorded. Univariate and multivariate logistic regression analyses were performed between pericolic fat stranding and each factor. Multi-group comparisons were performed for the CPtumor and depth of invasion. RESULTS: Pericolic fat stranding was identified in 57 lesions (36.8%). Univariate analysis revealed significant associations of pericolic fat stranding with all factors (P < 0.027), except for lymph node metastasis (P = 0.087). Multi-group comparisons revealed that pericolic fat stranding was more frequent with increasing CPtumor (P < 0.001); however, no significant differences were observed beyond subserosal infiltration (P = 0.225). Logistic regression analysis revealed the CPtumor (<75% vs. ≥75%; P = 0.008, <50% vs. 50-75%; P = 0.047) and longitudinal length (P = 0.001) as explainable variables. CONCLUSION: Pericolic fat stranding identified on CT images of colon cancer is demonstrated more frequently with increasing circumferential proportion of the tumor and longitudinal length.

Three-dimensional computed tomographic angiography with computed tomographic colonography for laparoscopic colorectal surgery.

PURPOSE: To prospectively correlate the preoperative vessel anatomy in three-dimensional computed tomographic angiography with computed tomographic colonography (3D-CTA with CTC) with that in laparoscopic surgery for colorectal cancer. METHODS: The study protocol was approved by our institutional review board. The study population consisted of 101 patients with colon cancer who underwent 3D-CTA with CTC between June 2016 and January 2018. Two radiologists assessed the branching patterns of sigmoid arteries (SAs) and right colonic artery (RCA), the position between the ileocolic artery (ICA) and superior mesenteric vein (SMV), and the existence of an accessory middle colonic artery (aMCA). The vessel anatomy on 3D-CTA with CTC was correlated with that of intraoperative findings. RESULTS: Ninety-eight examinations (97.0%) were technically successful. Between preoperative and intraoperative vessel anatomy, the branching patterns of SAs were concordant in all 29 cases with rectosigmoid and descending colon cancer. The branching patterns of RCA and the position between the ICA and SMV were completely concordant in 32 cases of cecal and ascending colon cancer. No aMCA was identified either intraoperatively or by imaging analysis. CONCLUSIONS: 3D-CTA with CTC guided the surgeons to determine the resection margin of the relevant vessels for laparoscopic colorectal surgery.

Selective venous sampling supports localization of adenoma in primary hyperparathyroidism.

BACKGROUND: Selective venous sampling (SVS) is an invasive localization study for persistent or recurrent hyperparathyroidism. PURPOSE: To assess the role of SVS in addition to non-invasive imaging for primary hyperparathyroidism (pHPT). MATERIAL AND METHODS: This study was approved by the institutional review board and included 14 patients who underwent SVS and subsequent parathyroidectomy between January 2014 and April 2017 following a clinical diagnosis of pHPT. All patients underwent pre-SVS non-invasive imaging, including ultrasound, computed tomography (CT), and 99mTc-MIBI scintigraphy, and sensitivity was assessed using the operative and pathological findings. RESULTS: In all but one case, a single parathyroid adenoma was responsible for the pHPT; the remaining case exhibited a chemical response following surgical removal of parathyroid tissue. The sensitivity (%) for ultrasound, CT, 99mTc-MIBI scintigraphy, and SVS was 76.9, 84.6, 69.2, and 76.9, respectively. SVS yielded positive results in four patients with discordant results and one patient with non-detectable results on imaging. In seven patients, a significant increase in the intact parathyroid hormone level was recognized only in the thyroid veins. The procedure time was in the range of 52-183 min (median = 89.5 min). CONCLUSION: The addition of SVS to a non-invasive imaging study would be helpful to locate the responsible lesion of pHPT with discordant or non-detectable results on imaging for initial surgical treatment as well.