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.

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.

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.

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.

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.

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.

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.

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.

A comparison of the surgical mortality due to colorectal perforation at different hospitals with data from 10,090 cases in the Japanese National Clinical Database.

Colorectal perforation has a high rate of mortality. We compared the incidence and fatality rates of colorectal perforation among different hospitals in Japan using data from the nationwide surgical database.Patients were registered in the National Clinical Database (NCD) between January 1st, 2011 and December 31st, 2013. Patients with colorectal perforation were identified from surgery records by examining if acute diffuse peritonitis (ADP) and diseases associated with a high probability of colorectal perforation were noted. The primary outcome measures included the 30-day postsurgery mortality and surgical mortality of colorectal perforation. We analyzed differences in the observed-to-expected mortality (O/E) ratio between the two groups of hospitals, that is, specialized and non-specialized, using the logistic regression analysis forward selection method.There were 10,090 cases of disease-induced colorectal perforation during the study period. The annual average postoperative fatality rate was 11.36%. There were 3884 patients in the specialized hospital group and 6206 in the non-specialized hospital group. The O/E ratio (0.9106) was significantly lower in the specialized hospital group than in the non-specialized hospital group (1.0704). The experience level of hospitals in treating cases of colorectal perforation negatively correlated with the O/E ratio.We conducted the first study investigating differences among hospitals with respect to their fatality rate of colorectal perforation on the basis of data from a nationwide database. Our data suggest that patients with colorectal perforation should choose to be treated at a specialized hospital or a hospital that treats five or more cases of colorectal perforation per year. The results of this study indicate that specialized hospitals may provide higher quality medical care, which in turn proves that government policy on healthcare is effective at improving the medical system in Japan.

Pediatric case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma forming a solitary skin tumor on the forearm.

A 5-year-old girl noticed a rapidly growing reddish nodule on her right forearm. Although oral antibiotics had been administrated for 2 weeks, the tumor enlarged. Skin biopsy revealed excessive infiltration of atypical neoplastic cells expressing CD4, CD30 and anaplastic lymphoma kinase (ALK). These histological and immunohistochemical findings were consistent with anaplastic large cell lymphoma (ALCL). Computed tomography showed multiple lymphadenopathy, but lymph node biopsy and bone marrow examination did not show any evidence of systemic dissemination. However, due to the positive results for ALK and multiple lymphadenopathy, we diagnosed ALK-positive ALCL forming a solitary skin tumor on the forearm. The patient received chemotherapy and presented marked improvement. This paper discusses the difficulty of diagnosing pediatric ALK-positive ALCL limited to the skin and reviews the medical published work.

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.

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.

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.

Phase 1 study of clofarabine in pediatric patients with relapsed/refractory acute lymphoblastic leukemia in Japan.

A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.

The imaging features of protruding esophageal lesions.

Except for squamous cell carcinoma and adenocarcinoma, lesions that protrude into the esophagus are rare, and include benign and malignant tumors. The imaging findings of these lesions on esophagography, computed tomography (CT), and magnetic resonance imaging (MRI) are often non-specific. However, some of them reveal characteristic imaging findings. In addition, esophagography, CT, and MRI are useful to evaluate location, extent, invasion, vascularity, lymphadenopathy, and metastasis. Knowledge of the imaging features of protruding esophageal lesions helps to narrow the differential diagnosis. We describe the main features of esophageal protruding lesions.

Relationship between the use of an electronic commercial prescribing system and medical and medication errors in a teaching hospital.

OBJECTIVE: To investigate the effects of a commercial electronic prescribing system on medical and medication errors. METHODS: We conducted a retrospective before-and-after study in a teaching hospital by applying a U control chart to monthly error rates that were calculated from the number of both medical and medication errors divided by the number of patient days. RESULTS: The process mean medical error rate from April 2008 to December 2010 was 0.0213±0.0004 (mean±SD), and consecutive data points after September in 2010 were under the process mean from April 2008 to December 2010. The process mean value from January 2011 to March 2012 was 0.0177±0.0005. A significant difference was seen in the process mean medical error rate between consecutive months before December 2010 and values after January 2011 (p<0.001). From April 2008 to December 2010, the process mean medication error rate was 0.0060±0.0002, and from January 2011 to March 2012, the mean value was 0.0045±0.0002 (p<0.001). CONCLUSION: We showed that it requires time to reach a significant reduction in medical and medication error rates after implementation of an electronic prescribing system. It is important to check and support ways to adjust to procedures involved in using a new system.

Comparative performance of a primary-reader and second-reader paradigm of computer-aided detection for CT colonography in a low-prevalence screening population.

OBJECTIVE: To compare the efficacy of computer-aided detection (CAD) for computed tomographic colonography (CTC) when employed as either primary-reader or second-reader paradigms in a low-prevalence screening population. METHODS: Ninety screening patients underwent same-day CTC and colonoscopy. Four readers prospectively interpreted all CTC data sets using a second-reader paradigm (unassisted interpretation followed immediately by CAD assistance). Three months later, randomized anonymous data sets were re-interpreted by all readers using a primary-reader paradigm (only CAD prompts evaluated). RESULTS: Compared with the average per-patient sensitivity for unassisted interpretation (0.57), both CAD paradigms significantly increased sensitivity: 0.78 (p < 0.001) for the second-reader paradigm and 0.83 (p < 0.001) for the primary-reader paradigm. There was no significant difference between CAD paradigms (p = 0.25). The average per-patient specificity for polyps ≥6 mm was significantly higher using the primary-reader paradigm than the second-reader paradigm (0.90 vs. 0.83, respectively, p = 0.006), with ROC AUCs of 0.83 and 0.68, respectively. Reading time using CAD as a primary-reader paradigm (median 1.4 min) was significantly shorter than both unassisted (median 4.0 min, p < 0.001) and second-reader paradigms (median 5.5 min, p < 0.001). CONCLUSION: CAD improves radiologist sensitivity in screening patients when used as either a second- or primary-reader paradigm, although the latter may improve specificity and efficiency more.

Early diagnosis of asparaginase-associated pancreatitis based on elevated serum elastase-1 levels: Case reports.

L-asparaginase (L-asp) is a well-known anticancer agent used in the treatment of acute lymphoblastic leukemia (ALL) in children. However, it is also known to induce several acute complications, such as acute pancreatitis. This is a presentation of two pediatric acute lymphoblastic leukemia (ALL) cases of asparaginase-associated pancreatitis (AAP) diagnosed at an early stage based on elevated serum elastase-1 levels, in the presence of normal serum amylase levels. Early diagnosis and treatment of AAP, although imperative, is occasionally difficult if only standard diagnostic procedures are followed. Elastase-1 is a potentially useful marker for the early diagnosis of AAP. Therefore, the measurement of elastase-1 levels, in addition to amylase and lipase levels, is recommended in L-asp-treated patients.

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.

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.