Ultrasonography is an effective tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

BACKGROUND: Individuals with severe motor and intellectual disabilities have become an aging population, and high cancer morbidity and mortality are critical issues affecting their survival. Cancer screening is a crucial method of resolving this issue; however, a suitable screening method for them has not been established. METHODS: We used ultrasonography alone and performed breast cancer screening for women over 30 years old in our facility from 2016 to 2023. We observed the outcomes and calculated the recall/detection rate in this screening. RESULTS: Three cases among 379 tested positive in this screening, all of which underwent radical surgery. They are alive and well without relapse present. We detected these breast cancer cases with a low recall rate. CONCLUSION: We were able to successfully detect breast cancer cases using ultrasonography alone. Ultrasonography is an effective and feasible tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

Functional expression cloning of molecules inducing CD34 expression in bone marrow-derived stromal myofibroblasts.

We have previously shown a fraction of stromal fibroblasts/myofibroblasts (Fibs) from leukemic bone marrow cells expresses leukemia-specific transcripts along with hematopoietic and Fib-related markers. Normal bone marrow-derived Fibs (nFibs) do not express CD34 or CD45; however, nFibs may express hematopoietic markers with some specific stimulations. CD34 expression was detected in nFib cultures following the addition of a culture supernatant of blood mononuclear cells stimulated with phytohemagglutinin (PHA)-P. To identify the molecules responsible for inducing CD34 expression in nFibs, cDNA clones were isolated using functional expression cloning with a library constructed from PHA-P-stimulated human blood mononuclear cells. Positive clones inducing CD34 transcription in nFibs were selected. We confirmed that an isolated positive cDNA clone encoded human interleukin (IL)-1 beta (ß). CD34 expression was observed in the nFib cultures with recombinant human (rh) IL-1ß protein. And CD34 transcription was suppressed when a rhIL-1ß neutralizing antibody was added to the IL-1ß-stimulated nFib cultures. nFibs expressed gp130 and IL-6 receptors, and CD45 expression was detected in nFibs cultured with rhIL-1ß and rhIL-6. Chronic myelogenous leukemia (CML) cells reportedly respond well to IL-1ß. When CML-derived Fibs were cultured with rhIL-1ß and rhIL-6, CD45-positive cells increased in number. Cell fate may be influenced by an external specific stimulation without gene introduction.

Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation.

RUNX1 is essential for definitive hematopoiesis and T-cell differentiation. It has been shown that RUNX1 is phosphorylated at specific serine and threonine residues by several kinase families. However, it remains unclear whether RUNX1 phosphorylation is absolutely required for its biological functions. Here, we evaluated hematopoietic activities of RUNX1 mutants with serine (S)/threonine (T) to alanine (A), aspartic acid (D), or glutamic acid (E) mutations at phosphorylation sites using primary culture systems. Consistent with the results of knockin mice, RUNX1-2A, carrying two phospho-deficient mutations at S276 and S293, retained hematopoietic activity. RUNX1-4A, carrying four mutations at S276, S293, T300, and S303, showed impaired T-cell differentiation activity, but retained the ability to rescue the defective early hematopoiesis of Runx1-deficient cells. Notably, RUNX1-5A, carrying five mutations at S276, S293, T300, S303, and S462, completely lost its hematopoietic activity. In contrast, the phospho-mimic proteins RUNX1-4D/E and RUNX1-5D/E exhibited normal function. Our study identifies multiple phosphorylation sites that are indispensable for RUNX1 activity in hematopoiesis.

The FLT3 internal tandem duplication mutation at disease diagnosis is a negative prognostic factor in myelodysplastic syndrome patients.

The role of the FMS-like tyrosine kinase 3 (FLT3) gene in acute myeloid leukemia (AML) has been well documented and the FLT3-internal tandem duplication (FLT3-ITD) mutation has been identified as a prognostic factor in AML. Due to its low incidence, the role of the FLT3 mutation remains unclear in myelodysplastic syndrome (MDS) patients. To investigate the impact of the FLT3-ITD status on the prognosis of MDS at diagnosis, we retrospectively analyzed 72 MDS patients admitted to Teikyo University Hospital. FLT3-ITD was examined by a reverse transcription-polymerase chain reaction using complementary DNA synthesized from mRNA extracted from bone marrow mononuclear cells at the diagnosis of MDS. Fifteen patients (20.8 %) were positive for FLT3-ITD and had significantly worse overall survival (OS) and progression-free survival (PFS) than patients who were negative (P < 0.001 and P < 0.001, respectively) in a multivariate analysis. We also investigated whether the Wilms' tumor gene-1 (WT-1) copy number was associated with the FLT3-ITD mutational status using data available on WT-1 from 57 patients. A WT-1 transcript copy number ≥50/µg total mRNA in peripheral blood was detected in 35 patients (61.4 %). All FLT3-ITD-positive patients showed WT-1 ≥50. The FLT3-ITD-positive group showed significantly higher WT-1 transcription levels than the negative group. These results indicate that the FLT3-ITD mutation has a prognostic impact at the diagnosis of MDS and is associated with a high level of WT-1.

Serum high-density lipoprotein cholesterol level has a significant prognostic impact on outcomes of follicular lymphoma patients.

We investigated the potential of nutritional and inflammatory parameters as prognostic factors for follicular lymphoma (FL), and also examined the predictive value of the early progression of disease within 24 months of first-line chemo-immunotherapy (POD24). We retrospectively analyzed 46 patients with FL admitted to Teikyo University Hospital and treated with chemo-immunotherapy between May 2009 and July 2019. Physical characteristics, blood parameters, and markers or scores for consumptive/inflammatory and nutritional conditions were used as variables. Nine parameters correlated with poor overall survival (OS) in univariate analysis: An Eastern Cooperative Oncology Group (ECOG) scale performance status (PS) ≥2, five or more involved nodal sites, positive bone marrow (BM) involvement, a serum albumin level <3.5 g/dL, CRP >0.5 mg/dL, lactate dehydrogenase (LD) higher than the upper normal limit (UNL), high-density lipoprotein cholesterol (HDL-C) <40 mg/dL, modified Glasgow prognostic score of 1-2, and the geriatric nutritional risk index <82. In multivariate analysis, ECOG PS ≥2, positive BM involvement, and a serum HDL-C level <40 mg/dL remained significant for poor progression-free survival. One-year OS rate after receiving salvage chemotherapy was lower in the POD24 group (50%) and POD24 correlated with ECOG PS ≥2, positive BM involvement, a serum lactate dehydrogenase >UNL, and HDL-C <40 mg/dL by Fisher's exact test. These results indicate that low serum HDL-C levels appear to be important for predicting the risk of POD24 and the worse prognosis of FL.

Budd-Chiari Syndrome during Long-term Follow-up after Allogeneic Umbilical Cord Blood Transplantation.

A series of abdominal computed tomography scans of an asymptomatic 40-year-old woman with a history of umbilical cord blood transplantation (CBT) for leukemia at 19 years old revealed the long-term gradual development of a right hepatic vein thrombus and stenosis of the inferior vena cava, leading to a diagnosis of Budd-Chiari syndrome. The Budd-Chiari syndrome in this case might have been influenced by the patient's history of multiple liver abscesses after CBT and associated thrombus formation, in addition to the hormone replacement therapy with estradiol and dydrogesterone she was taking. This case provides insight into the development of Budd-Chiari syndrome.

Feasibility of reduced-intensity cord blood transplantation as salvage therapy for graft failure: results of a nationwide survey of adult patients.

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

[Acute myelogenous leukemia developed at the 26th week of gestation].

We report here a 35-year-old pregnant woman with acute myelogenous leukemia (AML). She was diagnosed with AML (M2) in August 2009, coinciding with the 26(th) week of pregnancy. She underwent a cesarean section at 27 weeks gestation, delivering a very low birth weight male infant (1,066 g). One week later, she received induction chemotherapy with idarubicin and cytarabine. She achieved complete remission after two courses of chemotherapy. The incidence of acute leukemia during pregnancy is low. Chemotherapy after the 2(nd) trimester is not associated with an increased rate of fetal malformation. However, there are some reports that in utero exposure to chemotherapy during any trimester of pregnancy carries a significant risk for an unfavorable outcome including low birth weight, fetal or neonatal death, and intrauterine growth retardation. Decision on the choice of treatment for acute leukemia during pregnancy should be case-dependent. If an infant has grown sufficiently to be viable outside uterus and the patient does not demonstrate a severe bleeding tendency, delivery by cesarean section preceding chemotherapy is one option.

Second allogeneic transplantation using umbilical cord blood for a patient with relapsed ALK+ anaplastic large cell lymphoma after allogeneic bone marrow transplantation in the era of ALK inhibitors: A case report.

RATIONALE: Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet. PATIENT CONCERNS: An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT). DIAGNOSIS: However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy. INTERVENTION: Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR. OUTCOMES: The patient has been in CR under maintenance therapy of alectinib for more than 16 months. LESSONS: Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.

Acute myelogenous leukemia cells with the MLL-ELL translocation convert morphologically and functionally into adherent myofibroblasts.

Bone marrow-myofibroblasts, a major component of bone marrow-stroma, are reported to originate from hematopoietic stem cells. We show in this paper that non-adherent leukemia blasts can change into myofibroblasts. When myeloblasts from two cases of acute myelogenous leukemia with a fusion product comprising mixed lineage leukemia and RNA polymerase II elongation factor, were cultured long term, their morphology changed to that of myofibroblasts with similar molecular characteristics to the parental myeloblasts. The original leukemia blasts, when cultured on the leukemia blast-derived myofibroblasts, grew extensively. Leukemia blasts can create their own microenvironment for proliferation.

Gemtuzumab ozogamicin monotherapy prior to stem cell infusion induces sustained remission in a relapsed acute myeloid leukemia patient after allogeneic stem cell transplantation: A case report.

RATIONALE: Patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have poor prognosis. Many patients are not eligible for 2nd HSCT due to organ dysfunction or other complications that prevent them from tolerating conditioning chemotherapy. In those ineligible patients for 2nd HSCT with myeloablative conditioning regimen, reduced intensity conditioning (RIC) are often used. RIC regimens are less toxic but has a less direct anti-tumor efficacy so that RIC regimens are not suitable for the patients with high tumor burden. To overcome this dilemma, Gemtuzumab Ozogamicin (GO) has been used as a part of RIC regimens to add anti-tumor efficacy. We report here a relapsed AML patient who was treated with GO monotherapy followed by stem cell infusion. PATIENT CONCERNS: A 25-year-old male with AML experienced relapse 9 months after allo-HSCT. DIAGNOSIS: Since he had mild renal and cardiac dysfunction and his AML did not progress rapidly, we decided not to give him an intensive chemotherapy. However, after azacitidine (AZA) and donor lymphocyte infusion therapy, his leukemic blasts did not decrease. INTERVENTIONS: Originally, we had planned to proceed with a 2nd allo-HSCT with RIC regimen that consisted of fludarabine, melphalan and fractionated GO (3 mg/m/dose) on day -21, -18, and -15. However, the patient developed appendicitis after the last dose of GO when his neutrophil was 0 cells/µl. Based on his medical acuity, we terminated the rest of the patients conditioning regimen and the patient did not receive any further chemotherapeutics. The patient was still infused with peripheral blood stem cells from the donor on day 0. OUTCOMES: His appendicitis was resolved by antibiotics without surgery. His AML has been in CR more than 18 months under AZA maintenance therapy. LESSONS: GO monotherapy could be a conditioning regimen of 2nd allo HSCT from the same donor as the first HSCT for relapsed AML patients.

Direct Factor X sequestration by systemic amyloid light-chain amyloidosis.

We present a lymphoplasmacytic lymphoma patient with Factor X (FX) deficiency. Despite the absence of FX inhibitor, the administration of fresh frozen plasma and anti-inhibitor coagulant complex did not increase the FX level. The autopsy showed that massive amyloid depositions to multiple organs and FX existed in union with amyloidosis.

Molecular analysis of chronic eosinophilic leukemia with t(4;10) showing good response to imatinib mesylate.

A 38-year-old Japanese man was referred to our hospital in June 2003 for treatment of acute respiratory failure with severe eosinophilia. Idiopathic hypereosinophilic syndrome had been diagnosed in 1994. However, karyotypic examination of bone marrow cells revealed that chromosomal translocation with t(4;10)(q12;p11) had occurred in 2000, and chronic eosinophilic leukemia was diagnosed. At admission, the patient's respiratory condition was extremely serious, and mechanical support was necessary. Despite treatment with steroid pulse therapy and cytarabine, the blood eosinophil count did not decrease, and the patient's respiratory condition worsened. After obtaining informed consent, we administered imatinib mesylate at a dose of 200 mg/day for 2 days and 100 mg/day for 3 days. The blood eosinophil count decreased dramatically over 5 days, and the patient's condition rapidly improved, such that the patient could be discharged. In this case, we performed molecular analysis using peripheral blood. The FIP1-like 1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRalpha) fusion transcript was found with the reverse transcriptase polymerase chain reaction analysis. In this case, eosinophilia was possibly caused by constitutive activation of tyrosine kinase produced by the FIP1L1-PDGFRalpha fusion transcript.

SHPS-1: a budding molecule against cancer dissemination.

The expression of SHPS-1 is down-regulated by several oncogene products such as v-Src in fibroblasts. In addition, the down-regulation of SHPS-1 is also found inhuman breast cancer tissues compared with the matched normal tissues. On the other hand, forced expression of SHPS-1 suppresses anchorage-independent cell growth of v-Src-transformed cells in vitro as well as peritoneal dissemination of the cells in nude mice. Surprisingly, the extracellular region (EC) of SHPS-1 seems to take part on the inhibitory effect. Because the EC domain interacts with fibronectin and DTT abrogates the inhibitory effects of the EC, we speculate that super-fibronectin may function with the EC as a suppressor of cancer cells. Here we show that SHPS-1 expression provides a unique potential that links suppression of anchorage-independent cell growth and cancer dissemination.

Acute myelogenous leukemia M5b developed during clinical remission of Castleman disease.

Castleman disease (CD) is a rare heterogeneous lymphoproliferative disease characterized by clinical symptoms due to an excess of interleukin-6 (IL-6) or IL-6-like activity. We describe the first case of CD associated with acute myelogenous leukemia (AML). A 55-year-old man presented with skin rash on his face and multiple cervical lymphadenopathy. The results of examination of his lymph node biopsy specimen led to a diagnosis of CD. The symptoms resolved after the administration of prednisolone. Three years after the onset of CD, the patient's white blood cell count had increased to 63.4 x 10(9)/L. His bone marrow aspirate showed that approximately 80% of cells were leukemic, including well-differentiated monocytic cells A diagnosis of AML M5b was made. The patient died of invasive pulmonary aspergillosis after chemotherapy.