GVHD targets organoid-forming bile duct stem cells via a TGF-ß-dependent manner.

Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF--dependent manner. Administration of SB-431542, an inhibitor of TGF-ß signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.

Clinical implications of NUP98::NSD1 fusion at diagnosis in adult FLT3-ITD positive AML.

OBJECTIVES: The cryptic fusion oncogene NUP98::NSD1 is known to be associated with FLT3-ITD mutation in acute myeloid leukemia (AML), and an independent poor prognostic factor in pediatric AML. However, there are little data regarding the clinical significance of NUP98::NSD1 in adult cohort. METHODS: We conducted a multicenter retrospective study to investigate the prevalence, clinical characteristics, and prognostic impact of NUP98::NSD1 in adult FLT3-ITD-positive AML patients. RESULTS: In a total of 97 FLT3-ITD-positive AML patients, six cases (6.2%) were found to harbor the NUP98::NSD1 fusion transcript. NUP98::NSD1 positive cases had significantly higher platelet counts and a higher frequency of FAB-M4 morphology than NUP98::NSD1 negative cases. NUP98::NSD1 was found to be mutually exclusive with NPM1 mutation, and was accompanied by the WT1 mutation in three of the six cases. The presence of NUP98::NSD1 fusion at the time of diagnosis predicted poor response to cytarabine-anthracycline-based intensive induction chemotherapy (induction failure rate: 83% vs. 36%, p = .038). Five of the six cases with NUP98::NSD1 underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two of the five cases have successfully maintained remission, with one of them being rescued through a second HSCT. CONCLUSIONS: Detecting NUP98::NSD1 in adult FLT3-ITD-positive AML is crucial to recognizing chemotherapy-resistant group.

Thiotepa-based high-dose chemotherapy with autologous stem cell transplantation for neurolymphomatosis.

Neurolymphomatosis (NL) is a rare clinical entity characterized by lymphomatous infiltration of the peripheral nervous system. According to recent retrospective data, consolidative high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may be beneficial for NL. However, few reports to date have discussed optimal conditioning regimens. Herein, we report two cases of NL in patients with relapsed intravascular large B-cell lymphoma who received consolidative thiotepa-containing HDC-ASCT. Case 1: A 56-year-old woman who relapsed 2 months after the first complete remission (CR) and underwent ASCT. Case 2: A 65-year-old woman who relapsed 8 months after the first CR and underwent ASCT. Both patients engrafted. Time to neutrophil engraftment was 10 and 12 days after HDC-ASCT, and CR was sustained for 26 and 18 months, respectively, as of the last follow-up. Although there is little evidence supporting the utility of thiotepa-based HDC-ASCT in patients with NL, the results of this case report suggest that further studies are warranted to determine its efficacy in this setting.

[Bing-Neel syndrome successfully treated with tirabrutinib].

Bing-Neel syndrome (BNS) is a rare disease manifestation of Waldenström's macroglobulinemia characterized by abnormal lymphoplasmacytoid cells infiltration of the central nervous system. In September 2019, a 46-year-old man presented to a previous hospital with hand tremors, nausea, and dysuria. Demyelination of cerebral white matter and the spinal cord was discovered using MRI. Steroid pulse therapy was used to treat inflammatory demyelinating disease, and it provided temporary relief, but the symptoms returned when the steroids were stopped. He was referred to our hospital in June 2020, for further evaluation with the possibility of hematological malignancy. BNS was diagnosed based on the presence of abnormal lymphoplasmacytoid cells in the bone marrow and cerebrospinal fluid (CSF), as well as the presence of the MYD88L265P mutation in the CSF specimen. In July 2020, BR (bendamustine, rituximab) therapy was administered, but it was ineffective. Oral administration of tirabrutinib, which was recently approved for WM, began in August 2020. He has achieved long-term remission and steroid withdrawal, with no notable side effects. This is the second report of successful treatment of BNS with tirabrutinib. More research is needed to confirm tirabrutinib's efficacy in the treatment of BNS.

[Successful treatment with gilteritinib for relapsed acute myeloid leukemia with FLT3-N676K mutation].

The patient was a 68-year-old woman, diagnosed with acute myelomonocytic leukemia with normal karyotype and FLT3-ITD-negative status in May 2019. She had achieved complete remission (CR) after "7+3" intensive induction chemotherapy and maintained CR by consolidation chemotherapy. However, she relapsed with swelling of the lips and gums in January 2020. She did not achieve CR by salvage chemotherapy with cytarabine-aclarubicin-G-CSF regimen. Comprehensive genomic analysis of leukemic cells revealed the presence of FLT3-N676K mutation, which was undetectable by companion diagnostics at the time. Complete remission with incomplete count recovery was obtained on day 28 after initiation of gilteritinib monotherapy, and the lip and gum swelling improved rapidly. However, she relapsed on day 106 after gilteritinib administration, and gilteritinib was discontinued. Genomic analysis at recurrence revealed NRAS mutation for the first time. Finally, the patient died of the uncontrolled primary disease. This is a case in which comprehensive gene mutation analysis was useful in determining a treatment strategy.

Non-age-related neoplastic loss of sex chromosome correlated with prolonged survival in real-world CBF-AML patients.

In this real-world clinical study, in which we determined eligibility for allogenic hematopoietic stem cell transplantation by prognostic factors and minimal residual disease status, we retrospectively evaluated cytogenetic, genetic, and clinical features in 96 patients with core-binding factor acute myeloid leukemia (CBF-AML) including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFß/MYH11. Multivariate analyses for 5-year overall survival (OS) in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI 1.47-8.11, P = 0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI 1.57-8.05, P = 0.002) were independently associated with worse OS and that loss of sex chromosome (LOS) was independently associated with better OS (HR: 0.09, 95% CI 0.01-0.71, P = 0.022). At the time of complete remission, all 21 karyotyped patients with LOS had a normal karyotype. Furthermore, in all 9 patients with LOS who had a mosaic of metaphase cells with and without t(8;21) or inv(16), the metaphase cells without t(8;21)/inv(16) showed a normal karyotype. These results proved that LOS was not age-related and physiological, but rather a neoplastic chromosomal abnormality.

Phlegmonous gastritis developed during chemotherapy for acute lymphocytic leukemia: A case report.

BACKGROUND: Phlegmonous gastritis (PG) is a rare bacterial infectious disease characterized by neutrophil-based purulent inflammation of the gastric wall. The most representative causative bacterium is Streptococcus pyogenes, followed by Staphylococcus, Pneumococcus and Enterococcus. Hepatic portal venous gas (HPVG) is considered a potentially fatal condition and is rarely associated with PG. CASE SUMMARY: The white blood cell count of a 70-year-old woman with acute lymphocytic leukemia in complete remission dropped to 100/µL after consolidation chemotherapy. Her vital signs were consistent with septic shock. Venous blood culture revealed the presence of Bacillus cereus. Abdominal computed tomography (CT) and esophagogastroduodenoscopy (EGD) showed marked thickening of the gastric wall. As with the other findings, CT was suggestive of HPVG, and EGD showed pseudomembrane-like tissue covering the superficial mucosa. Histopathological examination of gastric biopsy specimens showed mostly necrotic tissue with lymphocytes rather than neutrophils. Culture of gastric specimens revealed the presence of Bacillus cereus. We finally diagnosed this case as PG with Bacillus cereus-induced sepsis and HPVG. This patient recovered successfully with conservative treatment, chiefly by using carbapenem antibiotics. CONCLUSION: The histopathological finding of this gastric biopsy specimen should be called "neutropenic necrotizing gastritis".

[Therapy-Related Acute Myeloid Leukemia with 11q23 Abnormality That Developed after Chemotherapy for Colorectal Cancer].

The patient developed Stage Ⅳ transverse colon cancer at the age of 72 years and was treated with an 8-course XELOX regimen(capecitabine and oxaliplatin)every 3 weeks after resection. Six years and 9 months after the end of treatment, at the age of 79 years, WBC levels were found to have markedly increased to 10×104/µL in the patient, and acute leukemia was suspected; subsequently, the patient was hospitalized. Bone marrow was aspirated and analyzed, and the results showed that 95% of leukemic cells were positive for esterase staining. Chromosomal examination revealed t(6 ; 11)(q27 ; q23), ie, the diagnosis of therapy-related acute myeloid leukemia(t-AML)with 11q23 abnormality. CR was achieved by chemotherapy, but the disease soon recurred; the patient died 7 months after the onset of t-AML, with the cause being t- AML with 11q23 abnormality that developed 6 years and 9 months after treatment for colorectal cancer with oxaliplatin and capecitabine without undergoing MDS. Since there is a possibility of leukemia induction following oxaliplatin treatment, more such cases need to be monitored in the future.

Early prediction model of organ/space surgical site infection after elective gastrointestinal or hepatopancreatobiliary cancer surgery.

BACKGROUND: Organ/space SSI is a significant clinical problem. However, early detection of organ/space SSI is difficult, and previous predictive models are limited in their prognostic ability. We aimed to develop and validate a prediction model of organ/space surgical site infection (SSI) using postoperative day 3 laboratory data in patients who underwent gastrointestinal or hepatopancreatobiliary cancer resection. METHODS: This retrospective cohort study using a single-center hospital data from April 2013 to September 2017 included all adult patients who underwent elective gastrointestinal or hepatopancreatobiliary cancer resection. The primary outcome was a presence of organ/space SSI including anastomotic leakage, pancreatic fistula, biliary fistula, or intra-abdominal abscess. We developed and validated a logistic regression model to predict organ/space SSI using laboratory data on postoperative day (POD) 3. Similar models using laboratory data on POD 1 or 5 were developed to compare the predictive ability of each model. RESULTS: A total of 1578 patients were included. Organ/space SSI was diagnosed in 107 patients, with median diagnosis days of 6 (interquartile range, 4-9 days) after surgery. A prediction model using five commonly measured variables on POD 3 was created with the area under the curve (AUC) of 0.883 (95%CI 0.819-0.946). The AUC of a model with POD 1 laboratory data was 0.751 (95%CI 0.655-0.848), while that of POD 5 laboratory data was 0.818 (95%CI 0.730-0.906). CONCLUSIONS: Laboratory data on POD 3 could forecast organ/space SSI precisely. Further prospective studies are warranted to investigate the clinical impact of this model.