Effects of tumor spillage prevention in laparoscopic radical hysterectomy for early-stage cervical cancer: a propensity score-matched analysis.

OBJECTIVE: Minimally invasive radical hysterectomy has a worse prognosis than open surgery, but the reasons for the poor prognosis remain unclear. Tumor spillage occurs when the tumor is exposed to the surgical field and has been suggested to be related to a poor prognosis. This study aimed to compare the prognostic value of tumor spillage in laparoscopic radical hysterectomy and evaluate whether tumor spillage prevention improves oncological safety. METHODS: We compared the prognosis of patients who underwent laparoscopic radical hysterectomy between December 2014 and November 2021 with or without tumor spillage prevention, including surgeries without prevention and those with failed prevention. Prevention consisted of vaginal cuff formation or closure of the vaginal canal with clips to prevent tumor exposure at the time of colpotomy. The primary endpoint was disease-free survival, which was adjusted using propensity scores to compare patients. RESULTS: In total, 165 patients received tumor spillage prevention, and 61 did not or failed to receive such prevention. The median follow-up was 4.4 years. Patients who did not undergo prevention or failed prevention had significantly shorter disease-free survival than those who did (hazard ratio [HR]=3.54; 95% confidence interval [CI]=1.23-10.23). The same trend was observed after adjusting for propensity score matching. Patients who did not or failed to receive prevention were more likely to experience local recurrence (HR=4.01; 95% CI=1.13-14.24). CONCLUSION: Tumor spillage prevention was associated with longer disease-free survival in laparoscopic radical hysterectomy.

Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis.

AIM: Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS: We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS: Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS: The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.

Clinical implications of the superficial uterine vein pattern for the dissection of the anterior layer of the vesicouterine ligament in radical hysterectomy.

OBJECTIVE: To describe anatomic patterns of the superficial uterine vein (sUV) and assess their association with aspects of the dissection procedure of the anterior layer of the vesicouterine ligament (aVUL) by retrospectively reviewing surgical videos. METHODS: We analyzed patients who underwent laparoscopic radical hysterectomy for early-stage cervical cancer from 2014 to 2019. The primary endpoint was the time required for aVUL dissection. Multiple linear regression analyses were performed to identify factors influencing the time required for aVUL dissection. RESULTS: Fifty-three Japanese patients were included. Two sUV configurations were observed: type 1 (the vein ran ventral to the ureter along the uterine artery) and type 2 (the vein did not run along the usual ventral course; it ran dorsal to the ureter or was absent). Approximately 30% of the sUVs were type 2. The total time for dissection of both sides of the aVUL was significantly shorter for type 2 sUVs than for type 1 sUVs. The number of hemostatic interventions during dissection of each side of the aVUL was significantly lower for type 2 sUVs than for type 1 sUVs. In the multivariate analysis, the sUV configuration was the factor significantly influencing the duration of aVUL dissection on each side (right side: ß=-143.4; left side, ß=-160.4). CONCLUSION: We demonstrated that the sUV had 2 types of courses, ventral and others, and its course affected the time required for dissection and the number of hemostatic interventions. Our results provide information supportive of improved radical hysterectomy outcomes.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Fatal visceral varicella-zoster developing early after autologous hematopoietic stem cell transplantation for refractory diffuse large B-cell lymphoma.

A middle-aged woman who had undergone autologous hematopoietic stem cell transplantation (HSCT) 1 month previously suffered severe epigastralgia and relapse of lymphoma. The epigastralgia was not relieved by chemotherapy. Thereafter, her pancreatic and hepatic enzyme levels were markedly elevated and disseminated varicella emerged. Despite acyclovir administration, her general condition deteriorated rapidly and she died. Serum varicella zoster virus (VZV) DNA level was shown to be elevated and a diagnosis of disseminated VZV infection was established postmortem. In patients with severe abdominal pain following HSCT, early suspicion and therapeutic intervention for VZV are important, even in the absence of skin lesions.

GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells.

The bone marrow microenvironment comprises multiple cell niches derived from bone marrow mesenchymal stem cells. However, the molecular mechanism of bone marrow mesenchymal stem cell differentiation is poorly understood. The transcription factor GATA2 is indispensable for hematopoietic stem cell function as well as other hematopoietic lineages, suggesting that it may maintain bone marrow mesenchymal stem cells in an immature state and also contribute to their differentiation. To explore this possibility, we established bone marrow mesenchymal stem cells from GATA2 conditional knockout mice. Differentiation of GATA2-deficient bone marrow mesenchymal stem cells into adipocytes induced accelerated oil-drop formation. Further, GATA2 loss- and gain-of-function analyses based on human bone marrow mesenchymal stem cells confirmed that decreased and increased GATA2 expression accelerated and suppressed bone marrow mesenchymal stem cell differentiation to adipocytes, respectively. Microarray analysis of GATA2 knockdowned human bone marrow mesenchymal stem cells revealed that 90 and 189 genes were upregulated or downregulated by a factor of 2, respectively. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell cycle regulation, and the number of G1/G0 cells increased after GATA2 knockdown. Concomitantly, cell proliferation was decreased by GATA2 knockdown. When GATA2 knockdowned bone marrow mesenchymal stem cells as well as adipocytes were cocultured with CD34-positive cells, hematopoietic stem cell frequency and colony formation decreased. We confirmed the existence of pathological signals that decrease and increase hematopoietic cell and adipocyte numbers, respectively, characteristic of aplastic anemia, and that suppress GATA2 expression in hematopoietic stem cells and bone marrow mesenchymal stem cells.

Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia.

Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, there is considerable clinical heterogeneity among patients, and the molecular basis for the evolution of immunodeficiency into MDS/AML remains unknown. Thus, we conducted whole-genome sequencing on a patient with a germline GATA-2 heterozygous mutation (c. 988 C > T; p. R330X), who had a history suggestive of immunodeficiency and evolved into MDS/AML. Analysis was conducted with DNA samples from leukocytes for immunodeficiency, bone marrow mononuclear cells for MDS and bone marrow-derived mesenchymal stem cells. Whereas we did not identify a candidate genomic deletion that may contribute to the evolution into MDS, a total of 280 MDS-specific nonsynonymous single nucleotide variants were identified. By narrowing down with the single nucleotide polymorphism database, the functional missense database, and NCBI information, we finally identified three candidate mutations for EZH2, HECW2 and GATA-1, which may contribute to the evolution of the disease.

Induction of thymic stromal lymphopoietin in mesenchymal stem cells by interaction with myeloma cells.

Recently, the bone marrow (BM) microenvironment has been reported to support the survival of multiple myeloma (MM) cells. In this study, we examined changes in gene expression profile in human mesenchymal stem cells (MSCs) by co-culture with MM cells. cDNA array analysis indicated that co-culture induced multiple factors which have positive effects on the survival of MM cells, such as interleukin-6 (IL-6) and insulin-like growth factor-1. Other than these factors, thymic stromal lymphopoietin (TSLP), which is a cytokine involved in the progression of pancreatic and breast cancer through induction of T helper 2 cell responses, was up-regulated in MSCs. TSLP exhibited no effect on proliferation or drug resistance of MM cells, but TSLP secreted from MSCs by co-culture expanded IL-13+ CD4+ T cells through stimulation of dendritic cells. These results suggested that MM cells positively act to induce various molecules in MSCs, leading to the formation of a more advantageous BM microenvironment for their survival.

Gene expression profiling identifies HOXB4 as a direct downstream target of GATA-2 in human CD34+ hematopoietic cells.

Aplastic anemia is characterized by a reduced hematopoietic stem cell number. Although GATA-2 expression was reported to be decreased in CD34-positive cells in aplastic anemia, many questions remain regarding the intrinsic characteristics of hematopoietic stem cells in this disease. In this study, we identified HOXB4 as a downstream target of GATA-2 based on expression profiling with human cord blood-derived CD34-positive cells infected with control or GATA-2 lentiviral shRNA. To confirm the functional link between GATA-2 and HOXB4, we conducted GATA-2 gain-of-function and loss-of-function experiments, and HOXB4 promoter analysis, including luciferase assay, in vitro DNA binding analysis and quantitative ChIP analysis, using K562 and CD34-positive cells. The analyses suggested that GATA-2 directly regulates HOXB4 expression through the GATA sequence in the promoter region. Furthermore, we assessed GATA-2 and HOXB4 expression in CD34-positive cells from patients with aplastic anemia (n = 10) and idiopathic thrombocytopenic purpura (n = 13), and demonstrated that the expression levels of HOXB4 and GATA-2 were correlated in these populations (r = 0.6573, p<0.01). Our results suggested that GATA-2 directly regulates HOXB4 expression in hematopoietic stem cells, which may play an important role in the development and/or progression of aplastic anemia.