Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome.

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Clinical characteristics and outcomes of Epstein-Barr virus viral load after allogeneic hematopoietic stem cell transplantation.

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II-IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival ("not reached" vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.

Pulmonary tumor thrombotic microangiopathy during good response to immuno-chemotherapy for advanced non-small cell lung cancer: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a rapidly progressive and fatal disease in which tumor cells embolize to the pulmonary microvasculature. This condition is characterized by severe dyspnea and right heart failure. Although pulmonary tumor thrombotic microangiopathy typically occurs in patients with untreated and/or advanced cancer, its occurrence in patients who are responding well to medical therapy is poorly documented. CASE PRESENTATION: A 68-year-old Japanese woman who had received four cycles of immuno-chemotherapy (pembrolizumab, carboplatin, and pemetrexed) followed by three cycles of maintenance therapy (pembrolizumab and pemetrexed) for advanced non-small cell lung cancer and had achieved a partial response with a stable clinical course was admitted to the emergency ward because of worsening breathlessness and general fatigue for 1 week. Chest computed tomography showed no evidence of tumor progression or any new lung lesion. Two-dimensional transthoracic echocardiography demonstrated right atrial and ventricular dilatation, tricuspid regurgitation, and a high trans-tricuspid pressure gradient of 65 mmHg. Despite her percutaneous oxygen saturation being 96% on room air at the time of admission, it worsened rapidly; the patient requiring 8 L/min of oxygen within 4 h. Repeat computed tomography with contrast medium revealed no evidence of pulmonary embolism. The patient developed progressive respiratory failure that was unresponsive to optimal cardio-pulmonary supportive therapy. An autopsy revealed tumorous clusters in pre-capillary lung vessels, whereas the primary lesion had shrunk to the point of almost complete resolution. CONCLUSION: Pulmonary tumor thrombotic microangiopathy occurs not only in patients with advanced and/or uncontrolled cancer but also in those whose primary lesion seems to have been well controlled by medical treatment.

Clinical and genetic diagnosis of Cowden syndrome: A case report of a rare PTEN germline variant and diverse clinical presentation.

INTRODUCTION: Cowden syndrome is a rare autosomal dominant disease characterized by the development of hamartomas and increased risks of other tumors, including breast, thyroid, and uterine cancers. Most patients with Cowden syndrome show mutations of the phosphatase and tensin homolog (PTEN) gene on chromosome 10; however, some patients with mutations do not show clinical symptoms, while patients with clinical symptoms may not have detectable PTEN mutations. CASE PRESENTATION: A 39-year-old woman with macrocephaly had previously been diagnosed with Cowden syndrome at another hospital, when she presented with the onset of breast cancer. A wide variety of complications were detected, including cerebellar tumors treated by resection, hydrocephalus, and multiple polyps in the stomach and large intestine. She was further diagnosed with adult-onset Lhermitte-Duclos disease as a complication of Cowden syndrome. She subsequently developed a dural arteriovenous fistula treated by transvenous embolization. After transfer to our hospital, she developed adenomatous goiter treated by resection, recurrent breast cancer treated with hormonal therapy, and multifocal oral mucosal papillomatosis. Her older sister had previously been diagnosed with Cowden syndrome and her father was undiagnosed but had macrocephaly, hydrocephalus, and multifocal oral mucosal papillomatosis, suggestive of Cowden syndrome. After consultation with a genetic specialist, analysis of the PTEN gene showed a rare but likely pathogenic germline c.801 + 2T>A variant located at the splice donor site of intron 7. The patient's clinical diagnosis of Cowden syndrome was accordingly confirmed by the genetic findings. Appropriate surveillance procedures were put in place to detect any further tumors. CONCLUSIONS: The clinical symptoms of Cowden syndrome do not always correlate with the genetic results. However, recent improvements in genetic testing suggest the importance of diagnosing this disease using both clinical and genetic approaches, in collaboration with genetic experts, to ensure an accurate diagnosis and appropriate surveillance for malignant tumors.

Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia.

Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML.

Increased rice yield and reduced greenhouse gas emissions through alternate wetting and drying in a triple-cropped rice field in the Mekong Delta.

For sustainable food production in the Mekong Delta, greenhouse gas (GHG) emissions from rice cropping activities need to be reduced without sacrificing rice productivity. Each year, a substantial amount of straw is incorporated into paddy soils through triple rice cropping, which is characterized by a short cropping period and nearly year-round flooding, such that a large amount of methane is emitted. Exposing these soils to oxidative conditions by altering the cropping-period water regime might have the potential to reduce GHG emissions with increased rice yield. To test this potential, a split-plot experiment was conducted in a typical triple-cropped alluvial farmer's paddy in a central delta area over five years and 15 consecutive cropping seasons. The emissions observed from the continuously inundated paddies were 1.1-2.7 times greater than the reported emission factors for Vietnamese continuously inundated paddies. A significantly higher emission peak was detected at the beginning of the rice cropping and flooding fallow periods in continuously flooded (CF) paddies than in alternate wetting and drying (AWD) paddies, although the differences in field water level and soil moisture among the paddies were negligible. AWD reduced annual methane emissions (-51 %) and increased rice yield (+9 %), presumably through enhanced translocation of carbohydrates from leaves to panicles. The amount of GHGs emitted from straw use also decreased (11 %) under AWD management because the straw production rate was significantly lowered (9 %) by enhanced nutrient translocation. These results indicate that GHG emission reduction potentials in the Mekong Delta have been underestimated by previous studies, corroborate the necessity of additional long-term observations of triple rice cropping systems and demonstrate the need for a robust methodology for monitoring the permanence of AWD effects after policies promoting its widespread dissemination take effect.

Paraneoplastic Opsoclonus-myoclonus Syndrome with Anti-Hu and Anti-SOX-1 Antibodies after Immune-checkpoint Inhibitor Treatment Combined with Chemotherapy in a Patient with Small-cell Lung Cancer.

A 69-year-old man with advanced small-cell lung cancer achieved partial remission after 3 courses of immunochemotherapy that included atezolizumab. Ten days after the last treatment, he developed paraneoplastic opsoclonus-myoclonus syndrome and required mechanical ventilation. Serology testing detected anti-Hu and anti-SOX-1 antibodies. Despite steroid pulse therapy, various anticonvulsants, continuous intravenous sedation, and a fourth course of chemotherapy without atezolizumab, his condition failed to improve. Paraneoplastic opsoclonus-myoclonus syndrome with autoantibodies after immune-checkpoint inhibitor treatment has not been reported previously. Although a causal relationship between immune-checkpoint inhibitors and paraneoplastic syndromes has been suggested, the mechanism remains unknown.

[Simultaneous Double Cancer of Unknown Primary and Advanced Lung Cancer-A Case Report].

A 60-year-old woman was diagnosed with simultaneous double cancer of the inguinal lymph node(squamous cell carcinoma) and the right lung(combined small cell carcinoma; cT3N0M0, Stage ⅡB)after observing and reporting a right inguinal swelling. Both were local lesions, and standard definitive treatments were administered. Right inguinal malignant tumor resection and right femoral arteriovenous resection with artificial blood vessel replacement and pedicled transverse rectus abdominis musculocutaneous flap were performed for the unknown primary cancer. Right upper lobectomy, lymph node dissection, and chest wall resection were performed for the right lung cancer. The postoperative stage of the right lung cancer was pT3N0M0, Stage ⅡB, and cisplatin(CDDP)/vinorelbine(VNR)was administered as postoperative adjuvant chemotherapy. The 2 surgeries and adjuvant chemotherapy were well-tolerated, and there has been no recurrence for 1 year and 5 months.

Changes in Central Venous Catheter Use in the Hematology Unit with the Introduction of Ultrasound Guidance and a Peripherally Inserted Central Venous Catheter.

Objective A central venous catheter (CVC) is often needed to treat hematologic diseases, but it is accompanied by many complications. Ultrasound guidance (USG) or a peripherally inserted central venous catheter (PICC) can reduce such complications. Meterials We collected data of patients with attempted CVC placement in our hematology unit in 2012 (before introduction of USG and PICC) and 2018 (after introduction) and compared both periods. Results In total, 187 CVC insertions were attempted in 2018 and 198 in 2012. USG was used 154 times (82%) in 2018 and 4 times (2%) in 2012 (p<0.001). The success rates of insertion were 95% in 2018 and 89% in 2012 (p=0.063). The incidence of acute complications was 4.3% in 2018 and 9.1% in 2012 (p=0.069). The incidence of CVC removal owing to delayed complications was 26% in 2018 and 21% in 2012 (p=0.327). The sites of approach in 2018 and 2012 were the internal jugular in 42 (22%) and 54 (27%), subclavian in 52 (28%) and 128 (65%), brachial (PICC) in 89 (48%) and 14 (7%), and femoral in 4 (2%) and 2 (1%), respectively (p<0.001). Conclusion USG has become commonplace since its introduction. The landmark-based subclavian approach was largely replaced by PICC with USG in 2018. USG and PICC can help improve success rates and safety profiles.

Influence of dose reduction of vincristine in R-CHOP on outcomes of diffuse large B cell lymphoma.

Dose intensity (DI) of chemotherapy affects prognosis of diffuse large B cell lymphoma (DLBCL). Myelotoxicity is the major dose-limiting toxicity (DLT) of most cytotoxic agents for hematological malignancies, whereas DLT of vincristine (VCR) is mainly neurological toxicity. Although VCR is a key drug and its combination with other cytotoxic agents needs consideration, studies focused on relative DI (RDI) of VCR have not been done before. We retrospectively analyzed 86 cases of DLBCL that received six or more cycles of cyclophosphamide (CPM), doxorubicin (DXR), VCR, prednisolone, and rituximab [R-CHOP] and calculated RDI of each cytotoxic agent to analyze its influence on treatment outcome. The median RDI of CPM, doxorubicin, and VCR was 80.0, 81.7, and 78.4 %, respectively (p = 0.002). The average RDI (ARDI) of these three agents was 80.0 %. The overall survival was significantly worse in the low ARDI (<85 %) than in the high ARDI (>85 %) group (2-year survival rate 67.2 vs 93.4 %, p = 0.011). The survival rate with low RDI VCR (<85 %) was lower than that with high RDI VCR (>85 %), even when the remaining two agents had high ARDI (2-year survival rate 74.3 vs 95.8 %, p = 0.047). In conclusion, VCR dose tended to be reduced compared with CPM and DXR in R-CHOP. Lower ARDI of cytotoxic agents and lower RDI of VCR could lead to poor prognosis in the treatment of DLBCL with R-CHOP. We thought these observations should be confirmed in a prospective study.