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Cytomegalovirus (CMV) oophoritis is an extremely rare and fatal condition. We encountered a 63-year-old woman with CMV oophoritis who had been treated for Burkitt's lymphoma. Positron emission tomography/computed tomography performed after chemotherapy showed a high

We aimed to assess the efficacy and safety of synbiotics, including live microorganisms and non-digestible food ingredients, in patients undergoing high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT). This prospective, randomized, double-blind study, included patients with malignant lymphoma eligible for auto-HSCT. The patients were randomized to either a synbiotic group receiving Bifidobacterium longum (BB536) and guar gum or a placebo group receiving a placebo including dextrin. The supplements were administered twice daily from the start of conditioning chemotherapy up to 28 days after auto-HSCT. The primary endpoint was the duration of total parenteral nutrition (TPN). The secondary endpoint was safety. A total of 12 patients were included and randomized. The median duration of TPN was 15 days (range, 12–33 days) in the synbiotic group and 17.5 days (range, 0–32 days) in the placebo group, with no clear difference between the two groups. The median duration of grade 3 or higher diarrhea was shorter in the synbiotic group (2.5 vs. 6.5 days), as was the duration of hospital stay (31.5 vs. 43 days). Oral intake and quality of life regarding diarrhea and anorexia improved in the synbiotic group after engraftment. Synbiotic infections, including bacteremia, were not observed. Synbiotics may reduce gastrointestinal toxicity leading to nutritional problems and improve the quality of life of patients undergoing auto-HSCT, without severe adverse events. (The Japan Registry of Clinical Trials, No. jRCTs051180026.)

A 45-year-old woman was diagnosed with hepatosplenic T-cell lymphoma (HSTCL), a rare subtype of peripheral T-cell lymphoma. She received different types of chemotherapy, but disease progression was observed. To reduce the tumor burden before an unrelated bone marrow transplantation, combination chemotherapy consisting of the gemcitabine, carboplatin, and dexamethasone (GCD) was administered as bridging therapy, resulting in a reduction in the number of lymphoma cells. We were then able to perform bone marrow transplantation. Although she experienced some adverse events, she successfully achieved long-term remission. We herein report a successful case of HSTCL treated with unrelated stem cell transplantation following the GCD regimen as bridging chemotherapy.

Chromosomal rearrangements involving the MECOM locus, which consists of two genes MDS1 and EVI1 located at 3q26.2, are found in different types of myeloid malignancies [1,2]. Among these, the t(3;1...

A 69-year-old woman who had been diagnosed with unresectable papillary thyroid cancer was referred to our hospital. We initially treated her with sorafenib, but she subsequently developed erythema multiforme, which was suspected to be a drug rush due to sorafenib; therefore, sorafenib was discontinued. At the time of discontinuation, immature blast cells were detected in her peripheral blood. Approximately two weeks later, her skin rash improved substantially, but the proportion of blasts in the peripheral blood increased. We performed a bone marrow examination, and she was diagnosed with FLT3-ITD-positive acute myeloid leukemia. FLT3-ITD expression is found in 20–25% of AML and is a known independent poor prognostic factor. To overcome the poor prognosis associated with FLT3-ITD, molecular drugs targeting FLT3-ITD are attracting much attention. Sorafenib, a multi-kinase inhibitor, also has an effect on FLT3-ITD. Although primary disease flares after tyrosine kinase inhibitor discontinuation have been reported, this is the first report to describe discontinuation of sorafenib treatment as a potential trigger of FLT3-ITD-positive acute myeloid leukemia in papillary thyroid cancer.

The prognosis of chronic myeloid leukemia (CML) has improved dramatically with the introduction of tyrosine kinase inhibitors. Although the use of second-generation tyrosine kinase inhibitors is now available for initial cases, a small number of patients with CML unfortunately still experience progression to the accelerated or blastic phase of the disease. We recently managed a patient with chronic-phase CML, who developed a T315 mutation early in the course of treatment with dasatinib and progressed to the lymphoid blastic phase. The patient responded quickly to ponatinib therapy in combination with hyper CVAD, leading to cord blood transplantation. We report here the first case of a patient with CML in the lymphoid blastic phase treated with ponatinib in combination with hyper CVAD, which was tolerable despite adverse events such as infection, bilirubin elevation, and hypertension, and who was able to proceed to transplantation after achieving a complete molecular response.

BACKGROUND Autoimmune myelofibrosis (AMF) is a rare clinicopathologic entity of bone marrow fibrosis that occurs in association with autoimmune disorders. Steroids are very effective for treatment of AMF and the disease has a good prognosis and should be distinguished from primary myelofibrosis. CASE REPORT A 49-year-old man with bleeding and petechial hemorrhage of the extremities presented to our institution. His platelet count was 1×10⁹/L. Bone marrow aspiration revealed a dry tap, and bone marrow biopsy confirmed small lymphocyte infiltration and increased reticular fibers, consistent with immune thrombocytopenia. Testing for mutations in JAK2, MPL, and CALR was negative. Because the patient had a history of Raynaud's phenomenon, he was suspected to have collagen disease. Anti-Sjögren's-syndrome-related antigen-A antibody testing, Schirmer's test, and fluorescein staining all came back positive, which led to a diagnosis of Sjögren's syndrome. Given the bone marrow findings, the patient also was diagnosed with AMF. Treatment with steroids resulted in an immediate improvement in his platelet count. CONCLUSIONS In the present case, treatment with steroids resulted in prompt improvement in platelet counts and subsequent marrow biopsy showed MF-0 reticulin fibrosis. Bone marrow fibrosis rarely is seen in association with autoimmune disease, and its significance and mechanism are still to be determined.

Gemtuzumab ozogamicin (GO), the first antibody-drug conjugate (ADC), has attracted the interest of hematologists because more than 90% of acute myeloid leukemia (AML) blasts express its target, CD33. Although GO and subsequently developed ADCs depend on lysosomes for activation, lysosome number and activity in tumor cells has not been well elucidated. In this study, we investigated whether an mTORC1/2 kinase inhibitor, PP242, which was reported to activate lysosomal function, potentiates the cytotoxicity of GO in AML cells. Eight AML cell lines (U937, THP-1, SKM-1, SKK-1, SKNO-1, HL-60, MARIMO and KO52) were treated with GO and PP242. The cytotoxic effect of GO was enhanced by concurrent treatment with a non-cytotoxic concentration (500 nM) of PP242 in most cell lines, except MARIMO and KO52 cells. We then used LysoTracker to label acidic lysosomes in U937, THP-1, SKM-1, MARIMO and KO52 cells. LysoTracker fluorescence was dramatically increased by treatment with PP242 in U937, THP-1 and SKM-1 cells, and the intensified fluorescence was retained with PP242 + GO. In contrast, PP242 did not induce a significant increase in fluorescence in MARIMO cells, consistent with the lack of combinatory cytotoxicity. LysoTracker fluorescence was also increased by PP242 in KO52 cells, which have been reported to strongly express multidrug resistance (MDR). Further, PP242 suppressed GO-induced Chk1 activation and G2/M cell cycle arrest, which in turn triggered cell cycle promotion and cell death. These results indicate that inhibition of mTORC1/2 kinase by PP242 enhanced the cytotoxicity of GO by increasing lysosomal compartments and promoting the cell cycle via suppression of GO-induced Chk1 activation. This combination may represent an attractive new therapeutic strategy for the treatment of leukemia.

Scopulariopsis alboflavescens is a soil saprophyte that is widely distributed in nature. Recently, there have been increasing number of reports of invasive infections with Scopulariopsis species in immunocompromised patients. In this report, we described an adult woman with acute myeloid leukemia and who developed S. alboflavescens pneumonia. Liposomal amphotericin B and voriconazole combination therapy was unsuccessful and the patient died because of pneumonia. Scopulariopsis is highly resistant to available antifungal agents and almost invariably fatal. This case report should alert clinicians to the importance of listing Scopulariopsis as a pathogenic fungus in immunocompromised patients.

Immune reconstitution affects clinical outcomes after allogeneic hematopoietic stem cell transplantation (HSCT), and it has been suggested that lymphocyte recovery affects survival after HSCT. However, few studies have examined lymphocyte recovery in Asian patients who received mycophenolate mofetil (MMF) prophylaxis for graft-versus-host disease. We retrospectively evaluated early lymphocyte recovery after HSCT among Japanese adults who received MMF prophylaxis. Patients were divided into two groups according to their median absolute lymphocyte count (ALC) on day 28 after HSCT as follows: the “low ALC group” (≤ 0.22 × 109 cells/L) and the “high ALC group” (> 0.22 × 109 cells/L). With a median follow-up of 317 days, the high ALC group showed significantly better overall survival than the low ALC group (at 1 year: 62 vs. 46%, P = 0.02). The high ALC group also tended to have better non-relapse mortality than the low ALC group (at 1 year: 13 vs. 23%, P = 0.08). There was no significant difference in relapse rate between the high and low ALC groups (at 1 year: 29 vs. 35%, P = 0.2). We conclude that among Japanese patients who received MMF prophylaxis, ALC on day 28 after HSCT was effective in predicting overall survival and non-relapse mortality.

Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation. Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography. The MPA AUC0 − tau was 31.9 ± 3.4, 26.2 ± 2.4, and 21.0 ± 2.2 µg*h/mL, the mean Ctrough was 0.25, 0.35, and 0.37 µg/mL, and the Cmax was 10.8, 9.2, and 5.5 µg/mL on days 2, 9, and 16, respectively. The AUC0 − tau and Cmax were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed. Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients.

The t(10;17)(p15;q21) translocation is a very rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML), which would be classified as AML, not otherwise specified by World Health Or...

The recent global pandemic of coronavirus disease 2019 (COVID-19) has led to vaccination in many parts of the world for herd immunity, and as vaccination has progressed, several rare adverse events have been reported. Immune thrombocytopenia (ITP) has been reported to be one of the rare adverse events caused by vaccination with MMR (measles-mumps-rubella) vaccine and influenza vaccine. In addition, ITP has been reported to occur in a small number of cases associated with the COVID-19 messenger ribonucleic acid (mRNA) vaccine. However, there are few reports on the details of the treatment and clinical course; optimal treatment has not yet been established. We report the case of a 20-year-old woman who developed ITP after receiving Pfizer-BioNTech’s BNT162b2 vaccine. She had generalized subcutaneous hemorrhage, 14 days after vaccination. At the time of our visit, she had marked thrombocytopenia and intraoral bleeding; she was diagnosed with ITP. Treatment with oral steroids was started and the platelet count promptly improved after 4 days of treatment. Since the response to treatment was very good, we tapered off the steroids. As these vaccines will be increasingly used in the future, it is important to recognize ITP as a possible adverse event.

Lymph node infarction is very rare, and is frequently associated with neoplasms, such as malignant lymphoma and non-neoplastic disease, or interventions such as fine-needle aspiration (FNA). A 76-year-old-man presented with cervical lymph node swelling. Although FNA was performed, the findings were insufficient for a definitive diagnosis. Consequently, surgical biopsy of the cervical lymph node was performed, which revealed total infarction; a diagnosis of classical Hodgkin lymphoma was made later. Both lymphoma itself and FNA may cause total lymph node infarction, which makes diagnosis confusing. Therefore, it is important to repeat the biopsy rather than repeat FNA to correctly diagnose malignant lymphoma, including Hodgkin lymphoma.

To identify strategies for reducing emesis induced by the CHOP regimen, which includes high-dose steroids, we prospectively evaluated the efficacy of palonosetron in Japanese patients. Palonosetron was administered at a dose of 0.75 mg via intravenous injection over 30 min before chemotherapy on day 1. Patients kept diaries of chemotherapy-induced nausea and vomiting (CINV) incidence from the start of chemotherapy until 168 h afterwards, in which they documented the occurrence and severity of nausea, vomiting, anorexia, and the use of rescue medication. The primary endpoint was the overall occurrence rate of nausea, vomiting, and anorexia; these rates were 56, 12, and 62 %, respectively, including all grades. The rates and severity of symptoms tended to worsen 120-168 h after completing oral prednisolone. We defined complete response (CR) as no vomiting and no use of rescue therapy. The CR rates of post palonosetron 0.75 mg treatment in the acute (0-24 h), delayed (24-168 h), and overall phases (0-168 h) were 86, 66, and 62 %, respectively. Antiemetic strategies of CHOP regimen for day 6 and, thereafter, should be investigated.

Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF‐04449913 (PF‐913) is a selective, small‐molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof‐of‐concept and mechanism of action of PF‐913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF‐913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34− cells. In vitro treatment with PF‐913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF‐913 attenuated the leukemia‐initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF‐913 modulated self‐renewal signatures and cell cycle progression. Furthermore, PF‐913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS‐5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia‐initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.

Rhabdomyolysis is characterized by a marked elevation of the creatine kinase (CK) levels and myoglobinuria, thus leading to renal dysfunction. Various viruses or bacteria can be etiologic agents, but mycosis has only rarely been reported to be a cause of rhabdomyolysis. In this report, we describe an adolescent male with acute myeloid leukemia who underwent allogeneic bone marrow transplantation and thereafter developed rhabdomyolysis and Candida parapsilosis fungemia almost at the same time. Following treatment for C. parapsilosis, the transaminase and CK levels both satisfactorily decreased. This case illustrates that C. parapsilosis infection may be a causative agent of rhabdomyolysis in immunocompromised patients.

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling.

Background Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. Methods and results We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/d) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (ie, bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. Conclusions Mycophenolate mofetil may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT.

Rhabdomyolysis is characterized by a marked elevation of the creatine kinase (CK) levels and myoglobinuria, thus leading to renal dysfunction. Various viruses or bacteria can be etiologic agents, but mycosis has only rarely been reported to be a cause of rhabdomyolysis. In this report, we describe an adolescent male with acute myeloid leukemia who underwent allogeneic bone marrow transplantation and thereafter developed rhabdomyolysis and Candida parapsilosis fungemia almost at the same time. Following treatment for C. parapsilosis, the transaminase and CK levels both satisfactorily decreased. This case illustrates that C. parapsilosis infection may be a causative agent of rhabdomyolysis in immunocompromised patients.

Tolvaptan is an oral vasopressin V2-receptor antagonist recognized as effective for fluid retention associated with congestive heart failure and liver cirrhosis. However, there have been no reports concerning clinical experience with tolvaptan for sinusoidal obstruction syndrome (SOS). A 42-year-old male with primarily refractory T-lymphoblastic lymphoma underwent allogeneic peripheral blood stem cell transplantation from an HLA-matched sibling donor. The myeloablative conditioning regimen consisted of busulfan and cyclophosphamide. On day 20, the total bilirubin level was elevated to 2.0 mg/dL, and body weight increased from 76 to 85 kg, allowing a diagnosis of SOS to be made. Treatments with thrombomodulin, furosemide, carperitide, and low-dose dopamine were ineffective. By day 27, the patient's body weight had increased to 90 kg, and he subsequently developed cardiopulmonary failure. Therefore, we administered low-dose tolvaptan for 2 days (3.75 mg on day 27 and 7.5 mg on day 28). Consequently, his ascites and edema were significantly reduced, and body weight returned to 77 kg by day 34. However, he died of lymphoma progression on day 55. Tolvaptan may be an alternative and promising treatment for refractory fluid retention associated with SOS, although it is unclear whether tolvaptan administration leads to improvement in clinical outcome.

We report a case of possible immunoglobulin G4-related disease(IgG4-RD)that resulted in complications such as retroperitoneal fibrosis and infundibulohypophysitis. The patient was a 72-year-old male who presented with polyuria and polydipsia. Magnetic resonance imaging(MRI)revealed a thickened pituitary stalk and contrast enhancement with gadolinium. T1-weighted imaging revealed that the posterior pituitary high-signal zone had disappeared. Central diabetes insipidus was diagnosed on the basis of results of the hypertonic saline test. In addition, pressure due to retroperitoneal fibrosis resulted in hydronephrosis and elevated serum IgG4 levels. Because it was determined that the patient could have IgG4-RD, he was administered prednisolone, following which a decrease in the size of the pituitary stalk and retroperitoneal fibrosis was observed. IgG4-RD is characterized by elevated serum IgG4 levels and the infiltration of IgG4-positive plasma cells into various organs, including the central nervous system. Recently, IgG4-RD research teams organized by the Ministry of Health, Labour and Welfare established guidelines for the diagnosis of IgG4-RD. According to these guidelines, this case would fall under the category of "possible IgG4-RD." This case suggested that when infundibulohypophysitis is detected by neuroradiology, further investigation into the possibility of IgG4-RD should be recommended.

Background: Cumulative evidence suggests that dormant self-renewing leukemic stem cells (LSCs) contribute to acute myeloid leukemia (AML) propagation and relapse by evading conventional chemotherapies that target cycling cells. Therefore, there is a great need to find innovative therapies for AML that eliminate LSCs by targeting their specific properties. Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in maintenance of the LSC populations in several experimental systems. PF-0444913 (PF-913) is a novel oral small molecule inhibitor that selectively binds and targets Smoothened (SMO), a membrane protein regulating the Hh pathway. Treatment with PF-913 has shown promising results regarding safety, tolerability, and early signs of efficacy in the early phase study of hematologic malignancies, including AML (Jamieson, et al. ASH, 2011). However, the detailed mode of action and biomarkers remain to be elucidated in AML therapy with the Hh pathway inhibitors. Methods: We used AML cell lines and patient-derived primary AML cells and bone marrow cells in PF-913 treatment. Using RQ-PCR assays, we examined the change of gene expressions in the canonical Hh pathway molecules. We carried out comprehensive gene set enrichment analysis (GSEA), and pathway analysis during PF-913 treatment both in the pre-clinical experimental systems and the clinical setting (bone marrow blast-rich mononuclear cells derived from AML patients during the PF-913 mono-therapy). We also examined cell cycle analyses using flow-cytometory and Ki-67 immuno-staining assays. Results: In primary AML cells, the Hh signaling pathway was activated more in CD34+ cells than in CD34- cells. In vitro treatment with PF-913 induced a minimal cell death-accompanied decrease of the quiescent (Hoechst-33342low/Pyronin-Ylow) cell population. Through the serial transplantation immunodeficient NOD/SCID/IL2rgnull (NOG) mouse model xenotransplanted with primary AML cells, in vivo treatment with PF-913 attenuated leukemia initiation potential in AML cells (0% human-CD45+ cells in bone marrow cells derived from the 2nd recipient mice), while limiting reduction of tumor burden in the primary xenotransplanted recipient mice. In the NOG mouse model and the ex vivo culturing system of AML cell lines, GSEA revealed that PF-913 treatment induced effects on the self-renewal signatures and the cell-cycling regulations associated with LSC-like properties. Moreover, GSEA revealed that PF-913 treatment in the clinical setting modulated the LSC-like signature, the cell-cycling regulation signature, and the chemokine activity signature in the AML bone marrow cells. Ki-67 immuno-staining of bone marrow derived from AML patients showed that PF-913 treatment temporarily increased cell-cycling status during shorter periods of treatment. We also examined the pluripotency factor, Nanog expression in bone marrow cells derived from AML patients during the PF-913 therapy, based on the previous report that downstream effectors in the Hh pathway, GLI1 and GLI2, directly bind to the Nanog promoter and that the GLI-Nanog axis promotes stemness and growth in several cancers. Change of Nanog transcripts was closely associated with the GLI-target genes in bone marrow blast-rich mononuclear cells derived from AML patients during the PF-913 therapy. Furthermore, by backing to the pre-clinical experimental systems, we are investigating more detailed mechanisms of Nanog regulation during PF-913 treatment and more rationale methods of combination treatment with PF-913 and other candidate drugs (such as conventional chemo-drugs and other type of molecular targeted inhibitors). Conclusion: Gene profiling analyses revealed that treatment with Hh signaling inhibitor, PF-913 modulates self-renewal and cell-cycling signatures in AML, and Nanog transcript can be a responsive biomarker during the therapy.Our findings imply that PF-913 treatment can improve AML therapy through sensitizing dormant LSCs to chemotherapy and overcoming residual LSC-like diseases in the bone marrow microenvironment. Disclosures Minami: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Naoe:Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Toyama Chemical CO., LTD.: Research Funding; Celgene K.K.: Research Funding. Minami:Novartis: Honoraria, Other: Member of IDMC , Research Funding.

We examined the efficacy of auraptene (AUR), an antioxidant agent of a citrus coumarin derivative, for suppressing gastric inflammation introduced by Helicobacter pylori (Hp) infection in Mongolian gerbils (MGs). Hp-infected MGs were placed on diets containing 100 or 500 ppm AUR for 7 weeks. Real-time PCR was used to estimate the Hp population in glandular stomach lesions, and a histological assessment of inflammation was performed. At a dose of 500 ppm, AUR reduced the Hp population to 21.9+/-12.0% of the control group (p

Background: Cancer patients who are receiving chemotherapy are at risk for influenza infections and its severe complications. Although influenza vaccination is recommended, preliminary data have raised questions about the immune response to vaccination in such patients. Furthermore, recent studies suggest that some tyrosine kinase inhibitors (TKIs) induce significant impairment of B cell responses and reduce vaccine efficacy. The two-dose influenza vaccination is proposed to be one of the strategies to increase the efficacy of influenza vaccination in cancer patients, but its efficacy has yet to be confirmed. Methods: This was a prospective multicenter study to evaluate the efficacy of the two-dose influenza vaccination in cancer patients receiving chemotherapy. We administered a triple-strain (A/California/7/2009 [H1N1], A/Texas/50/2012 [H3N2], and B/Massachusetts/2/2012) 2013/14 influenza vaccine to patients with pathologically confirmed malignancies. All patients were under the treatment with chemotherapy including cytotoxic agents, rituximab, or TKIs. Vaccination was performed on days when chemotherapy was not given (except for TKIs). The second vaccination was performed in patients who did not respond to all three strains after the first vaccination. Hemagglutination inhibition (HI) titers were measured, and 1:40 or greater HI titers were considered protective because these titers were reported to be associated with at least a 50% reduction in influenza infection in general populations. HI titers were measured within two weeks prior to the first vaccination, within 3-5 weeks after each vaccination, and at the end of the influenza season in May 2014. Results: A total of 109 patients (median age 61 years [range 21–89 years]) were enrolled; 55 females and 54 males, 36 hematological malignancies (multiple myeloma [n=15], malignant lymphoma [n=10], chronic myeloid leukemia [n=10], and acute lymphoblastic leukemia [n=1]), 70 solid tumors (breast [n=14], colorectal [n=11], biliary tract [n=10], and others [n=35]), and both cancer types (n=3). The flow chart of patients is shown in Figure. Table lists the proportions of patients with protective titers. The proportion of patients who had protective titers against all three strains was increased from 2 to 24% by the first vaccination. Similarly patients with protective titers against individual strains were increased; further 3-10% of patients achieved protective titers against individual strains after the second vaccination. When we compared the proportion of patients with protective titers against all strains after the first vaccination between the two disease types, the efficacy was similar; 22% (8/36) in hematological malignancies and 24% (17/70) in solid tumors (p=1.0). Similarly, there were no significant differences after the second vaccination between the two disease types. We also assessed differences in the response between patients treated with TKIs alone and those treated with other therapies. After the first vaccination, the proportion of patients who had protective titers against all three strains was 32% (6/19) for TKIs alone while it was 22% (20/90) for other therapies (p=0.39). Also there were no differences after the second vaccination regardless of the use of TKIs. When the effect on immunization of age, leukocyte and lymphocyte counts, and duration from chemotherapy to the first vaccination was evaluated, none of these factors influenced vaccine response. Serious adverse events associated with influenza vaccination were not reported, even among patients who received the two-dose vaccination. Conclusions: We recommend influenza vaccination for cancer patients who are receiving chemotherapy, and two-dose vaccination might be an effective strategy to augment vaccine efficacy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell (LSC) populations in several experimental systems. Cumulative evidence suggests that dormant self-renewing LSC contribute to acute myeloid leukemia (AML) propagation and relapse by evading conventional chemotherapies that target cycling cells. PF-913 is a novel oral small molecule inhibitor that selectively binds and targets Smoothened (SMO), a membrane protein regulating the Hh pathway. Treatment with PF-913 has shown promising results regarding safety, tolerability, and early signs of efficacy in AML patients. However, the detailed mechanisms and biomarkers remain to be elucidated in AML therapy. Results: In primary AML cells, the Hh signaling pathway was activated more in CD34+ cells than CD34- cells. Ex vivo-treatment with PF-913 in AML cells induced minimal cell death as well as decrease of the quiescent cell population. In vivo-treatment with PF-913 attenuated leukemia-initiation potential in AML cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Also in the colony-assay system using primary AML cells, treatment with PF-913 reduced serially colony formation. Comprehensive Gene Set Enrichment Analysis (GSEA) revealed that PF-913 treatment modulated embryo stem (ES) cell-like signature in primary AML cells. Moreover, combined treatment with PF-913 abrogated resistance to Ara-C in AML cell lines co-cultured with HS-5 stromal cells and sensitized AML cells to Ara-C in the cutaneous tumor system. Conclusions: Our findings imply that PF-913 treatment can attenuate the leukemia-initiation potential in AML cells, and can also improve AML therapy through sensitizing dormant LSC to chemotherapy and overcoming the resistance in the bone marrow microenvironment.