Discovery of flometoquin, a novel quinoline insecticide.

Flometoquin, 2-ethyl-3,7-dimethyl-6-[4-(trifluoromethoxy)phenoxy]quinolin-4-yl methyl carbonate, is a novel insecticide with a structurally unique phenoxy-quinoline. It was discovered in 2004 by the collaborative research of Nippon Kayaku and Meiji Seika Kaisha, Ltd. (currently, Mitsui Chemicals Crop & Life Solutions, Inc.). The compound demonstrates strong and quick insecticidal action against a variety of thrips species at the nymphal and adult stages through contact and feeding activity, which could minimize crop damage and economic loss by insect pest species. In addition, flometoquin is safe for tested non-target arthropods, which makes it suitable for controlling the insect pests mentioned above under Integrated Pest Management (IPM) programs. Here, we describe a structure-activity relationship study from lead generation to the discovery of flometoquin and its insecticidal properties, including knockdown activity and effects against non-targeted arthropods.

Health Literacy among Japanese College Students: Association with Healthy Lifestyle and Subjective Health Status.

The improvement of health literacy (HL) is a critical issue for college students who are in the transitional period to adulthood and are establishing their subsequent lifestyles. The present study aimed to evaluate the current state of HL among college students and to explore the factors that influence HL. Moreover, it investigated the relationship between HL and health conditions. For this study, the researchers conducted an online survey of college students. The questionnaire consisted of the Japanese version of the 47-item European Health Literacy Survey Questionnaire (HLS-EU-Q47), which is a self-assessment tool for HL that covers the major health issues of college students and health-related quality of life. The study analyzed 1049 valid responses. Based on the HLS-EU-Q47 total score, 85% of the participants exhibited problematic or unsatisfactory HL levels. Participants who reported high levels of healthy lifestyles obtained high HL scores. High levels of HL were associated with high levels of subjective health. Results from quantitative text analysis suggested that specific mindsets were correlated with high levels of competency in appraising health information among male students. In the future, educational intervention programs for college students need to be established to improve HL levels.

Outcomes of poor peripheral blood stem cell mobilizers with multiple myeloma at the first mobilization: A multicenter retrospective study in Japan.

Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one-third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.

Simultaneous Discordant B-Lymphoblastic Lymphoma and Follicular Lymphoma.

OBJECTIVES: We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. METHODS: A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. RESULTS: Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. CONCLUSIONS: B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.

[Cooperation between Clinics and Hospitals Using a Critical Path for G-CSF Prophylaxis in Cancer Chemotherapy].

BACKGROUND: Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011. METHODS: We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital. RESULTS: Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%). CONCLUSION: Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and ß2-microglobulin levels. In the two determinants, ß2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.

Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan-Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

A prospective study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in malignant lymphoma patients following highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a troublesome issue in chemotherapy for cancer patients. A second-generation 5HT3 receptor antagonist (5HT3RA), palonosetron, is effective and safe for the prevention of CINV in breast cancer patients treated with cyclophosphamide and anthracycline, but there is little data for malignant lymphoma. We conducted a prospective phase 2 study at a single institution to clarify the efficacy and safety of palonosetron in lymphoma patients. METHODS: Chemotherapy-naïve lymphoma patients who were treated with highly emetogenic chemotherapy (HEC) received a single intravenous bolus of palonosetron, 0.75 mg/body, before chemotherapy on day 1 during the first course of chemotherapy. The occurrence of CINV was assessed using the Multinational Association for Supportive Care in Cancer (MASCC) antiemesis tool, which was recorded by patients during the first course of chemotherapy. RESULTS: A total of 59 patients were enrolled, and 49 patients were eligible and evaluated. The complete response (CR) rate was 93.9% (95% confidence interval 83.1-98.7%) at 0-120 h post-chemotherapy. The proportion of patients who developed nausea of any grade and vomiting at 0-120 h post-chemotherapy was 34.7 and 6.1%, respectively. Although treatment-related adverse events were observed in 36 (73.5%) patients, these were mild and they recovered by the next cycle of chemotherapy. CONCLUSION: The present study demonstrated that a single dose of palonosetron was highly effective and safe for the prevention of CINV in lymphoma patients.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

A retrospective study of R-CHOP/CHOP therapy-induced nausea and vomiting in non-Hodgkin's lymphoma patients: a comparison of intravenous and oral 5-HT3 receptor antagonists.

Chemotherapy-induced nausea and vomiting (CINV) is a serious problem for cancer patients receiving chemotherapy. The CHOP regimen is the standard treatment for non-Hodgkin's lymphoma (NHL) and is categorized as highly or moderately emetogenic in the CINV guidelines. The efficacy of oral 5-HT3 receptor antagonists is equivalent to that of the intravenous form in patients with solid tumors, but there is no clear comparative data for the use of these agents NHL patients receiving CHOP. We analyzed retrospective CINV data from medical records of 72 NHL patients who received CHOP or rituximab-combined CHOP therapy (R-CHOP). All patients received 5-HT3 receptor antagonists alone for prevention of CINV; 39 of the patients received an intravenous form (mostly granisetron) and 33 an oral form (all ramosetron). Complete response (CR: defined as no vomiting and no rescue therapy) was observed in 58 of 72 patients (80.6 %) overall (0-120 h post-CHOP). The CR rate was not statistically different in patients treated with oral or intravenous 5-HT3 receptor antagonists (82.1 vs 78.8 %, P = 0.77). These findings suggest that oral 5-HT3 receptor antagonists represent a good alternative to intravenous forms in NHL receiving CHOP/R-CHOP chemotherapy. Further studies are needed to identify the optimal anti-emetic supportive therapy for NHL.

Tamoxifen enhances the differentiation-inducing and growth-inhibitory effects of all-trans retinoic acid in acute promyelocytic leukemia cells.

All-trans retinoic acid (ATRA) is valuable in differentiation therapy for acute promyelocytic leukemia (APL). However, ATRA has had limited success as a single agent, due to the development of resistance. We found that tamoxifen effectively enhanced the differentiation-inducing effect of ATRA. Tamoxifen alone inhibited the proliferation of myeloid leukemia cell lines while only slightly increasing morphologic differentiation. Tamoxifen effectively enhanced the growth-inhibiting actions of various differentiation-inducing agents. ATRA in the presence of tamoxifen increased NBT reduction and the expression of CD11b in HL-60 cells more effectively than ATRA alone. Tamoxifen also enhanced the differentiation induced by the other inducers tested. ATRA induced the differentiation of APL cell lines NB4 and HT93 and APL cells in primary culture, and this differentiation was also enhanced by tamoxifen. Tamoxifen is one of the most widely used drugs for the treatment of cancer and has few side effects. The combination of ATRA and tamoxifen might be considered for the treatment of APL patients in whom it can be difficult to apply arsenic trioxide or anthracyclines.

Combined treatment with tamoxifen and a fusicoccin derivative (ISIR-042) to overcome resistance to therapy and to enhance the antitumor activity of 5-fluorouracil and gemcitabine in pancreatic cancer cells.

Although progress has been made in chemotherapeutic strategies against pancreatic cancer, overall survival has not significantly improved over the past decade. Thus, the development of better therapeutic regimens remains a high priority. Pancreatic cancer cell lines were treated with tamoxifen, a novel antitumor fusicoccin derivative (ISIR-042), and anticancer drugs, and their effects on cell growth, signaling and gene expression were determined. Xenografts of Panc-1 cells were treated with tamoxifen, ISIR-042 and 5-fluorouracil (5FU) to determine the effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by tamoxifen was effectively reduced by α-tocopherol, a membrane stabilizer. ISIR-042 produced synergistic effects with tamoxifen in inhibiting cell growth. Tamoxifen elevated lipid peroxidation and the release of cytochrome c, and these effects of tamoxifen were reduced by α-tocopherol. ISIR-042 significantly inhibited colony formation and the expression of stemness-related genes of pancreatic cancer cells. The triple combination of tamoxifen, ISIR-042, and 5FU or gemcitabine was effective at inhibiting cell growth and the appearance of drug-resistant cells. This combined treatment significantly inhibited the growth of Panc-1 cells as xenografts without apparent adverse effects. The triple combination of tamoxifen and ISIR-042 with 5FU or gemcitabine may be highly effective against pancreatic cancer by overcoming resistance to therapy.

Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models.

Multiple myeloma is a malignant proliferative disease of plasma cells in the bone marrow and remains largely incurable. Cotylenin A, a fusicoccane diterpene glycoside with a complex sugar moiety, was isolated as a plant-growth regulator. Cotylenin A has been shown to inhibit the growth of various cancer cells. Herein, we examined the anti-myeloma effects of cotylenin A using five human myeloma cell lines (RPMI-8226, KMS-11, KMS-26, KMS-12 PE and KMS-12 BM) and xenografts in immunodeficient mice. Cotylenin A and vincristine synergistically inhibited the growth and induced apoptosis in myeloma cells. While other microtubule-disturbing agents also showed co-operative effects with cotylenin A, other anticancer agents, such as doxorubicin, cisplatin, camptothecin, methotrexate, gemcitabine and 5-fluorouracil, did not show such co-operation with cotylenin A. These differences might be attributed to the effects on autophagic responses. Combined treatment with cotylenin A and vincristine induced autophagy (formation of LC3-II and degradation of p62 protein). However, doxorubicin did not enhance the autophagy induced by cotylenin A. A colony-forming assay indicated that the combined treatment with cotylenin A and vincristine more effectively suppressed the formation of large colonies, which have higher self-renewal activity than vincristine alone. Expression of pluripotency-associated transcription factor Sox2 mRNA in RPMI-8226 myeloma cells was significantly suppressed by treatment with cotylenin A. Combined treatment with cotylenin A and vincristine significantly inhibited the growth of KMS-26 myeloma cells as xenografts. Our results suggest that the combination of cotylenin A and vincristine may have therapeutic value. Recently, it was reported that cotylenin A modulates the 14-3-3 intracellular signaling pathway. The 14-3-3 proteins may be novel targets in treating myeloma. However, our study could not explain how the sensitization to vincristine is related to the effects of cotylenin A on the 14-3-3 signaling pathway and further studies will be needed.

Spontaneous Regression of Intravascular Large B-Cell Lymphoma and Apoptosis of Lymphoma Cells: A Case Report.

A 61-year-old Japanese woman presented with hemophagocytic syndrome (HPS) and suffered from intravascular large B-cell lymphoma (IVLBCL). After a few days of supportive care, her condition improved without any anti-cancer drugs or steroids. She experienced recurrences of HPS at 15 mon and 21 mon after first presentation, but lymphoma cells were not observed. Relapse of IVLBCL with pulmonary involvement occurred 27 mon after first presentation. She underwent R-CHOP therapy followed by autologous stem cell transplantation. She is currently alive and without lymphoma. Immunostaining by anti-ssDNA suggested that spontaneous regression may have been due to apoptosis of the lymphoma cells.

[Relativity in multiple myeloma and KL-6].

KL-6 is a high-molecular-weight mucinous glycoprotein discovered as a pulmonary adenocaricinoma related antigen. Its levels are used as a biomarker of lung injury in interstitial pneumonia. We here report a case of multiple myeloma with Bence-Jones lambda type whose serum KL-6 level was revealed high at a concentration of 19,400 U/ml. Next, we analyzed the blood test profiles and the concentrations of KL-6 in 20 patients with multiple myeloma. CD19/CD56 double negative fraction on myeloma cells with high expression of CD38 was found in all 5 patients with multiple myeloma having elevated KL-6 level. Patients with interstitial pneumonia show high level of KL-6. We, therefore, need to differentiate the interstitial pneumonia and the above-mentioned multiple myeloma when serum KL-6 level is high.

Asian variant of intravascular large B cell lymphoma causes patients to frequently develop the syndrome of inappropriate antidiuretic hormone secretion.

The Asian variant of intravascular large B cell lymphoma is a special type of intravascular lymphoma with hemophagocytic syndrome and hypercytokinemia including interleukin-6, which stimulates antidiuretic hormone synthesis in the hypothalamus. We present here that the syndrome of inappropriate antidiuretic hormone secretion frequently occurs in patients with the Asian variant of intravascular large B cell lymphoma. The syndrome of inappropriate antidiuretic hormone secretion was found in eight of 118 (6.8%) lymphoma patients at the first diagnosis. Although there were six (5.1%) among 118 lymphoma patients with the Asian variant of intravascular large B cell lymphoma, four of the six patients (66.7%) developed the syndrome of inappropriate antidiuretic hormone secretion. In four patients with the Asian variant of intravascular large B cell lymphoma with the syndrome of inappropriate antidiuretic hormone secretion, elevated serum interleukin-6 and low sodium levels were almost normalized after chemotherapy. The Asian variant of intravascular large B cell lymphoma patients frequently develop the syndrome of inappropriate antidiuretic hormone secretion, and interleukin-6 might play a role in the occurrence of this disease. We should pay attention to hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion in patients with the Asian variant of intravascular large B cell lymphoma.

L-asparaginase-induced complete response in a relapsed patient with Epstein-Barr virus and cytotoxic peripheral T-cell lymphoma not otherwise specified.

We present a patient with Epstein-Barr virus (EBV)-positive cytotoxic peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) who was successfully treated using only L-asparaginase. A 46-year-old Japanese man was diagnosed with EBV-positive cytotoxic PTCL-NOS. Although he underwent chemotherapy using multiple agents, he relapsed with hemophagocytic syndrome. L-asparaginase treatment was initiated at 6,000 U/m(2) on days 1, 3, 5, 10, and 12 together with prednisolone at 1 mg/kg. Although he developed grade 2 liver dysfunction and grade 2 coagulopathy, the patient achieved complete response status. Finally, he underwent allogeneic bone marrow stem cell transplantation, and he is currently still alive without disease at 24 months after the start of L-asparaginase therapy.

Small bowel perforation caused by Epstein-Barr virus-associated B cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma.

On rare occasions, secondary Epstein-Barr virus (EBV)-associated B cell lymphoma can develop in a patient with angioimmunoblastic T-cell lymphoma (AITL). We report a case of a 66-year-old Japanese woman who developed diffuse large B-cell lymphoma (DLBCL) in her small intestine after chemotherapy for AITL. She was found to have panperitonitis due to perforation of the small intestine. Partial ileectomy specimen showed DLBCL cells infiltrating into the intestinal wall. In situ hybridization for EBV-encoded RNA revealed positivity in the lymphoma cells. The lymph nodes diagnosed as AITL were negative for EBV infection and there was no coexistence of B cell neoplasms in them. We thought small bowel perforation in this case was caused by EBV-associated B cell lymphoma secondary to AITL. Our case showed a remarkable deficiency of cellular immunity after chemotherapy, which we postulate was related to the cause of occurrence of B-cell lymphoma.