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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.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 + 2TA 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.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.

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 10^7/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0–85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 10^9/L on day 60 was 80.6% (68.2–88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 10^9/L and platelets ≥ 50 × 10^9/L on day 100 were 75.8% (62.6–84.9%) and 72.6% (59.4–82.1%), respectively, with median time to platelets ≥ 20 × 10^9/L and platelets ≥ 50 × 10^9/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II–IV and III–IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

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.

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

A novel method to fabricate undulator magnets of a-few-millimetre-period length is being explored. Plate-type magnets, 100 mm-long with 4 mm-period length, have been successfully fabricated. They produce an undulator field of approximately 3 kG at a gap of 1.6 mm. Prototype undulators based on this technology have been constructed. Field measurements and characterization show that the quality of the undulator field of these plate magnets is sufficient for an undulator light source, and the calculated spectrum shows that the fundamental radiation emitted from this field is quite satisfactory. Test experiments for light generation using a real electron beam have been carried out at a test accelerator at the Research Center for Electron Photon Science (ELPH), Tohoku University, Japan, which is able to realize optics conditions to accept a very short gap of ∼1.6 mm. First observation and characterization of blue light was successfully accomplished.

Cord blood transplantation (CBT) is associated with delayed hematopoietic recovery and graft failure. To overcome these problems, we conducted a prospective, multicenter phase II study of intrabone marrow transplantation in which patients received reduced-intensity conditioning without anti-thymocyte globulin (ATG). The primary endpoint was the probability of full donor engraftment. Forty patients with hematologic malignancies were enrolled. Cord blood (CB) cells were injected without washing into 4 iliac bone sites (2 at each hemipelvis), at which approximately 6 mL of CB was administered at one site with local anesthesia. Full donor engraftment rate was 86.8%. The cumulative incidence of neutrophil and platelet engraftment was 86.4% and 85.5%, respectively. The median time to neutrophil (>0.5 × 109 /L) and platelet (2.0 × 109 /L) recovery was 17.5 and 44 days, respectively. The probability of severe acute graft-vs-host disease (GVHD) was 47.5%. The cumulative incidence of extensive chronic GVHD was 3.0%. The probability of relapse and non-relapse mortality was 30.4% and 28.0%, respectively. The survival rate at 3 years was 45.6%, although most patients were at an advanced stage. These results suggest that our intrabone marrow-CBT procedure without using ATG improves hematopoietic recovery and decreases the incidence of chronic GVHD, but does not decrease the incidence of acute GVHD.

The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m

As the potent, selective Fms-Like Tyrosine Kinase 3 (FLT3) inhibitor gilteritinib has only been approved for use for a few years, its efficacy and complications remain incompletely understood. We herein report an elderly patient with FLT3 internal tandem duplications (FLT3-ITD) mutated acute myeloid leukemia (AML) who developed natural killer cell large granular lymphocytes (NK-LGL) in the bone marrow and peripheral blood during gilteritinib treatment. Case: A 79-year-old Japanese female had been diagnosed with FLT3-ITD-mutated AML. The patient received hydroxycarbamide 2000 mg daily for induction chemotherapy but did not achieve remission at day 28 postinduction. The treatment was then changed to gilteritinib 120 mg daily. Although the reduction of blasts in peripheral blood occurred immediately, it was revealed abnormal lymphocytes with large granules developed in bone marrow and peripheral blood. These lymphocytes were analyzed by flow cytometry, which revealed that these cells were NK-LGL because they expressed CD2, CD7, CD16, and CD56 and did not express CD3, CD19, and CD20. The patient achieved partial remission (PR) in a month with gilteritinib treatment. Leukemia eventually could not be controlled, but PR persisted for about 4 months and leukemia was controlled for 4 months after progression disease (PD) with gilteritinib treatment alone. Conclusion: Gilteritinib may induce the NK-LGL. The exact mechanism and effect of LGL in patients with FLT3 mutated AML treated with gilteritinib warrants further investigation.

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.

Propagation of relativistically intense azimuthally or radially polarized laser pulses (RPP) in underdense plasmas is demonstrated to be unstable, via 3D particle-in-cell simulation and disregarding the Kerr non-linearity. Strong pulse filamentation occurs for RPP in transversely uniform plasma with an increment, $\Gamma$, close to the well-known one depending on acceleration, $\alpha$, and modulated density gradient length, $L$, as $\Gamma \approx (\alpha/L)^{1/2}$. In deep plasma channels the instability vanishes. Electron self-injection and acceleration by the resulting laser pulse wake is explored., Comment: The paper need to be written in a more proper way

Underdense plasma produced in gas jets by low intensity laser prepulses in the presence of a static magnetic field, $B\ensuremath{\sim}0.3\text{ }\text{ }\mathrm{T}$, is shown experimentally to become an optical element allowing steering of tightly focused high power femtosecond laser pulses within several degrees along with essential enhancement of pulse's focusability. Strong laser prepulses form a density ramp perpendicularly to magnetic field direction and, owing to the light refraction, main laser pulses propagate along the magnetic field even if it is tilted from the laser axis. Electrons generated in the laser pulse wake are well collimated and follow in the direction of the magnetic field; their characteristics are measured to be not sensitive to the tilt of magnetic field up to angles $\ifmmode\pm\else\textpm\fi{}5\ifmmode^\circ\else\textdegree\fi{}$.

High quality intense relativistic electron beams are generated by the interaction of two colliding laser pulses to inject plasma electrons into a wakefield excited by one of the laser pulses. The mechanism of the injection is analyzed theoretically and the generation of a high quality electron beam is verified by the numerical simulation. An electron beam has a small energy spread of 1%, ultrashort pulse duration less than 10 fs and normalized transverse emittance less than 1 π mm mrad.

By utilizing a pulsed laser beam of TEM(1,0)+TEM(0,1) mode, it was found numerically for the first time that an electron bunch can be effectively trapped by the transverse ponderomotive force in the transverse direction and at the same time accelerated by the longitudinal ponderomotive force to about 378 MeV at the laser peak intensity of I∼5.48×1018 W/cm2. In addition, the electron bunch size is preferably small: at this laser intensity the electron bunch thickness is ∼10λ in the longitudinal direction and the bunch radius is about 625λ in the transverse direction.

Laser wakefield acceleration (LWFA) experiment using 100TW laser is planned at JAERI-Kansai. High quality short pulse electron beams and the precise electron-laser synchronization are necessary to accelerate the electron beam by the laser. A microtron with a photocathode rf-gun was developed as a high quality electron injector. The quantum efficiency(QE) of the photocathode was measured to be 2 × 10 −5 . Emittance and a pulse width of the electron beams were 6π mm-mrad and 10ps, respectively. In order to produce a short pulse electron beam, and to synchronize between the electron beam and the laser pulse, the inverse free electron laser (IFEL) is planed. A gas jet was set up and a density of the gas was measured by Mach-Zehnder interferometer. In order to overcome a short acceleration length of the LWFA, the Z-pinch plasma waveguide has been developed for 1 GeV laser wakefield acceleration.

The coherent wakefield excited by 2 TW, 50 fs laser pulses in a gas-jet plasma around 1018 cm−3 is measured with a time-resolved frequency domain interferometer. The density distribution of the helium gas is measured with a time-resolved Mach–Zehnder interferometer to search for the optimum laser focus position and timing in the gas jet. The results show an accelerating wakefield excitation of 20 GeV/m with good coherency, which is useful for ultrahigh gradient particle acceleration in a compact system. This is the first time-resolved measurement of laser wakefield excitation in a gas-jet plasma.

Yoshio Mizuta, Tomonao Hosokai, Shinichi Masuda, Alexei Zhidkov, Nobuhiko Nakanii, Zhan Jin, Hiroki Nakahara, Tomohiro Kohara, Kenta Iwasa, Masaki Kando, Sergei Bulanov, and Ryosuke Kodama 1 Graduate School of Engineering, Osaka University,2-1 Yamada-oka, Suita, Osaka, 565-0871, Japan 2 Photon Pioneers Center, Osaka University, 2-8 Yamada-oka, Suita, Osaka, 565-0871, Japan 3 Japan Science and Technology Agency (JST), CREST 4 Kansai Photon Science Institute, Japan Atomic Energy Agency, 8-1-7 Umemidai, Kidugawa, Kyoto 619-0215, Japan 5 Institute of Laser Engineering, Osaka University, 2-6 Yamada-oka, Suita, Osaka, 565-0871, Japan

[Background] Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702). [Methods] Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point. [Results] A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (>6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm. After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months. [Conclusions] Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population. Disclosures Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

Interaction of relativistically intense axisymmetrically polarized (radially or azimuthally polarized) laser pulses (RIAPLP) with underdense plasma is shown experimentally and theoretically to be essentially different from the interaction of conventional Gaussian pulses. The difference is clearly observed in distinct spectra of the side-scattered laser light for the RIAPLP and Gaussian pulses, as well as in the appearance of a spatially localized strong side emission of second harmonic of the laser pulse in the case of RIAPLP. According to our analysis based on three-dimensional particle-in-cell simulations, this is a result of instability in the propagation of RIAPLP in uniform underdense plasma.

A 51-year-old woman diagnosed as having left breast cancer with axillary lymph node and liver metastases seven years earlier was seen in our office because of severe pancytopenia. She had received chemotherapy including several cycles of doxorubicin plus cyclophosphamide and docetaxel followed by hormone therapy containing leuprorelin and tamoxifen over four years. For management of bone pain due to metastasis, she had also undergone stereotaxic radiation therapy of the neck one and a half years earlier and unsealed internal radiation therapy with (89)Sr injection five months prior to the current presentation, Subsequently, myelosuppression progressively worsened and she finally required a blood transfusion. Although bone marrow examination showed severe hypoplasia, but neither blastic nor dysplastic, a test for PML-RARA fluorescence in situ hybridization was positive. After administration of all-trans retinoic acid, hematogenesis improved within three weeks. Neither disseminated intravascular coagulation nor retinoic acid syndrome was observed during the course of her illness. This is the first report describing acute promyelocytic leukemia after administration of (89)Sr, to our knowledge, and with an atypical onset and progression. As the number of cancer survivors increases due to improvements in medical intervention, clinicians must take more notice of special characteristics of therapy-related leukemia modified by previous treatments.

We retrospectively analyzed the bone mineral density (BMD) of postmenopausal Japanese women taking an aromatase inhibitor (AI), exemestane, anastrozole or letrozole, and calculated the decrease rate constant of BMD in each individual to compare the influence of the three AIs on BMD. We also aimed to evaluate the preventive effect of bisphosphonates (BPs) on the AI-induced decrease in BMD. The decrease rate constant of BMD (k(e)) in each individual was determined as a slope of linear regression of the relationship between time and logarithm of BMD value in each patient during the AI therapy. To compensate for the age-related change in BMD level, we estimated the age-related decrease rate constant of BMD (ke,0) in healthy Japanese postmenopausal women from the literature. AIs decreased BMD with a ke value of -0.0329 yr(-1), which was 4.7-fold larger than the k(e,₀) value of -0.00699 yr(-1). No significant difference was detected in the influence on BMD among AIs. Co-administration of BP ameliorated the ke value to -0.0117 yr(-1), a value similar to k(e,₀). The influence of AIs on BMD was quantitatively evaluated by using the decrease rate constant of BMD (k(e)). The present study also suggests that BPs may be useful to prevent the decrease in BMD induced by AIs.

Strong disturbance in the wake of the laser pulses propagating in underdense plasma and consequent unstable electron acceleration by the wakefield can be provoked by pulse's halo, which always exists as a result of an imperfect optical focusing. When the power in the halo part exceeds a critical level for the self-focusing, it evolves in the plasma as an independent mode, which later gets coupled with the propagation of the central Gaussian spot of the pulse resulting in a novel instability. Here, this instability is investigated numerically via fully relativistic 3D particle-in-cell simulations and is shown to be partially suppressed by using plasma channels for pulse guiding.

Background; The number of non-Hodgkin's lymphoma (NHL) patients in the elderly has been increasing due to the long-lived society. It is not rare to treat elderly NHL patients aged over 85 years old. Individualizing the doses of cancer chemotherapy agents and progress in supportive therapy has improved the prognosis for elderly patients with NHL. Prolonged hospitalization elderly patients have adverse effects, which include dementia, difficulty in walking, and depression. Optimal treatment for these patients is unknown. Patients and Methods; In our hospital between April 2012 and December 2014, we treated 19 elderly patients (85 and over 85 years) with NHL as outpatients with VDS 3mg (day 1) and Dexa. (day 1-4) which repeated every 3 weeks for as long as possible. Results; Complete remission was achieved in 5 patients and partial remission in 6; the median duration of survival was 14 months. Adverse effects included leukopenia in 1 patient ( Disclosures No relevant conflicts of interest to declare.

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially λ-restricted. Here we determined complete nucleotide sequences of monoclonal immunoglobulin λ light chain (IGL) variable regions in 11 patients with POEMS syndrome. The V-region of the Igλ gene of all 11 patients was restricted to the Vλ1 subfamily. Searching for homologies with IGL germlines revealed that 2 germlines, IGLV1-44*01 (9/11) and IGLV1-40*01 (2/10), were identified, with an average homology of 91.1%. The IGLJ3*02 gene was used in 11 of 11 re-arrangements with an average homology of 92.2%. These data suggest that the highly restricted use of IGL Vλ1 germlines plays an important role in the pathogenesis of POEMS syndrome.

Electron ponderomotive acceleration in a vacuum by a short-pulsed laser of TEM (1, 0) + TEM (0, 1) mode is studied in this paper using a 3-dimensional (3D) particle simulation. It was found that the laser can trap electrons in transverse and accelerate them with the longitudinal ponderomotive force at the same time. Through this electron trapping and acceleration scheme of TEM (1, 0) + TEM (0, 1) mode laser, the electron bunch is confined well in transverse and compressed remarkably in longitudinal. Therefore, a high energy, high density, and low emittances electron bunch is generated. For example, the result shows that for a laser with intensity of a0 = eE0 /mωc = 10, the laser spot size of w0 = 15λ, and the laser pulse length of Lz = 10λ, the maximum energy gain reaches 301 MeV and the average energy 57.7 MeV. The electron bunch transverse radius is about 350λ and the longitudinal size about 20λ. The property of this accelerated bunch is improved compared with that generated by the laser of TEM (0, 0) mode.

We study experimentally the interaction of the shortest at present $(23\text{\ensuremath{-}}\mathrm{fs})$, relativistically intense $(20\text{\ensuremath{-}}\mathrm{TW})$, tightly focused laser pulses with underdense plasma. MeV electrons constitute a two-temperature distribution due to different plasma wave-breaking processes at a plasma density of ${10}^{20}\phantom{\rule{0.3em}{0ex}}{\mathrm{cm}}^{\ensuremath{-}3}$. These two groups of electrons are shown numerically to constitute bunches with very distinctive time durations.

Recent activities related to laser‐plasma acceleration at Advanced Photon Research Center, Japan Atomic Energy Research Institute are presented. Gas density measurements of a pulsed gas valve and wakefield measurements have been performed with two types of interferometers. A wakefield of 20 GV/m excited in the gas‐jet plasma has been obtained at a plasma density of 7×1017 cm−3. We have shown by 1D‐3V particle‐in‐cell simulation that a high quality electron beam with a transverse emittance of 0.3 π mm‐mrad and with an energy of 7.0±0.5 MeV can be produced using a colliding optical injection. Our proposed experiments using a 100 TW laser beam and a 150 MeV electron beam are also presented.

We investigate a laser wakefield excited by intense laser pulses, and the possibility of generating an intense bright electron source by an intense laser pulse. The coherent wakefield excited by 2 TW, 50 fs laser pulses in a gas‐jet plasma around 1018 cm−3 is measured with a time‐resolved frequency domain interferometer (FDI). The results show an accelerating wakefield excitation of 20 GeV/m with good coherency. This is the first time‐resolved measurement of laser wakefield excitation in a gas‐jet plasma. The experimental results agree with the simulation results and linear theory. The pump‐probe interferometer system of FDI will be modified to the optical injection system as a relativistic electron beam injector. In 1D particle in cell simulation we obtain results of high quality intense electron beam generation.

A plasma lens experiment is planned at SLAC with high energy electron beams and high plasma density. We have developed a PIC code, SPLASH (Simulation of Plasma Lens and Synchrotron-radiation in Hybrid), for computer simulations of this experiment. The plasma lens focusing effects are simulated for the beam energy at 30 and 50 GeV and the plasma density between np/nb=0.1 and 100. The original bunch size is 3 and 5 μm in radius. Due to plasma focusing, the beam size is reduced, which is progressively more effective when the relative plasma density increases from the “underdense” regime to the “overdense” one. However, field compensation due to the plasma return current renders the plasma focusing effect suppressed when the plasma density further increases to the “superdense” regime. The beam waist is located between ±20 mm around the original focal point. In the most effective case, the beam is focused from 5 μm to 2 μm and from 3 μm to 1 μm.

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Successful engraftment by second cord blood transplantation with reduced-intensity conditioning after graft rejection due to hemophagocytic syndrome following initial CBT

Background: POEMS syndrome is a rare plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes associated with multiorgan involvement and monoclonal plasma cell dyscrasia. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF) probably secreted by plasma cells is considered to be responsible. High-dose melphalan (Mel) with autologous stem cell transplantation (ASCT) has been recently considered to be an effective strategy, but its treatment related mortality is considered to be high. Here, we report the results of ASCT for POEMS syndrome. Methods: Between January 2004 and June 2008, twelve patients with POEMS syndrome underwent ASCT at Chiba University Hospital and were retrospectively analyzed in the study. Conditioning treatment for ASCT was Mel 200 mg/m2, while Mel dose was reduced to 140 mg/m2 if a patient had poor performance status (PS). Results: Ten out of twelve patients were male and their median age was 48 years (range 34–61). Median time from first symptom and diagnosis to ASCT was 21 and 10 months, respectively. Seven patients received induction therapy before preparation of ASCT, thalidomide-dexamethasone in four, intravenous Mel in two, and bevacizumab followed by thalidomide in one patient. Peripheral blood stem cells were mobilized by cyclophosphamide/G-CSF in nine cases and G-CSF alone in three. Median serum VEGF level before ASCT was 2835 pg/ml (range; 334–5300). Median number of infused CD34+ cells was 2.3 × 106/kg (range; 2.1–4.3 × 106/kg). Eleven patients were conditioned with Mel 200 mg/m2, while one patient with poor PS (Karnofsky score 30%) received Mel 140 mg/m2. Median time to neutrophil recovery (>500/mm3) was 13 days post transplant (range 9–17 days). Only two patients developed respiratory distress during neutrophil engraftment period. Both cases were successfully treated with corticosteroid therapy, none of them required intubation. During a median follow up period of 16.5 months (range 2–54), there was no transplant related death. Neurologic improvement was significantly observed in all patients and median post transplantation serum VEGF level was decreased to 330 pg/ml (range 87–3250). Only one patient experienced relapse of polyneuropathy at 43 months post transplant following reincrease of serum VEGF level. Conclusions: ASCT is an effective therapy for POEMS syndrome. Despite previous published reports arousing potential risk of life-threatening engraftment syndrome, treatment related mortality and periengraftment pulmonary complications were significantly low in our patient series. We speculate that stabilization of serum VEGF level by induction therapy before ASCT could play a potential role for reducing the risk of peritransplant complications.

Background: POEMS syndrome (also known as Crow-Fukase or Takatsuki syndrome) is a rare plasma cell disorder characterized by peripheral neuropathy, a monoclonal plasma cell disorder, and other paraneoplastic features including organomegaly, endocrinopathy, skin changes, edema and effusions. High levels of vascular endothelial growth factor (VEGF) in the serum may contribute to pathology seen in this disease but exact pathogenetic mechanisms are still unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are virtually always λ-restricted. Here, we determined complete nucleotide sequences of monoclonal immunoglobulin λ light chain (IGL) variable regions in 10 patients with POEMS syndrome and found that Vλ germline usage is highly restricted to the Vλ1 family and oligoclonal germlines. Materials and methods: Total RNA was extracted from bone marrow mononuclear cells of patients with POEMS syndrome and the V-J region of the IGL gene was amplified by RT-PCR using 5′ degenerative primers for the Vλ consensus leader lesion (5′-ATGGCCKGSWYYSYTCTCCTC-3′) and 3′ primers matching the consensus upstream part of the cl exon (5′-CTCCCGGGTAGAGAAGTCACT-3′). Monoclonal bands were detected by heteroduplex analysis or TA cloning and subjected to nucleotide sequencing. Sequence data were analyzed using the International ImMunoGeneTics information system (IMGT, http://imgt.cines.fr) and mutations were identified by comparison with the germline sequence databases. Results: Of 13 POEMS syndrome patients with λ-type M protein, nucleotide sequencing of the IGL gene was successful in 10. The V-region of the IGL gene of all 10 patients was restricted to the Vλ1 family. Searching for homologies with IGL germlines revealed that only two were used, with an average homology of 90.1%. IGLV1-40*01 was used in 8 patients and IGLV1-44*01 in the remaining two. In the IGL-J region, the IGLJ3 gene was found in 9 of 10 patients and IGLJ2 in one (10%). All IGLV-J rearrangements were mutated with homologies to the germline sequence ranging from 77.66% to 96.10% (average homology: 90.1%). All CDR3 were composed of 11 amino acids, with identical acidic isoelectric point (pI) values (13.0) and similar molecular weights ranging from 1394.7 to 1552.8 (median, 1506.2). Conclusions: IGL-M protein in POEMS syndrome belongs to the Vλ1 family and is markedly restricted to specific oligoclonal germlines. Our results suggest that the restricted use of IGL plays an important role in the pathogenesis of POEMS syndrome. These data provide an important insight for elucidating the pathogenesis of POEMS syndrome. To the best of our knowledge, this the first report of restricted oligo-clonal usage of monoclonal immunoglobulin germlines in plasma cell disorders.

Introduction The MLL gene located on 11q13 is a frequent target of chromosomal translocation and induces acute leukemia with a poor prognosis. The ELL gene, one of partner genes with MLL translocation, is located on 19p13.1 and involved in about 5% of spontaneous acute leukemias and about 30% of secondary acute leukemias with MLL gene rearrangement. Here we present a case who had clonal expansion of MLL-ELL- positive cells in bone marrow (BM) with normal morphology after achieving complete remission (CR) and successfully underwent unrelated bone marrow transplantation (UR-BMT). We also analyzed the breakpoint of MLL-ELL by RT-PCR and sequencing and identified a novel type of breakpoint in MLL gene. Patient and methods A 32-years-old Japanese woman, who had no previous medical history, suffered from dyspnea and severe pancytopenia and referred to a hospital in Dec. 2001. BM aspiration showed hypercellular marrow with 89% of blasts which were positive for myeloperoxidase staining and expressed myeloid immunophenotypes (i.e. CD7, CD13, CD33, CD34 and HLA-DR), leading to the diagnosis of AML. BM cytogenetics revealed t(11;19)(q23;p13.1), along with trisomy 8. After one course of induction therapy, she achieved CR. BM cytogenetics showed normal chromosome (46, XX) and FISH analysis of MLL gene showed negative for MLL rearranged cells. Consolidation chemotherapies were carried out and BM aspirations showed CR throughout the entire course. However, repeated FISH analyses revealed the number of MLL rearrangement positive cells were gradually increasing without expanding of leukemic blasts. Since MLL-ELL positive leukemia shows a very poor prognosis, UR-BMT was planned through Japan Marrow Donor Program. She was re-admitted on April 2003. Before transplantation, her complete blood counts were normal and BM aspirate showed hypercellular marrow with 0.4% blasts with myeloid/erythroid ratio 4.5. There were no morphological abnormalities, however, cytogenetic study showed 100 % of cells were positive for t(11;19)(q23;p13.1) without trisomy 8. FISH analysis showed 90.1% of cells were positive for MLL rearrangement and negative for trisomy 8. She underwent UR-BMT successfully and is still alive in good health. We analyzed MLL-ELL gene rearrangement by RT-PCR and determined DNA sequence of MLL-ELL fusions. Results We obtained unexpected longer PCR products than that of previously reported and sequencing analysis revealed exon 12 of MLL gene fused to ELL gene, although it has been reported that exons 10 or 11 of MLL is fused in frame with ELL in most cases of MLL-ELL translocations. Discussion We identified new type of MLL gene breakpoint which contains exon 12 of MLL gene in MLL-ELL positive AML. This type of MLL fusion, which contains an intact PHD domain, may cause clonal expansion of MLL-ELL rearrangement positive cells with no obvious differentiation block. Now, we are analyzing biological differences between common type MLL-ELL and exon12 type MLL-ELL by using retroviral gene transfer system.

Relativistic electron scattering by a high intensity linearly polarized Gaussian (TEM00 mode) laser beam is studied in detail using three-dimensional numerical simulations. It is observed that the longitudinal components of the electromagnetic field in a tight focus effectively suppress transverse electron scattering in the relativistic laser ponderomotive acceleration scheme. The simulations show that the relativistic ponderomotive acceleration can produce high quality electron bunches characterized by an extremely short bunch length of subfemtosecond, energy spread less than 1%, and normalized transverse emittance less than 10πmmmrad.

A novel method for the preparation of Kyn 62-lysozyme, in which tryptophan 62 is replaced by kynurenine, is reported. Hen egg-white lysozyme was ozonized in aqueous solution to yield one N'-formylkynurenine residue and deformylated with hydrochloric acid in frozen solution at -10 degrees C. Crude Kyn 62-lysozyme was purified by affinity and Bio Rex 70 chromatography successively. Kyn 62-lysozyme retains affinity for chitin and is essentially an active enzyme with a slightly weakened but distinct catalytic activity. After this modification, the enzyme activity was changed differently depending on the kind of substrate. At the individual optimum pH's, lytic activity was largely retained (80% active), but the catalytic efficiency for hydrolyzing glycol chitin was relatively low (30% active). Lysis of M. lysodeikticus cell suspensions was optimally catalyzed by Kyn 62-lysozyme at pH 6.2 and at 0.088 ionic strength. These values are lower by 1.3 pH unit and 0.04 ionic strength, respectively, than those of intact lysozyme. The optimum pH and ionic strength for the hydrolysis of neutral substrates were scarcely affected. These results suggest the significance of electrostatic interaction in the lysis of lysozyme. Relatively limited loss of activity induced by modification of the 62nd residue, which is thought to participate directly in the binding of the substrate at subsite C, is discussed on the basis of the similarity of side chain structure in tryptophan and kynurenine.

Ethyl N-(2-pyridyl) formimidate (Va) reacted with diketene to give 3-acetyl-4H-pyrido [1, 2-a] pyrimidin-4-one (VIIa) and ethyl 2-(2-pyridylaminomethylene) acetoacetate (VIIIa). Reaction of diketene with ethyl N-(2-pyridyl) acetimidate (Vb) and ethyl N-(2-pyridyl) propionimidate (Vc) afforded 4H-pyrido [1, 2-a] pyrimidine derivatives (VIIb and VIIc), respectively. Similarly 2-benzylideneaminopyridine (VIa) reacted with diketene to give 3-acetyl-4-hydroxy-2-phenyl-4H-pyrido-[1, 2-a] pyrimidine (XI). On the other hand, reaction of trimethylsilyl isocyanate with Va, Vb, and Vc gave rise to 4H-pyrido [1, 2-a]-sym-triazin-4-one derivatives (XIXa, XIXb, and XIXc), respectively. Reaction of phenyl isocyanate with VIa afforded 2, 3-diphenyl-4H-pyrido [1, 2-a]-sym-2, 3-dihydrotrazin-4-one (XX).