パルボシクリブ併用内分泌治療が著効した閉経前再発乳癌の１例

　パルボシクリブ併用内分泌療法が著効した閉経前再発乳癌の１例を報告する．８年前に乳房温存手術を受け，残存乳房への放射線治療後に化学内分泌補助療法（シクロフォスファミド＋エピルビシン（CE 90）を４サイクル後に毎週パクリタキセルを４サイクル施行．化学療法終了後からLH-RH アゴニスト２年間とタモキシフェン５年間）を行った．治療継続中も含め定期で外来受診を継続しており，年１回の画像検査（肺，肝，骨を標的）と３か月ごとの腫瘍マーカー測定では再発の兆候はなく経過していた．しかし，補助治療終了後約３年で発熱と肝機能障害をきっかけに多発遠隔再発（肺・骨・肝・子宮体部）を発見した．ホルモン感受性は残存している可能性はあったが，急速な再発であるために，再発後初回治療としてドセタキセルおよびデノスマブの投与を開始した．有効ではあったが投与後約半年でマーカーの再上昇と体動時呼吸困難（在宅酸素療法導入）および疲労・倦怠感の増強が出現した．有害事象と病勢進行のため再発後の二次治療としてパルボシクリブ，フルベストラント，LH-RH アゴニストを導入した．導入後１か月で体動時呼吸困難が消失し，３か月で在宅酸素療法が中止できた．半年後のPET/CT で集積が消失しており画像上は著効と判断できた．有害事象は白血球・好中球減少が出現した以外に認めなかった．再発治療としてパルボシクリブ併用内分泌治療が有用であった．　We have a case of pre-menopausal patient with recurrent breast cancer showing an excellent response to endocrine therapy with palbociclib. Eight years ago, she underwent breast conserving operation followed by adjuvant chemo-endocrine therapy (4 cycles of cyclophosphamide and doxorubicin, 4 cycles of paclitaxel and tamoxifen adding LHRH agonist). The administration of tamoxifen continued for 5 years as an adjuvant therapy. After 3 years of discontinuation of adjuvant medication, fever and liver dysfunction led to find the recurrence of breast cancer in lung, bone, liver and uterus. We chose to treat with chemotherapy as the first line, because the recurrence was rash and multiple. After 6 months of treatment of docetaxel and denosumab, serum decreased tumor markers elevated gradually and dyspnea and general fatigue worsened. She recieved palbociclib, fluvestrant and LH-RH agonist as a second endocrine therapy. Six months after the treatment, PET/CT revealed an excellent effect on each metastatic lesion. Adverse event was only seen in neutropenia to make one-level reduction of dose. Palbociclib and endocrine therapy appeared to be useful as a second-line treatment for recurrent breast patient

Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates

Abstract The role of the influenza virus polymerase complex in host range restriction has been well-studied and several host range determinants, such as the polymerase PB2-E627K and PB2-D701N mutations, have been identified. However, there may be additional, currently unknown, human adaptation polymerase mutations. Here, we used a database search of influenza virus H5N1 clade 1.1, clade 2.3.2.1 and clade 2.3.4 strains isolated from 2008–2012 in Southern China, Vietnam and Cambodia to identify polymerase adaptation mutations that had been selected in infected patients. Several of these mutations acted either alone or together to increase viral polymerase activity in human airway cells to levels similar to the PB2-D701N and PB2-E627K single mutations and to increase progeny virus yields in infected mouse lungs to levels similar to the PB2-D701N single mutation. In particular, specific mutations acted synergistically with the PB2-D701N mutation and showed synergistic effects on viral replication both in human airway cells and mice compared with the corresponding single mutations. Thus, H5N1 viruses in infected patients were able to acquire multiple polymerase mutations that acted cooperatively for human adaptation. Our findings give new insight into the human adaptation of AI viruses and help in avian influenza virus risk assessment

Unsteady Wing-Pylon-Nacelle Interference in Transonic Flow

The interference effects between an unswept supercritical airfoil model and an annular wing representing an engine nacelle were investigated. The investigation aims to better understand and predict the impact of the interence effects on the aeroelastic stability of large, modern transport aircraft at transonic speeds. The main objective was to identify potential aerodynamic instabilities in the interference region due to unsteady shock-wave/boundary-layer interactions. The applied model allows to roll and yaw th nacell relative to the model wing and to pitch the entire model. The aerodynamic response to these movements affects the aeroelastic stability of an aircraft and was also investigated here. The overlap between the wing and the nacelle, and the height of the pylon were designed by numerical simulations such as that locally supersonic velocities and flow separation in the interference region might occur. Two linear hydraulic jacks inside the model were used to perform prescribed yaw and roll movements of the nacelle including the pylon. The experiments were conducted up to Mach numbers of 0.84 in an adaptive solid-wall wind tunnel using a hydraulic driven pitch-oscillation setup. Boundary-layer transition was tripped on the wing as well as on the nacelle. The unsteady tests reveal a strong dependency of the aerodynamic response to the structural movement on the topology of the time-averaged flow field. During the static tests, an aerodynamic instability was detected for certain Mach-number/model-incidence combinations. In addition to the initial objectives, a simple countermeasurement was applied in the interference region and its effectiveness was demonstrated