Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/µL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.

[A Patient with Recurrent Invasive Thymoma Obtaining Long-Term Survival by Chemotherapy with Amrubicin Alone as the Third Treatment].

The patient was a 68-year-old woman. She was diagnosed with invasive thymoma 12years prior and underwent chemoradiotherapy( adriamycin, cisplatin, vincristine, and cyclophosphamide: ADOC)plus radiation exposure(62G y). After 11 years, the disease relapsed. Carboplatin plus paclitaxel(CP)therapy as a second-line therapy was ineffective, leading to enlargement of the primary tumor and the development of pleurisy. The third-line treatment with a single dose of amrubicin resulted in good disease control. There were no serious adverse events, and the drug tolerance was good. The patient has undergone 21courses of this treatment as of the time of this report and continues to maintain complete response(CR). No chemotherapy regimen as more than a second-line therapy demonstrated efficacy against recurrent thymoma. Amrubicin monotherapy may be an effective treatment option that may result in long-term survival with minor side effects.

[A Case in Which Toxic Epidermal Necrosis Developed during Treatment with the Immune Checkpoint Inhibitor Pembrolizumab for Recurrent Patients Following Lung Cancer Surgery].

The patient was a 66-year-old male. Following surgery for pulmonary adenocarcinoma in the upper right lobe and adjuvant chemotherapy, the patient relapsed. We carried out treatment using the immune checkpoint inhibitor pembrolizumab (KEYTRUDA®)for high expression of PD-L1. Following the first administration, severe drug eruption occurred and despite temporary improvement seen by intravenous infusion of steroids in combination with oral administration and external use thereof, it relapsed in the early stages and toxic epidermal necrosis developed. Skin problems were improved by multidisciplinary treatments such as gammaglobulin therapy, systemic steroid administration, and broad-spectrum antibiotics. There were no reports oftoxic epidermal necrosis occurring during pembrolizumab administration for lung cancer. This case went through a unique course in which the disease relapsed into a more severe condition at an early stage following temporary remission.

[A Case in Which Good Control of Carcinomatous Serositis Was Achieved Using Chemotherapy Including Albumin-Bound Paclitaxel(Nab-PTX)for Advanced-Stage Pulmonary Adenocarcinoma Exhibiting Carcinomatous Pleurisy and Carcinomatous Pericarditis].

The subject was a 63-year-old man. The patient was transported by ambulance to the hospital because of dyspnea caused by carcinomatous pleurisy and carcinomatous pericarditis, after which pericardial drainage was performed; however, Staphylococcus aureus bacteremia arose as a complication. Adequate control of carcinomatous serositis was achieved usingchemotherapy, includingalbumin -bound paclitaxel(nab-PTX), which is a nanoparticle formulation bindinghuman serum albumin and paclitaxel, in combination with 1 course of antibiotics. For cancerous serositis cases, platinum combination chemotherapy usingnab -PTX is believed to be 1 treatment option in which good disease control can be expected along with bevacizumab, whose efficacy has already been confirmed.

Identification of MK-1925: a selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist.

Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.

Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists.

The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.

A novel class of cycloalkano[b]pyridines as potent and orally active opioid receptor-like 1 antagonists with minimal binding affinity to the hERG K+ channel.

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.

Design, synthesis, and structure-activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine.

Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.

Asymmetric total syntheses of (+)-cheimonophyllon e and (+)-cheimonophyllal.

The highly enantiocontrolled total syntheses of natural (+)-cheimonophyllon E (5) and (+)-cheimonophyllal (6), biologically intriguing oxygenated bisabolane-type sesquiterpenoids, have been completed. The present synthetic strategy featured the use of an asymmetric aldol-type reaction for preparing in the first synthetic step an optically active 6-C-substituted 3-methyl-2-cyclohexenone derivative. Thus, a Mukaiyama aldol reaction of 1-methyl-3-silyloxy-1,3-cyclohexadiene 31 with alpha,beta-unsaturated aldehyde 11 in the presence of a chiral (acyloxy)borane (CAB)-type Yamamoto catalyst 33 proceeded with high levels of both diastereo- and enantioselectivities. The predominant aldol adduct, syn-9, was transformed into gamma,delta-epoxy allylic alcohol 8 by a nine-step sequence, including the substrate-controlled 1,2-reduction of enone, syn-12, also the epoxidation of allylic alcohol 15. Epoxy-alcohol 8 underwent 5-exo-cyclization in a high regioselective manner under acidic conditions to produce a bicyclic key intermediate (+)-7, which was eventually efficiently converted to (+)-cheimonophyllon E (5) or (+)-cheimonophyllal (6).