Incorporating participants' welfare into sequential multiple assignment randomized trials.

Dynamic treatment regimes (DTRs) are sequences of decision rules that recommend treatments based on patients' time-varying clinical conditions. The sequential, multiple assignment, randomized trial (SMART) is an experimental design that can provide high-quality evidence for constructing optimal DTRs. In a conventional SMART, participants are randomized to available treatments at multiple stages with balanced randomization probabilities. Despite its relative simplicity of implementation and desirable performance in comparing embedded DTRs, the conventional SMART faces inevitable ethical issues, including assigning many participants to the empirically inferior treatment or the treatment they dislike, which might slow down the recruitment procedure and lead to higher attrition rates, ultimately leading to poor internal and external validities of the trial results. In this context, we propose a SMART under the Experiment-as-Market framework (SMART-EXAM), a novel SMART design that holds the potential to improve participants' welfare by incorporating their preferences and predicted treatment effects into the randomization procedure. We describe the steps of conducting a SMART-EXAM and evaluate its performance compared to the conventional SMART. The results indicate that the SMART-EXAM can improve the welfare of the participants enrolled in the trial, while also achieving a desirable ability to construct an optimal DTR when the experimental parameters are suitably specified. We finally illustrate the practical potential of the SMART-EXAM design using data from a SMART for children with attention-deficit/hyperactivity disorder.

Incorporating ethics and welfare into randomized experiments.

Randomized controlled trials (RCTs) enroll hundreds of millions of subjects and involve many human lives. To improve subjects' welfare, I propose a design of RCTs that I call Experiment-as-Market (EXAM). EXAM produces a welfare-maximizing allocation of treatment-assignment probabilities, is almost incentive-compatible for preference elicitation, and unbiasedly estimates any causal effect estimable with standard RCTs. I quantify these properties by applying EXAM to a water-cleaning experiment in Kenya. In this empirical setting, compared to standard RCTs, EXAM improves subjects' predicted well-being while reaching similar treatment-effect estimates with similar precision.

Use of biologics for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

OBJECTIVES: Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated. METHODS: We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008-2021). RESULTS: In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year. CONCLUSIONS: Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common.

Clinical evaluation of a fully automated and high-throughput molecular testing system for detection of influenza virus.

INTRODUCTION: We investigated the performance of the cobas® 6800 system and cobas SARS-CoV-2 & Influenza A/B, a fully automated molecular testing system for influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This enabled an assay in a batch of 96 samples in approximately 3 h. METHODS: An assay was performed using the cobas SARS-CoV-2 & Influenza A/B on the cobas 6800 system for samples collected in four facilities between November 2019 and March 2020 in our previous study. The results were compared with those obtained using the reference methods. RESULTS: Of the 127 samples analyzed, the cobas SARS-CoV-2 & Influenza A/B detected influenza A virus in 75 samples, of which 73 were positive using the reference methods. No false negative results were observed. The overall positive and negative percent agreement for influenza A virus detection were 100.0% and 96.3%, respectively. There were no positive results for the influenza B virus or SARS-CoV-2. CONCLUSION: The cobas 6800 system and cobas SARS-CoV-2 & Influenza A/B showed high accuracy for influenza A virus detection and can be useful for clinical laboratories, especially those that routinely assay many samples.

Use of mycophenolate mofetil in patients with pediatric and adult primary nephrotic syndrome: information from a Japanese hospital claims database.

BACKGROUND: Current treatment for frequently relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome focuses on immunosuppressive therapies. Although the clinical guideline suggests the use of mycophenolate mofetil (MMF), limited information is available on patients with primary nephrotic syndrome who receive off-label treatment with MMF in Japan. METHOD: The dose, treatment duration, previous treatment, and characteristics of primary nephrotic syndrome patients receiving MMF were investigated using data from a Japanese hospital claims database (April 2008-September 2021). RESULTS: Data on 424 primary nephrotic syndrome patients receiving MMF (146 patients < 18 years old; 278 patients ≥ 18 years old) were captured. The most common initial daily doses of MMF capsules (% of patients < 18 and ≥ 18 years old) were 1000 mg (31.9%, 36.8%), 1500 mg (16.0%, 23.8%), and 500 mg (23.6%, 17.3%), and the most common maximum daily doses were 1000 mg (43.8%, 32.9%), 1500 mg (23.6%, 28.9%), and 2000 mg (6.3%, 16.2%). Most patients (97.9%, 99.3%) were treated with a daily dose of 2000 mg or less. Among patients < 18 years old, the younger the patient, the lower the dose. MMF was used for more than 1 year in 30.8% of patients < 18 years old and in 28.8% of patients ≥ 18 years old. CONCLUSIONS: Our study suggested that off-label use of MMF for primary nephrotic syndrome has increased since 2012 in Japan. The dose of MMF used in patients with primary nephrotic syndrome was generally within the approved dose range for lupus nephritis and transplant-related diseases in Japan.

Use of mycophenolate mofetil for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

OBJECTIVES: Limited information is available on patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) receiving mycophenolate mofetil (MMF) in Japan. The dose, treatment duration, and patient characteristics of SSc and SSc-ILD patients receiving MMF were investigated. METHODS: We used data from a Japanese hospital claims database (2008-2020). RESULTS: Data on 486 SSc patients ≥18 years old receiving MMF were captured; 314 had SSc complicated with ILD. The most common initial daily doses were 1000 mg (SSc, 39.5%; SSc-ILD, 38.1%) and 500 mg (SSc, 36.6%; SSc-ILD, 34.6%). The most common maximum daily doses were 1000 mg (SSc, 33.3%; SSc-ILD, 34.9%), 1500 mg (SSc, 24.4%; SSc-ILD, 23.1%), and 2000 mg (SSc, 23.8%; SSc-ILD, 24.4%). Doses ranged from 250 to 3000 mg/day and were similar for SSc and SSc-ILD patients. Over 27% of patients received treatment for >1 year. There was a gradual decrease in steroid doses during MMF treatment. CONCLUSIONS: Our study suggests that the off-label use of MMF for SSc and SSc-ILD has been increasing annually since 2015 in Japan. The doses used in patients with SSc and SSc-ILD were similar to the approved doses of MMF for lupus nephritis in Japan.

Multicenter evaluation of molecular point-of-care testing and digital immunoassays for influenza virus A/B and respiratory syncytial virus in patients with influenza-like illness.

INTRODUCTION: Digital immunoassays (DIAs) and molecular point-of-care (POC) tests for influenza were recently developed. We aimed to evaluate and compare the positive rate with molecular POC tests and DIAs in detecting influenza virus A, B and respiratory syncytial virus (RSV). METHODS: A prospective observational study was conducted in 2019-2020. Nasopharyngeal swab samples were collected from adult outpatients with influenza-like illness who visited four hospitals and clinics in Japan. DIAs were performed at each facility. The clinical diagnosis was determined based on the findings of DIAs, history taking, and physical assessment. Molecular POC test and reverse transcription polymerase chain reaction (RT-PCR) were performed later. RESULTS: A total of 182 patients were evaluated. The positive rate for influenza virus with molecular POC test was significantly higher than that with DIAs (51.6% versus 40.7%, p = 0.046). In patients who tested positive for influenza virus with only molecular POC test, the presence of influenza virus was confirmed by RT-PCR. In a comparison between the patients who were positive for influenza virus with only molecular POC test and those with both molecular POC test and DIA, the percentage of patients who sought consultation within 18 h after the onset of symptoms was significantly higher in the molecular POC test only group than in the both methods group (70.0% versus 43.2%, p = 0.044). CONCLUSIONS: A molecular POC test could contribute to the accurate diagnosis of influenza in patients with influenza-like illness, especially those who visited a hospital immediately after the onset of symptoms.

[Successful treatment of post-allogeneic hematopoietic transplant immune thrombocytopenia with eltrombopag].

A 44-year-old woman in the first remission phase of mixed-phenotype acute leukemia (T-lymphoid and myeloid lineages) suddenly exhibited thrombocytopenia (1.1×104/µl) with generalized petechiae approximately 150 days after bone marrow transplantation (BMT) from a one-locus (HLA-B) mismatched unrelated donor. Until then, the donor bone marrow had smoothly engrafted, and the platelet count had promptly normalized. Despite extensively searching for the triggering agent such as GVHD, graft failure, relapsed leukemia, or adverse drug effects, it could not be determined. Suspecting immune thrombocytopenia secondary to BMT, prednisolone (1 mg/kg/2 days) therapy was initiated, but its effects were unsatisfactory. Next, eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was administered, which exhibited a marked effect on thrombocytopenia, resulting in the withdrawal of prednisolone. Even though the efficacy of eltrombopag against immune thrombocytopenia is well established, limited studies have reported the efficacy and safety of eltrombopag against immune thrombocytopenia after allogeneic stem cell transplantation. Herein we report a case in which thrombocytopenia occurred late after transplantation but was successfully treated with a TPO-RA. In addition, we discuss suspected causative mechanisms and review the literature.

P2Y6 receptor-Galpha12/13 signalling in cardiomyocytes triggers pressure overload-induced cardiac fibrosis.

Cardiac fibrosis, characterized by excessive deposition of extracellular matrix proteins, is one of the causes of heart failure, and it contributes to the impairment of cardiac function. Fibrosis of various tissues, including the heart, is believed to be regulated by the signalling pathway of angiotensin II (Ang II) and transforming growth factor (TGF)-beta. Transgenic expression of inhibitory polypeptides of the heterotrimeric G12 family G protein (Galpha(12/13)) in cardiomyocytes suppressed pressure overload-induced fibrosis without affecting hypertrophy. The expression of fibrogenic genes (TGF-beta, connective tissue growth factor, and periostin) and Ang-converting enzyme (ACE) was suppressed by the functional inhibition of Galpha(12/13). The expression of these fibrogenic genes through Galpha(12/13) by mechanical stretch was initiated by ATP and UDP released from cardiac myocytes through pannexin hemichannels. Inhibition of G-protein-coupled P2Y6 receptors suppressed the expression of ACE, fibrogenic genes, and cardiac fibrosis. These results indicate that activation of Galpha(12/13) in cardiomyocytes by the extracellular nucleotides-stimulated P2Y(6) receptor triggers fibrosis in pressure overload-induced cardiac fibrosis, which works as an upstream mediator of the signalling pathway between Ang II and TGF-beta.

Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm.

PURPOSE: We compared overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-amplified, treatment-refractory metastatic colorectal cancer (mCRC) receiving pertuzumab plus trastuzumab (PER-HER) in the phase IIa MyPathway multibasket study (ClinicalTrials.gov identifier: NCT02091141) with OS in those receiving routine clinical care in an electronic health record-derived external control arm. METHODS: A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with HER2-amplified treatment-refractory mCRC receiving routine clinical care. This study used a deidentified US-based clinico-genomic database (CGDB). For patients in the CGDB who met study eligibility criteria at multiple index dates (treatment initiation dates in the treatment-refractory setting), all eligible index dates were used for the analysis. Standardized mortality ratio weighting on the basis of propensity score derived a pseudopopulation (postweighting population) balancing key prognostic variables between arms. Multivariate Cox proportional hazards models were used for estimation of the hazard ratio (HR) in the primary OS analysis. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis. RESULTS: The PER-HER arm comprised 57 patients enrolled in the MyPathway study by August 1, 2017 (data cutoff); the external control arm comprised 18 patients (27 index dates) with HER2-amplified mCRC who met the major MyPathway eligibility criteria in CGDB collected between 2011 and 2019. The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR. CONCLUSION: Despite a small sample size, these findings suggest that PER-HER could have a potential OS benefit for this population.

Preparation of Magnetic Hydrogel Microparticles with Cationic Surfaces and Their Cell-Assembling Performance.

Cationic magnetic hydrogel microparticles with high retention on cell surfaces were prepared using a two-step procedure. Using these magnetic hydrogel microparticles, cells were clustered with each other, and cell aggregates were prepared effectively. Cross-linked poly(vinyl alcohol) (PVA) hydrogel microparticles containing iron oxide nanoparticles were prepared. The diameter of the microparticles was in the range of 200-500 nm. Water-soluble cationic polymers containing both trimethyl ammonium (TMA) groups and phenylboronic acid (PBA) groups were synthesized for the surface modification of the microparticles. To regulate the composition, electrically neutral phosphorylcholine groups were introduced into the polymer. Covalent bonds were formed between the hydroxy groups of PVA microparticles and PBA groups in the polymer. The surface zeta potential of the microparticles reflected the composition of the TMA groups. The particles responded to an external magnetic field and clustered rapidly. Microparticles were adsorbed on the floating cell surface and induced cell aggregation quickly when a magnetic field was applied. Under the most effective conditions, the diameter of the cell aggregates increased to approximately 1 mm after 30 min. Denser cell aggregates were formed by the synergistic effects of the magnetic field and the properties of the microparticles. The formed cell aggregates continued to grow for more than 4 days under an applied magnetic field, indicating that the ability of the cells in the aggregate to proliferate was well maintained.

[A case of Wegener's granulomatosis with seronegative for PR-3 ANCA and seropositive for MPO-ANCA].

A 60-year-old woman was admitted with low fever, dry cough and occult hematuria with abnormality on her chest X-ray film showing patchy shadows in the apices of both lungs. The patient was seronegative for PR-3 ANCA and seropositive for MPO-ANCA and transbronchial lung biopsy showed inflammatory granulation tissue. We performed an open lung biopsy to achieve a definitive diagnosis. The lung specimen showed the typical findings of Wegener's granulomatosis. Renal biopsy revealed necrotizing glomerulonephiritis. A systemic form of Wegener's granulomatosis was diagnosed. Initilal treatment combined oral prednisolone at 30 mg daily with oral cyclophosphamide at 50 mg daily improved not only the clinical course, but also the radiographic findings. Finally, she became seronegative for MPO-ANCA.

[Recurrence of the acute respiratory distress syndrome (ARDS) in a patient with Sai-rei-to-induced pneumonitis].

An 83-year-old woman was admitted to our hospital because of fever and difficulty in walking with marked hypoxemia and diffuse ground glass opacities in bilateral lung fields by chest radiography and CT scanning. Treatment with antibiotics and corticosteroids resulted in improvement of the clinical findings and successful weaning from mechanical ventilation. At first, we diagnosed severe mycoplasma pneumonia because of a 2560 titer in a particle agglutiation (PA) test. Five days after discharge, she was given a second emergency admission, because of fever and difficulty in walking. Chest X-ray film revealed improvement after administration of methylprednisolone. Her detailed medical history proved that she had been treated with a Chinese herbal drug, Sai-rei-to, for several weeks before first admission. We finally diagnosed her disease as Sai-rei-to-induced pneumonitis. Despite intensive treatment, she finally died. The histopathological findings (H-E stain) of the autopsied lungs showed hyaline membrane formation and hyperplasia of type II alveolar epithelium cells, so-called, diffuse alveolar damage. This case and other referred in the literature suggest that Sai-rei-to-induced pneumonitis can become severe.

[Case of bilateral chylothorax with systemic lupus erythematosus complicated by steroid-/immunosuppressant-resistant pleural effusion].

A 20-year-old woman, with systemic lupus erythmatosus complicated by steroid-and immunosuppressant-resistant bilateral pleural effusion, was admitted to the emergency room because of dyspnea and fever. Chest Xray film revealed bilateral massive pleural effusion. Bilateral thoracocentesis yielded fluid with chyle. Conservative treatment including intravenous hyper-alimentation and continuous drainage were performed but with no remarkable improvement. She underwent thoracoscopy-aided ligation of the thoracic duct. After the operation, bilateral pleurodesis was performed by intrathoracic injection of OK-432, because of uncontrolled pleural effusion. There have been no signs of recurrence at 10 months in this case of SLE with steroid-and immunosuppressant-resistant pleural effusion.

[Pulmonary injury by an over-the-counter drug, Nospole G].

A 78-year-old woman was admitted with dyspnea. She had caught a cold and took an over-the-counter drug (Nospole G) for 2 weeks before admission. Chest radiography and CT scanning showed bilateral diffuse and interstitial shadows, and arterial blood gas analysis demonstrated severe hypoxemia. Withdrawal of Nospole and treatment with both corticosteroid and sivelestat sodium resulted in improvement of clinical findings and successful recovery from mechanical ventilation. A drug lymphocyte stimulation test for Nospole G was positive. Based on these findings, we determined that this patient had drug-induced pneumonitis caused by Nospole G. Finally, she died of sepsis caused by multidrug-resistant Staphylococcus aureus (MRSA) infection. In summary, we report here an elderly case of drug-induced pneumonitis successfully weaned from mechanical ventilation by early treatment with corticosteroid and sivelestat sodium, monitored by changes of markers for interstitial pneumonitis (KL-6, SP-A, SP-D).

[A case of legionella pneumonia associated with acute respiratory distress syndrome (ARDS) and acute renal failure treated with methylprednisolone and sivelestat].

A 48-year-old man with diabetes mellitus and alcholic chronic pancreatitis was admitted to our hospital with fever and dyspnea. Chest x-ray film showed infiltration of the right upper lung field and blood exam demonstrated marked increase in CPK and renal dysfunction. Intravenous ceftriaxone sodium was started, but the next day, we started intravenous ciprofloxacin because the urine sample was positive for the Legionella antigen. Hemodialysis was started for acute renal failure due to rhabdomyolysis, and mechanical ventilation was introduced due to worsening of acute respiratory failure. Despite these treatments, bilateral infiltration on chest x-ray worsened, resulting in acute respiratory distress syndrome (ARDS). After administration of intravenous pulse methylpredonisolone and sivelestat (neutrophil elastase inhibitor), the patient was successfully weaned from mechanical ventilation. He was also removed from hemodialysis, and discharged from hospital with a good performance status 28 days later. The outcome in this case suggested that treatment with pulse steroid and sivelestat sodium in addition to antibiotics may be effective for Legionella pneumonia complicated by ARDS and acute renal failure.

[Perforation of the small intestine caused by metastasis from primary lung cancer: report of two cases and the discussion of 48 cases published in the Japanese literature].

Case 1 was a 62-year-old man who had performance status (PS) of 1 and stage IIIB adenocarcinoma of the lung. Because he showed progressive disease after induction chemoradiotherapy, he started to receive best supportive care alone. Three months after initial diagnosis, he complained of abdominal pain. As a result of computed tomography of the abdomen. He was diagnosed with abdominal pain probably caused by ileal perforation. An operation was undertaken and the surgical findings showed perforation by small intestine metastasis from lung adenocarcinoma. After the operation, he survived more than ten months. Case 2 was a 54-year-old man who had a PS of 3 and stage IV large cell carcinoma. After chemotherapy and sequential cranial radiotherapy, he developed anemia of unknown cause. He also complained of an abdominal pain during hospitalization and digestive tract perforation was diagnosed by a CT scan of the abdomen. He underwent surgery and the surgical findings showed a metastasis of large cell carcinoma in the small intestine. He died in a hospice two months after the operation. In the Japanese literature from 1983 to 2006. 48 operated cases with perforation caused by small intestine metastasis of lung cancer have been reported in full-length papers. Although the postoperative median survival time was 48 days, only one surgery-related death occurred. Patients who had a history of prior cancer treatment before surgery tended to achieve more prolonged survival compared to those who had not cancer treatment, probably due to poor PS. The preoperative PS may be one important prognostic factor in these patients.

Structure of the carboxypeptidase Y inhibitor IC in complex with the cognate proteinase reveals a novel mode of the proteinase-protein inhibitor interaction.

Carboxypeptidase Y (CPY) inhibitor, IC, shows no homology to any other known proteinase inhibitors and rather belongs to the phosphatidylethanolamine-binding protein (PEBP) family. We report here on the crystal structure of the IC-CPY complex at 2.7 A resolution. The structure of IC in the complex with CPY consists of one major beta-type domain and a N-terminal helical segment. The structure of the complex contains two binding sites of IC toward CPY, the N-terminal inhibitory reactive site (the primary CPY-binding site) and the secondary CPY-binding site, which interact with the S1 substrate-binding site of CPY and the hydrophobic surface flanked by the active site of the enzyme, respectively. It was also revealed that IC had the ligand-binding site, which is conserved among PEBPs and the putative binding site of the polar head group of phospholipid. The complex structure and analyses of IC mutants for inhibitory activity and the binding to CPY demonstrate that the N-terminal inhibitory reactive site is essential both for inhibitory function and the complex formation with CPY and that the binding of IC to CPY constitutes a novel mode of the proteinase-protein inhibitor interaction. The unique binding mode of IC toward the cognate proteinase provides insights into the inhibitory mechanism of PEBPs toward serine proteinases and into the specific biological functions of IC belonging to the PEBP family as well.

A combination chemotherapy of carboplatin and irinotecan with granulocyte colony-stimulating factor (G-CSF) support in elderly patients with small cell lung cancer.

BACKGROUND: We have previously reported that carboplatin plus etoposide is an effective and relatively non-toxic regimen in elderly patients with small cell lung cancer (SCLC). Recently, the Japan Clinical Oncology Group reported that irinotecan plus cisplatin was more effective than etoposide plus cisplatin in the treatment of non-elderly patients with extensive disease (ED)-SCLC. Therefore, we conducted a prospective feasibility study designed specifically to evaluate the efficacy of carboplatin (day 1) and irinotecan (days 1, 8, 15) with granulocyte colony-stimulating factor (G-CSF) support in elderly SCLC patients. METHODS: Three carboplatin AUC and irinotecan dose levels were used: 4 mg/ml x min and 50 mg/m2, respectively (level 1); 5 mg/ml x min and 50 mg/m2, respectively (level 2), and 5 mg/ml x min and 60 mg/m2, respectively (level 3). Although a phase I trial using this drug combination against non-SCLC performed at our institution found that the recommended dose was level 3, as the current trial included only elderly patients, the starting dose used was level 2. However, if a patient had history of prior chemotherapy, performance status (PS) of 2, or was aged 75 years or more, the dose administered was reduced by 1 level. If a patient had a PS of 0, the dose was increased by 1 level. Cycles were repeated every 4 weeks, and patients aged 70 years or more with a PS of 0-2 were eligible. RESULTS: Eighteen patients were enrolled, of which nine were given the level 1 dose, seven the level 2 dose, and two the level 3 dose. The patient group had a median age of 75 years, 8 patients had limited disease (LD) versus 10 with ED, 9 had received previous treatment for SCLC versus 9 previously untreated, and 13 had a PS of 0-1 versus 5 with a PS of 2. Seventeen (94%) patients received two or more cycles of chemotherapy, and the median actual delivery of irinotecan was 84% of the projected dose. Grade 3/4 neutropenia, anemia, and diarrhea occurred in 50%, 33% and 6% of patients, respectively. Other toxicities were mild and no treatment-related deaths occurred. The response rate was 89%, with two complete responses and 14 partial responses. The median survival time was 13.3 months and the 1-year survival rate was 62%. CONCLUSIONS: The combination of carboplatin and irinotecan with G-CSF support was an effective and non-toxic regimen in elderly SCLC patients and should be further evaluated in phase III trials.

Beta-arrestin2 enhances beta2-adrenergic receptor-mediated nuclear translocation of ERK.

Beta-arrestin mediates desensitization and internalization of beta-adrenergic receptors (betaARs), but also acts as a scaffold protein in extracellular signal-regulated kinase (ERK) cascade. Thus, we have examined the role of beta-arrestin2 in the betaAR-mediated ERK signaling pathways. Isoproterenol stimulation equally activated cytoplasmic and nuclear ERK in COS-7 cells expressing beta1AR or beta2AR. However, the activity of nuclear ERK was enhanced by co-expression of beta-arrestin2 in beta2AR-but not beta1AR-expressing cells. Pertussis toxin treatment and blockade of Gbetagamma action inhibited beta-arrestin2-enhanced nuclear activation of ERK, suggesting that beta-arrestin2 promotes nuclear ERK localization in a Gbetagamma dependent mechanism upon receptor stimulation. beta2AR containing the carboxyl terminal region of beta1AR lost the beta-arrestin2-promoted nuclear translocation. As the carboxyl terminal region is important for beta-arrestin binding, these results demonstrate that recruitment of beta-arrestin2 to carboxyl terminal region of beta2AR is important for ERK localization to the nucleus.