Effect of the third dose of BNT162b2 COVID-19 mRNA vaccine on anti-SARS-CoV-2 antibody levels in healthcare workers.

PURPOSE: Administration of three doses of Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine was completed in Japan in the spring of 2022. This study aimed to evaluate the antibody responses, and kinetics of three doses of vaccine in healthcare workers (HCWs). PATIENTS AND METHODS: We conducted a longitudinal cohort study with HCWs, who had no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, from a single hospital. Immunoglobulin G (IgG) titers of anti-SARS-CoV-2 spike protein (SP) and nucleocapsid protein (NP) titers were measured using an automated chemiluminescent enzyme immunoassay system. RESULTS: A total of 636 HCWs participated in the study. The anti-SP IgG titers decreased slowly after the second dose of the BNT162b2 vaccine in all participants, and robust antibody response was observed after the third dose of the vaccine. The peak anti-SP IgG titer after the third dose was approximately 4.1-fold higher than that after the first and second doses, and the rate of decrease in the anti-SP IgG titer after the third dose was significantly more gradual, than that after the second dose. After the second dose of vaccine, the antibody response was weaker in older participants than in younger participants, and in males than in females respectively, whereas the response to the third dose of vaccine did not differ significantly by sex or age. Adverse events following immunization were generally mild to moderate. CONCLUSION: The third dose of the BNT162b2 vaccine induced a significant and sustained increase in anti-SP IgG titers, and was generally safe and well-tolerated.

Muscarinic M3 positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats.

OBJECTIVES: Muscarinic M3 (M3 ) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M3 receptors for micturition disorders have a risk of cholinergic side effects due to excessive receptor activation and insufficient selectivity. We investigated the effect of ASP8302, a novel positive allosteric modulator (PAM) of M3 receptors, on bladder function in rats. METHODS: Modulation of carbachol-induced increases in intracellular Ca2+ was assessed in cells expressing rat muscarinic receptors. Potentiation of bladder contractions was evaluated using isolated rat bladder strips and by measuring intravesical pressure in anesthetized rats. Conscious cystometry was performed to investigate the effects on residual urine volume and voiding efficiency in rat voiding dysfunction models induced by the α1 -adrenoceptor agonist midodrine and muscarinic receptor antagonist atropine, and bladder outlet obstruction. To assess potential side effects, the number of stools and tracheal insufflation pressure were measured in conscious and anesthetized rats, respectively. RESULTS: ASP8302 demonstrated PAM effects on the rat M3 receptor in cell assays, and augmented cholinergic bladder contractions both in vivo and in vitro. ASP8302 improved voiding efficiency and reduced residual urine volume in two voiding dysfunction models as effectively as distigmine bromide, but unlike distigmine bromide did not affect the number of stools or tracheal insufflation pressure. CONCLUSIONS: Our results in rats indicate that ASP8302 improves voiding dysfunction by potentiating bladder contraction with fewer effects on cholinergic responses in other organs, and suggest a potential advantage over current cholinomimetic drugs for treating micturition disorders caused by insufficient bladder contraction.

Potentiation of Muscarinic M3 Receptor Activation through a New Allosteric Site with a Novel Positive Allosteric Modulator ASP8302.

Muscarinic M3 (M3) receptors mediate a wide range of acetylcholine (ACh)-induced functions, including visceral smooth-muscle contraction and glandular secretion. Positive allosteric modulators (PAMs) can avoid various side effects of muscarinic agonists with their spatiotemporal receptor activation control and potentially better subtype selectivity. However, the mechanism of allosteric modulation of M3 receptors is not fully understood, presumably because of the lack of a potent and selective PAM. In this study, we investigated the pharmacological profile of ASP8302, a novel PAM of M3 receptors, and explored the principal site of amino-acid sequences in the human M3 receptor required for the potentiation of receptor activation. In cells expressing human M3 and M5 receptors, ASP8302 shifted the concentration-response curve (CRC) for carbachol to the lower concentrations with no significant effects on other subtypes. In a binding study with M3 receptor-expressing membrane, ASP8302 also shifted the CRC for ACh without affecting the binding of orthosteric agonists. Similar shifts in the CRC of contractions by multiple stimulants were also confirmed in isolated human bladder strips. Mutagenesis analysis indicated no interaction between ASP8302 and previously reported allosteric sites; however, it identified threonine 230 as the amino acid essential for the PAM effect of ASP8302. These results demonstrate that ASP8302 enhances the activation of human M3 receptors by interacting with a single amino acid distinct from the reported allosteric sites. Our findings suggest not only a novel allosteric site of M3 receptors but also the potential application of ASP8302 to diseases caused by insufficient M3 receptor activation. SIGNIFICANCE STATEMENT: The significance of this study is that the novel M3 receptor positive allosteric modulator ASP8302 enhances the activation of human M3 receptor by interacting with a residue distinct from the reported allosteric sites. The finding of Thr230 as a novel amino acid involved in the allosteric modulation of M3 receptors provides significant insight into further research of the mechanism of allosteric modulation of M3 and other muscarinic receptors.

Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m2; days 1 and 8, vinorelbine 20 mg/m2). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period. RESULTS: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%. CONCLUSION: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma.

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (Ctrough) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the Ctrough of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.

Randomized phase II trial of adjuvant chemotherapy with docetaxel plus cisplatin versus paclitaxel plus carboplatin in patients with completely resected non-small cell lung cancer: TORG 0503.

OBJECTIVE: Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, optimum chemotherapy regimen has not been determined. TORG0503 was undertaken to select a preferred platinum-based 3rd generation regimen in this clinical setting. MATERIALS AND METHODS: Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institutions, and randomized to receive 3 cycles of docetaxel (60 mg/m2) plus cisplatin (80 mg/m2) (arm A) or paclitaxel (200 mg/m2) plus carboplatin (AUC 6) (arm B) on day 1, every 3 weeks. The primary endpoint of the study was 2-year relapse free survival, and the key secondary endpoints included overall survival, feasibility and toxicity. RESULTS: 111 patients were randomized, 58 patients to arm A and 53 to arm B. Patient demographics were balanced between the two arms. 93 % (54/58) of patients on the arm A and 92 % (49/53) patients on the arm B completed the planned 3 cycles of chemotherapy. There was no treatment-related death in both arms. The 2 and 5 year relapse free survival was 74.5 % (95 %CI: 68.6-80.4) and 61.6 % in the arm A, and 72.0 % (95 %CI: 65.7-78.3) and 46.0 % in the arm B. The overall 2, 5-year survival was 89.7 %, 73.9 % in the arm A and 86.9 %, 67.5 % in the arm B. CONCLUSION: Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy. We choose docetaxel plus cisplatin as the control regimen for the next clinical trial.

Prognostic significance of IMMT expression in surgically-resected lung adenocarcinoma.

BACKGROUND: Mitochondrial dysfunction contributes to many types of human disorders and cancer progression. Inner membrane mitochondrial protein (IMMT) plays an important role in the maintenance of mitochondrial structure and function. The aims of this study were to examine IMMT expression in lung adenocarcinoma and evaluate its correlation with clinicopathological parameters and patient prognosis. METHODS: IMMT expression was immunohistochemically studied in 176 consecutive lung adenocarcinoma resection tissues, and its correlations with clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox-proportional hazards models were used to estimate the effect of IMMT expression on survival. RESULTS: High-IMMT expression was detected in 84 of 176 (47.7%) lung adenocarcinomas. Levels were significantly correlated with advanced disease stage (stage II and III; P = 0.024), larger tumor size (>3 cm; P = 0.002), intratumoral vascular invasion (P < 0.001), and poorer adenocarcinoma patient prognosis (P = 0.002). Based on 176 patients with adenocarcinoma, multivariate analysis revealed that IMMT expression was an independent predictor of poorer survival (HR, 1.99; 95% confidence interval [CI], 1.06-3.74; P = 0.031). Further, treating A549 cells derived from lung adenocarcinoma, with IMMT siRNA resulted in significantly decreased proliferation. CONCLUSION: Here, we first demonstrated that high-IMMT expression is related to some clinicopathological parameters, and that its expression is an independent prognostic predictor of poorer survival in patients with lung adenocarcinoma; further studies are required to clarify the biological function of IMMT in lung adenocarcinoma. However, results suggest that this protein could be a novel prognostic indicator and therapeutic target.

Successful Desensitization with Crizotinib after Crizotinib-induced Liver Injury in ROS1-rearranged Lung Adenocarcinoma.

Crizotinib has been approved for patients with advanced lung adenocarcinoma harboring rearrangements of the c-ROS-1 (ROS1) and anaplastic lymphoma kinase (ALK) genes. We report a patient with ROS1-rearranged lung adenocarcinoma who developed a crizotinib-induced mixed/cholestatic type of liver injury. The patient discontinued crizotinib after 34 days due to liver toxicity. Twenty-four days later, when transaminases and C reactive protein (CRP) were normalized, crizotinib was resumed using an oral desensitization method. The patient was successfully treated for manageable recurrence of liver injury and has been able to continue the treatment.

Modulation of urinary frequency via type 1 lysophosphatidic acid receptors: Effect of the novel antagonist ASP6432 in conscious rats.

Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA1) receptor, suggesting the potential of the LPA1 receptor as a therapeutic target. However, the role of LPA and the LPA1 receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA1 receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}- 1,3-thiazole-4-carbonyl)- 3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-Nω-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA1 receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.

Effect of ASP2205 fumarate, a novel 5-HT2C receptor agonist, on urethral closure function in rats.

The pharmacological profile of ASP2205 fumarate (ASP2205), a novel 5-HT2C receptor agonist, was evaluated in vitro and in vivo. ASP2205 showed potent and selective agonistic activity for the human 5-HT2C receptor, with an EC50 of 0.85 nM in the intracellular Ca2+ mobilization assay. Rat 5-HT2C receptor was also activated by ASP2205 with an EC50 of 2.5 nM. Intraduodenal administration (i.d.) of ASP2205 (0.1-1 mg/kg) significantly elevated the leak point pressure (LPP) in anesthetized rats in a dose-dependent manner. This ASP2205 (0.3 mg/kg i.d.)-induced LPP elevation was inhibited by SB242084 (0.3 mg/kg i.v.), a selective 5-HT2C receptor antagonist. Urethral closure responses induced by intravesical pressure loading in rats were enhanced by ASP2205 (0.3 mg/kg i.v.), which was abolished by pretreatment with SB242084 (0.3 mg/kg i.v.) and bilateral transection of the pudendal nerve. In contrast, ASP2205 (0.3 mg/kg i.v.) did not change the resting urethral pressure in rats. These results indicate that ASP2205 can enhance the pudendal nerve-mediated urethral closure reflex via the 5-HT2C receptor, resulting in the prevention of involuntary urine loss.

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non-small-cell lung cancer in Japan.

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan.

ASP6432, a type 1 lysophosphatidic acid receptor antagonist, reduces urethral function during urine voiding and improves voiding dysfunction.

Current pharmacotherapies for voiding dysfunctions are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid that contracts the urethra by activating type 1 LPA receptors (LPA1). However, the role of LPA1 in regulating urethral tonus during urine voiding which primarily affects the voiding function has not been investigated. To elucidate the role of LPA1 in the regulation of urethral tonus during urine voiding, we investigated the effects of ASP6432, a novel LPA1 antagonist, and the α1-adrenoceptor antagonist tamsulosin on urethral perfusion pressure (UPP) at the filling phase (UPPbase) and the minimum UPP at the voiding phase (UPPnadir) in anesthetized rats under isovolumetric conditions. We further evaluated the effects of ASP6432 and tamsulosin on voiding dysfunction characterized by changes in post-void residual urine (PVR) and voiding efficiency (VE) induced by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) in conscious rats using single cystometry. ASP6432 dose-dependently decreased UPPbase and UPPnadir, while tamsulosin reduced UPPbase but did not change UPPnadir. ASP6432 dose-dependently suppressed the L-NAME-induced increase in PVR and decrease in VE, whereas tamsulosin did not affect either PVR or VE. We demonstrate that ASP6432 reduced UPPnadir and ameliorated L-NAME-induced voiding dysfunction, neither of which were affected by tamsulosin. Our study results suggest that LPA1 has a significant role in regulating urethral tonus during urine voiding, and highlight the potential of ASP6432 for improving voiding dysfunctions associated with various lower urinary tract diseases.

Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients With ALK-Positive NSCLC After Treatment With Crizotinib.

INTRODUCTION: The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting. METHODS: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. RESULTS: The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. CONCLUSIONS: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation.

Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biologic functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA1) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide), a novel LPA1 antagonist. ASP6432 exhibited potent and selective antagonistic activity against LPA1 in cells expressing LPA receptor subtypes. In isolated rat tissue strips and anesthetized rats, ASP6432 concentration-/dose-dependently inhibited LPA-induced urethra and prostate contractions. In addition, in anesthetized rats, ASP6432 maximally decreased the urethral perfusion pressure (UPP) in the absence of exogenous LPA stimulation by 43% from baseline, whereas tamsulosin, an α1-adrenoceptor antagonist, reduced UPP by 22%. Further, in human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. These results demonstrate a pivotal role for LPA and LPA1 in the regulation of urethral tonus and prostate cell proliferation. The potent urethral relaxation and inhibition of prostatic stromal cell growth indicate the potential of ASP6432 as a novel therapeutic agent for LUTS/BPH.

Intracranial Response to Nivolumab in a Patient with PD-L1-negative Lung Adenocarcinoma.

We herein report the case of a 52-year-old man with stage IV lung adenocarcinoma. The patient was negative for epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 (EML4) /anaplastic lymphoma kinase (ALK) rearrangement. He was treated with nivolumab as a third-line chemotherapy. After four cycles of nivolumab treatment, a partial response was observed in the brain and at the primary tumor site. Nivolumab treatment has been continued for 11 months without progression. Immunohistochemistry revealed that the programmed death-ligand 1 (PD-L1) expression was 0% (according to the tumor proportion score). Our case indicates that the efficacy of programmed cell death 1 inhibitors is not solely predicted by the PD-L1 status, and that immune checkpoint inhibitors might be effective for the treatment of central nervous system metastasis.

A promising response to osimertinib in a patient with erlotinib-resistant lung adenocarcinoma with an uncommon EGFR mutation.

Most patients with non-small cell lung cancer with common epidermal growth factor receptor (EGFR) mutations respond dramatically to EGFR tyrosine kinase inhibitors (TKIs), but data are limited on the response of tumours with uncommon mutations. We present the case of a 68-year-old man with stage IV lung adenocarcinoma with an uncommon EGFR mutation in exon 21 (L861Q). The disease progressed 2 years after he started erlotinib (150 mg daily). Using a transbronchial lung biopsy, we detected additional mutations in exon 20 (T790M) and exon 21 (L858R). He was treated with osimertinib (80 mg daily) and achieved a partial remission. This case demonstrates the value of repeating a biopsy after EGFR-TKI therapy in patients with uncommon EGFR mutations.

Nab-paclitaxel plus carboplatin as an effective and safe chemotherapy regimen for pulmonary carcinosarcoma with interstitial lung disease: A case report.

Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.

Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016.

BACKGROUND: Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. RESULTS: A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1-36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074). CONCLUSIONS: A combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004368 . Registered date; October 11, 2010 (Retrospectively registered).

Basigin expression as a prognostic indicator in stage I pulmonary adenocarcinoma.

We established the KU-Lu-8 monoclonal antibody (MoAb) using a lung cancer cell line as an antigen and a random immunization method. The KU-Lu-8 MoAb recognizes basigin (BSG), which is a transmembrane-type glycoprotein that is strongly expressed on the cell membranes of lung cancer cells. This study aimed to clarify the relationships between BSG expression and clinicopathological parameters and determine the prognostic significance of BSG expression in pulmonary adenocarcinoma (AC) patients. To evaluate the significance of BSG expression in lung cancer, we immunohistochemically analyzed 113 surgically resected pulmonary adenocarcinomas, and the associations between BSG expression and various clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to investigate the effects of BSG expression on survival. Clinicopathologically, BSG expression was significantly associated with tumor differentiation, vascular invasion, lymphatic invasion, and a poor prognosis. In particular, BSG expression was significantly correlated with poorer survival in patients with stage I AC. The high BSG expression group (compared with the low BSG expression group) exhibited adjusted hazard ratios for mortality of 4.694. BSG expression is indicative of a poor prognosis in AC patients, particularly in those with stage I disease.

Phase I study of Nedaplatin, a platinum based antineoplastic drug, combined with nab-paclitaxel in patients with advanced squamous non-small cell lung cancer.

Background This study was designed to determine the recommended dose of a combination of nedaplatin (NED) and nab-paclitaxel (nab-PTX) in chemotherapy-naive patients with advanced squamous non-small-cell lung cancer (NSCLC). Methods Patients received escalating doses of NED on day 1 and nab-PTX on days 1, 8, and 15 every 4 weeks by an intravenous infusion for up to six cycles. Results A dose of 100 mg/m2 NED and 100 mg/m2 nab-PTX was determined to be the recommended dose for patients with advanced squamous NSCLC. The study had an overall response rate of 66.7% (95% confidence interval [CI]: 38.4-88.2) and disease control rate of 93.3% (95% CI: 68.1-99.8). The median progression-free survival time and survival time was 7.0 months (95% CI: 5.9-8.1) and 13.1 months (95% CI: 6.2-20.1), respectively. The most common adverse events were neutropenia (grade 3/4, 33%) and leukopenia (grade 3/4, 27%). Although peripheral neuropathy was observed in 5 patients (grade 1/2), non-hematological toxic effects were relatively mild. Febrile neutropenia, pneumonitis, and treatment-related death were not observed. Conclusions The combination of NED and nab-PTX was a tolerable and effective regimen and its recommended dose was 100 mg/m2 and 100 mg/m2, respectively, in chemotherapy-naive patients with advanced squamous NSCLC (UMIN000010963).