Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas.

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B).

BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Interstitial lung disease associated with nanoparticle albumin-bound paclitaxel treatment in patients with lung cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. METHODS: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. RESULTS: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). CONCLUSION: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonias: a single-arm phase II study.

BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. METHODS: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. RESULTS: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1-6). Four patients (12.1%; 95% confidence interval 3.4-28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. CONCLUSIONS: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole.

Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, which makes it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the gastrointestinal simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug dipyridamole when coupled with in silico analysis. The GIS is a multicompartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state. Kinetic parameters for drug dissolution and precipitation were optimized by fitting a curve to the dissolved drug amount-time profiles in the United States Pharmacopeia apparatus II and GIS. Optimized parameters were incorporated into mathematical equations to describe the mass transport kinetics of dipyridamole in the GI tract. By using this in silico model, intraluminal drug concentration-time profile was simulated. The predicted profile of dipyridamole in the duodenal compartment adequately captured observed data. In addition, the plasma concentration-time profile was also predicted using pharmacokinetic parameters following intravenous administration. On the basis of the comparison with observed data, the in silico approach coupled with the GIS successfully predicted in vivo pharmacokinetic profiles. Although further investigations are still required to generalize, these results indicated that incorporating GIS data into mathematical equations improves the predictability of in vivo behavior of weakly basic drugs like dipyridamole.

The efficacy of a multidisciplinary team approach in critical limb ischemia.

The aim of the present study was to clarify the characteristics of Japanese critical limb ischemia (CLI) patients and analyze the rates of real-world mortality and amputation-free survival (AFS) in all patients with Fontaine stage IV CLI who were treated with/without revascularization therapy by an intra-hospital multidisciplinary care team. All consecutive patients who presented with CLI at Showa University Fujigaoka Hospital between April 2008 and March 2014 were prospectively registered. The intra-hospital committee consisted of cardiologists, plastic surgeons, dermatologists, diabetologists, nephrologists, cardiovascular surgeons, and vascular technologists. The primary endpoint of this study was all-cause mortality and AFS during the follow-up period. The present study included 145 patients with Fontaine stage IV CLI. The mean age was 76.5 ± 10.2 years. The all-cause mortality rate during the follow-up period (15.5 ± 16.1 months) was 21.4 %. The AFS rate during the follow-up period (14.1 ± 16.4 months) was 58.6 %. A multivariate Cox proportional hazards regression analysis found that age >75 years and hemodialysis were significantly associated with all-cause mortality; and that age >75 years, Rutherford 6, and wound infection were significantly associated with AFS. A multidisciplinary approach and comprehensive care may improve the outcomes and optimize the collaborative treatment of CLI patients. However, all-cause mortality remained high in patients with Fontaine stage IV CLI and early referral to a hospital that can provide specialized treatment for CLI, before the occurrence of major tissue loss or infection, is necessary to avoid primary amputation.

[Successful Emergency Management of an Infected Thoracic Aortic Aneurysm Rupture Using a Pedicled Latissimus Dorsi Flap after Stent-graft Implantation;Report of a Case].

We report a case of ruptured mycotic thoracic aortic aneurysm treated with a pedicled latissimus dorsi flap after stent-graft implantation. The patient was a 64-year-old woman with diabetes mellitus that had developed septicemia as a result of pyelonephritis and a perinephric abscess. The patient required emergency stent-graft implantation due to rupture of an infected thoracic aortic aneurysm on hospital day 10. On hospital day 19, the abscess cavity was debrided and irrigated, and a pedicled latissimus dorsi flap was created. No recurrence of the inflammatory reaction was observed at 1 year postoperatively.

Interstitial lung disease associated with amrubicin chemotherapy in patients with lung cancer: a single institutional study.

OBJECTIVE: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution. METHODS: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases. RESULTS: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy. CONCLUSION: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

Effects of oral moisturising gel containing egg yolk antibodies against Candida albicans in older people.

OBJECTIVE: The aim of this study was to evaluate the inhibitory effects of oral moisturising gel containing egg yolk antibody against Candida albicans (anti-CA IgY) in older people. Therefore, we measured the number of Candia CFU present on oral swabs at baseline and after using the gel. METHODS: A randomised, double-blind, placebo-controlled trial was conducted among volunteers living in a nursing home in Japan. The participants were divided into two groups. The group 1 participants received oral care using an experimental oral moisturising gel with anti-CA IgY, and those in group 2 received oral care using a placebo oral moisturising gel without anti-CA IgY. The oral care was performed by care workers three times a day for 4 weeks. The participants' tongues were sampled using a swab method at baseline and after 2 and 4 weeks of using the oral gel, and the number of C. albicans, Candida tropicalis and Candida krusei colonies was counted. RESULTS: The baseline oral condition of the participants in the two groups did not differ significantly. The experimental gel significantly reduced the number of C. albicans colonies from baseline to after 4 weeks of using the oral gel; however, no significant reductions were observed in the number of C. tropicalis or C. krusei colonies. CONCLUSION: The use of oral moisturising gel containing anti-CA IgY for 1 month significantly reduces the number of C. albicans CFU present on swabs in older people.

Control of the MYC-eIF4E axis plus mTOR inhibitor treatment in small cell lung cancer.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. METHODS: We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus. RESULTS: Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls. CONCLUSION: These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.

Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

Saliva viscosity as a potential risk factor for oral malodor.

OBJECTIVES: The objective of this study was to assess whether saliva viscosity, measured by a viscometer, was a predictor of oral malodor. MATERIALS AND METHODS: The subjects were 617 patients who visited an oral malodor clinic. The organoleptic test (OT) was used for diagnosis of oral malodor. An oral examination assessed the numbers of teeth present and decayed teeth as well as the presence or absence of dentures. Further, periodontal pocket depths (PD), gingival bleeding, dental plaque and tongue coating were investigated. Unstimulated saliva were collected for 5 min. Saliva viscosity was measured with a viscometer. Logistic regression analysis with oral malodor status by OT as a dependent variable was performed. Possible confounders including age, gender, number of teeth present, number of decayed teeth, number of teeth with PD ≥ 4 mm, number of teeth with bleeding on probing, presence or absence of dentures, plaque index, area of tongue coating, saliva flow rate, saliva pH and saliva viscosity were used as independent variables. RESULTS: Saliva viscosity (p = 0.047) along with the number of teeth with PD ≥4 mm (p = 0.001), plaque index (p = 0.037) and area of tongue coating (p < 0.001) were significant variables for oral malodor. Subjects with a higher number of teeth with PD ≥ 4 mm (OR = 1.32), plaque index (OR = 2.13), area of tongue coating (OR = 3.17) and saliva viscosity (OR = 1.10) were more likely to have oral malodor compared to those with lower values. CONCLUSIONS: The results suggested that high saliva viscosity could be a potential risk factor for oral malodor.

A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study).

INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

Induction of resistance to neurotrophic tropomyosin-receptor kinase inhibitors by HMGCS2 via a mevalonate pathway.

INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer.

Introduction: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. Methods: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. Results: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. Conclusions: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

The relationship between turbidity of mouth-rinsed water and oral health status.

OBJECTIVES: The purpose of this study was to examine the relationship between turbidity of mouth rinsed water and oral health status such as dental and periodontal conditions, oral hygiene status, flow rate of saliva and oral bacteria. MATERIALS AND METHODS: Subjects were 165 patients who visited the Dental Hospital, Tokyo Medical and Dental University. Oral health status, including dental and periodontal conditions, oral hygiene status and flow rate of saliva, was clinically examined. The turbidity was measured with a turbidimeter. Quantification of Fusobacterium spp, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola and total bacteria levels was performed using real-time PCR. The Pearson correlation and multiple regression analysis were used to explore the associations between the turbidity and oral health parameters. RESULTS: The turbidity showed significant correlations with the number of decayed teeth and deep pockets, the plaque index, extent of tongue coating and Fusobacterium spp, P. gingivalis, T. forsythia, T. denticola and total bacteria levels. In a multiple regression model, the turbidity was negatively associated with the flow rate of saliva and positively associated with the total number of bacteria (p < 0.001). CONCLUSION: Current findings suggested that turbidity of mouth rinsed water could be used as an indicator to evaluate oral health condition and the amount of bacteria in the oral cavity. In addition, the turbiditimeter appeared as a simple and objective device for screening abnormality of oral health condition at chair side as well as community-based research.

Predictive Impact of Diffuse Positivity for TTF-1 Expression in Patients Treated With Platinum-Doublet Chemotherapy Plus Immune Checkpoint Inhibitors for Advanced Nonsquamous NSCLC.

Introduction: Pervious studies reported the association of TTF-1 expression with the efficacy of platinum-doublet chemotherapy in combination with immune checkpoint inhibitors in advanced nonsquamous NSCLC. Nevertheless, the predictive value of extent of TTF-1 expression (diffuse or focal TTF-1 positivity) remains unclear. Methods: The present study retrospectively reviewed 74 patients with TTF-1-positive recurrent or advanced nonsquamous NSCLC receiving first-line chemoimmunotherapy in a single institution in Japan. TTF-1 expression score in pretreatment tumor specimens was evaluated using immunohistochemistry, and the impact of chemoimmunotherapy response was analyzed. Results: In the total cohort, ≥50% of the tumor cells were TTF-1 positive (i.e., diffusely TTF-1 positive) in specimens of 61 patients (82.4%), whereas 10% to 49% of the tumor cells were TTF-1 positive (i.e., focally TTF-1 positive) in specimens of the remaining 13 patients (17.6%). In multivariate analysis, the median progression-free survival and overall survival (OS) were significantly longer in patients with diffusely TTF-1-positive tumors than in those with focally TTF-1-positive tumors (14.2 versus 9.2 mo, p = 0.01 and 30.2 versus 17.3 mo, p = 0.01, respectively). Moreover, the median OS was significantly longer in patients receiving chemoimmunotherapy including pemetrexed than in those receiving chemoimmunotherapy not including pemetrexed among the patients with diffusely TTF-1-positive tumors (not attained versus 23.2 mo, p < 0.01). Conclusions: The positive extent of diffuse TTF-1 expression associated with patient outcome was an independent predictive factor for better progression-free survival and OS in patients with advanced nonsquamous NSCLC receiving chemoimmunotherapy.

Osimertinib early dose reduction as a risk to brain metastasis control in EGFR-mutant non-small cell lung cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. METHODS: We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. RESULTS: In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. CONCLUSION: Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

Standard versus low-dose nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer: A randomized phase II trial (JMTO LC14-01).

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.