Final Analysis Data and Exploratory Biomarker Analysis of a Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib Monotherapy for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: The WJOG9717L Study.

Introduction: EGFR tyrosine kinase inhibitors have been the standard treatment for patients with NSCLC who have sensitive EGFR mutations. This study revealed final analysis survival data, biomarkers, and resistance mechanisms of osimertinib plus bevacizumab or osimertinib monotherapy in previously untreated patients with advanced EGFR-positive nonsquamous NSCLC. Methods: We previously reported the primary results of a randomized, open-label, phase 2 study comparing osimertinib plus bevacizumab with osimertinib monotherapy for this population. In this exploratory analysis using tissue and plasma samples, we evaluated gene profiles at baseline and disease progression or the last dose using targeted deep sequencing. Results: The median progression-free survival (PFS) by the blinded independent central reviewer was 22.1 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (hazard ratio [HR] = 0.864, 95% confidence interval [CI]: 0.549-1.359). The 3-year overall survival was not different between the two arms (osimertinib plus bevacizumab: 57.1%; osimertinib monotherapy: 65.0%; HR 1.271, 95% CI: 0.727-2.223). A total of 94 patients had assessable plasma samples at baseline, and 40 had assessable pretreatment tissue samples. EGFR mutations (76.6%) and TP53 mutations (44.7%) were detected in plasma samples at baseline. In patients with plasma TP53 mutations (n = 42), the median PFS by blinded independent central reviewer was 19.8 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (HR = 1.107, 95% CI: 0.534-2.297). Conclusions: There was also no significant difference in the PFS between the two arms, even in patients with TP53 mutations.

Isolated unilateral absence of the pulmonary artery (IUAPA) presenting with progressive interstitial shadows: A case report.

Unilateral absence of the pulmonary artery (UAPA) is a rare congenital condition. When UAPA occurs without associated congenital heart disease, it is referred to as isolated unilateral absence of the pulmonary artery (IUAPA). IUAPA is frequently not diagnosed until adulthood. A 61-year-old female patient presented with right chest pain and a worsening interstitial shadow over 9 years. Contrast-enhanced computed tomography revealed the absence of blood flow from the pulmonary artery in the right lung, leading to the diagnosis of IUAPA. In this case, the diagnosis of UAPA was established after approximately 40 years. This case underscores the importance of identifying vascular abnormalities to differentiate this condition in patients presenting with nonspecific symptoms and interstitial shadows.

Impact of the COVID-19 pandemic on COPD exacerbations in Japanese patients: a retrospective study.

Various infection control measures implemented during the coronavirus disease (COVID-19) pandemic have reduced the number of respiratory infections, which are the most common cause of chronic obstructive pulmonary disease (COPD) exacerbations. Here, we investigated whether infectious disease prevention during the COVID-19 pandemic reduced COPD exacerbations and the characteristics of patients exhibiting exacerbations before and during the COVID-19 pandemic. We included outpatients and inpatients with moderate or severe COPD exacerbations who required systemic steroids between April 1, 2018 and March 31, 2022. Their medical records were retrospectively compared and analyzed in 2-year intervals (before and during the COVID-19 pandemic). During the 4-year observation period, 70,847 outpatients and 2,772 inpatients were enrolled; 55 COPD exacerbations were recorded. The number of COPD exacerbations decreased from 36 before to 19 during the COVID-19 pandemic. Regarding the characteristics of patients with exacerbations, the % forced expiratory volume in one second (52.3% vs. 38.6%, P = 0.0224) and body mass index (BMI) (22.5 vs. 19.3, P = 0.0127) were significantly lower during the COVID-19 pandemic than before the pandemic. The number of COPD exacerbations during the pandemic decreased. Additionally, the tendency for a reduction in COPD exacerbation was greatest in patients with preserved lung function or above-standard BMI patients.

Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy.

INTRODUCTION: Traditionally, relapsed SCLC has been classified as "sensitive" or "refractory" on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. METHODS: We conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. RESULTS: There were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95-1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56-4.93). CONCLUSIONS: We clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

PAR2-dependent phosphorylation of TRPV4 at the trigeminal nerve terminals contributes to tongue cancer pain.

OBJECTIVE: This study aimed to clarify the interactions between the tongue and primary afferent fibers in tongue cancer pain. METHODS: A pharmacological analysis was conducted to evaluate mechanical hypersensitivity of the tongues of rats with squamous cell carcinoma (SCC). Changes in trigeminal ganglion (TG) neurons projecting to the tongue were analyzed using immunohistochemistry and western blotting. RESULTS: SCC inoculation of the tongue caused persistent mechanical sensitization and tumor formation. Trypsin expression was significantly upregulated in cancer lesions. Continuous trypsin inhibition or protease-activated receptor 2 (PAR2) antagonism in the tongue significantly inhibited SCC-induced mechanical sensitization. No changes were observed in PAR2 and transient receptor potential vanilloid 4 (TRPV4) levels in the TG or the number of PAR2-and TRPV4-expressing TG neurons after SCC inoculation. In contrast, the relative amount of phosphorylated TRPV4 in the TG was significantly increased after SCC inoculation and abrogated by PAR2 antagonism in the tongue. TRPV4 antagonism in the tongue significantly ameliorated the mechanical sensitization caused by SCC inoculation. CONCLUSIONS: Our findings indicate that tumor-derived trypsin sensitizes primary afferent fibers by PAR2 stimulation and subsequent TRPV4 phosphorylation, resulting in severe tongue pain.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

Endobronchial Watanabe Spigot Placement for Hepatic Abscess and Bronchobiliary Fistula Following Radiofrequency Ablation for Hepatocellular Carcinoma.

A bronchobiliary fistula (BBF) is an uncommon but severe complication after radiofrequency ablation (RFA). However, the definitive salvage methods are controversial. We herein report a patient with hepatocellular carcinoma with hepatic abscess and BBF following RFA. We also review previous reports of BBF after RFA. The patient was a man in his 70s who underwent RFA for recurrent hepatocellular carcinoma in the subphrenic area. Despite percutaneous transhepatic abscess drainage, bilioptysis persisted. Finally, the BBF was occluded with an endobronchial Watanabe spigot under fiber-optic bronchoscopy. Placing an endobronchial Watanabe spigot should be considered as a salvage therapy for refractory BBF following RFA.

Pannexin 1-Mediated ATP Signaling in the Trigeminal Spinal Subnucleus Caudalis Is Involved in Tongue Cancer Pain.

Pain is one of the most severe concerns in tongue cancer patients. However, the underlying mechanisms of tongue cancer pain are not fully understood. We investigated the molecular mechanisms of tongue cancer-induced mechanical allodynia in the tongue by squamous cell carcinoma (SCC) inoculation in rats. The head-withdrawal threshold of mechanical stimulation (MHWT) to the tongue was reduced following SCC inoculation, which was inhibited by intracisternal administration of 10Panx, an inhibitory peptide for pannexin 1 (PANX1) channels. Immunohistochemical analyses revealed that the expression of PANX1 was upregulated in the trigeminal spinal subnucleus caudalis (Vc) following SCC inoculation. The majority of PANX1 immunofluorescence was merged with ionized calcium-binding adapter molecule 1 (Iba1) fluorescence and a part of it was merged with glial fibrillary acidic protein (GFAP) fluorescence. Spike frequencies of Vc nociceptive neurons to noxious mechanical stimulation were significantly enhanced in SCC-inoculated rats, which was suppressed by intracisternal 10Panx administration. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons increased significantly in the Vc after SCC inoculation, which was inhibited by intracisternal 10Panx administration. SCC inoculation-induced MHWT reduction and increased pERK-IR Vc neuron numbers were inhibited by P2X7 purinoceptor (P2X7R) antagonism. Conversely, these effects were observed in the presence of P2X7R agonist in SCC-inoculated rats with PANX1 inhibition. SCC inoculation-induced MHWT reduction was significantly recovered by intracisternal interleukin-1 receptor antagonist administration. These observations suggest that SCC inoculation causes PANX1 upregulation in Vc microglia and adenosine triphosphate released through PANX1 sensitizes nociceptive neurons in the Vc, resulting in tongue cancer pain.

Dramatic, significant metabolic response to a one-time pembrolizumab treatment following a relapse of pre-existing organizing pneumonia in a patient with advanced non-small cell lung cancer: A case report.

Immune checkpoint inhibitors can often trigger immune-related adverse events (irAEs), such as relapse of pre-existing interstitial pneumonia. Here, we report the case of an 88-year-Japanese man diagnosed with advanced lung adenocarcinoma with a high tumor proportion score of programmed death-ligand 1. Six years earlier, he had developed organizing pneumonia (OP), a subtype of interstitial pneumonia, that was treated with steroid pulse therapy maintained with prolonged prednisolone administration. We initiated pembrolizumab as the first-line treatment. One month after the first pembrolizumab administration, high resolution computed tomography (HRCT) of the chest demonstrated ground-glass opacities and consolidations. We suspected pembrolizumab-induced OP relapse, an irAE. His oxygenation was normal; therefore, we discontinued pembrolizumab without additional treatment for OP relapse. Four months after OP relapse, HRCT showed no new findings. After significant amelioration of OP, although the size of the tumor shadow remained the same on HRCT, positron emission tomography-computed tomography demonstrated the disappearance of the standardized uptake value of the primary tumor, mediastinal lymph nodes, and pleural nodules. In conclusion, this is the first report of a dramatic, significant metabolic response after a single pembrolizumab treatment despite the relapse of pre-existing OP in a patient with advanced lung adenocarcinoma.

Bevacizumab plus platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer: a randomized, open-label phase 2 study (CLEAR).

BACKGROUND: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes. METHODS: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m2) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%. RESULTS: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 vs. 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively. CONCLUSIONS: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).

Preparation of Isodehydrodigallic Acid Using Ullmann Condensation.

Isodehydrodigallic acid, which is an important component of several ellagitannin compounds, was easily synthesized using a classical Ullmann condensation reaction.

Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. METHODS: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. RESULTS: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. CONCLUSIONS: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.

Impact of the generation of EGFR-TKIs administered as prior therapy on the efficacy of osimertinib in patients with non-small cell lung cancer harboring EGFR T790M mutation.

BACKGROUND: There are few studies that directly compare the effects of osimertinib on patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation between the generation of prior EGFR tyrosine kinase inhibitors (TKIs). METHODS: We retrospectively reviewed clinical data from the medical records of consecutive patients with advanced NSCLC who had developed resistance to first- or second-generation EGFR-TKIs due to EGFR T790M mutation and were subsequently treated with osimertinib at Juntendo University Hospital. In patients with available tumor samples, target amplicon sequencing analyses were performed to explore the genetic biomarkers. RESULTS: A total of 38 patients with NSCLC harboring EGFR T790M mutation were treated with osimertinib. Eight patients were classified into group A (afatinib followed by osimertinib) and 30 patients were classified into group B (first-generation EGFR-TKI followed by osimertinib). Progression-free survival (PFS) was significantly longer in group A than in group B (median PFS; not reached vs. 11.0 months, P = 0.018). Fourteen patients had available tissue samples collected before osimertinib treatment for target sequencing. In group A we found no additional mutations, other than EGFR T790M mutation. On the other hand, there were three samples in which other mutations emerged, in addition to EGFR T790M mutation, in group B. CONCLUSIONS: PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR-TKIs. Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment. KEY POINTS: Significant findings of the study: PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR-TKIs. WHAT THIS STUDY ADDS: Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment.

Thermophysical Property Measurements of Tetrabutylphosphonium Oxalate (TBPOx) Ionic Semiclathrate Hydrate as a Media for the Thermal Energy Storage System.

With increasing global power demand, thermal energy storage technology could play a role ensuring a sustainable energy supply in power generation from renewable energy sources and power demand concentration. Hydrates have high potential as phase change materials (PCMs) for the use as a thermal energy storage medium. To develop thermal energy storage technology using a hydrate-based material, further investigation of thermophysical properties and the selection of a suitable hydrate are required. Tetrabutylphosphonium oxalate (TBPOx) ionic semiclathrate hydrate contains oxalic acid in salt form, as a guest compound, which is classified as carboxylic acid group with low environmental impact. In the present study, the phase equilibrium temperature and the dissociation heat of TBPOx hydrate were measured. The highest equilibrium temperature of the solid hydrate formed was 9.4°C at the mass fraction 0.35 of TBPOx in aqueous solution. The largest dissociation heat was 186.0 ± 0.5 kJ·kg-1 at the mass fraction of 0.35. Comparing with other PCMs with close phase equilibrium temperatures, TBPOx hydrate is superior in safety and sustainability. These results indicate that TBPOx hydrate would be suitable as the thermal storage medium for the general air conditioning systems.

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats.

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Involvement of Satellite Cell Activation via Nitric Oxide Signaling in Ectopic Orofacial Hypersensitivity.

: The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer.

OBJECTIVES: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). METHODS: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. RESULTS: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). CONCLUSIONS: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

Prognostic differences among patients with idiopathic interstitial pneumonias with acute exacerbation of varying pathogenesis: a retrospective study.

BACKGROUND: Acute exacerbation of chronic fibrosing idiopathic interstitial pneumonias (AE-IIPs) is associated with a high mortality rate. In 2016, an international working group proposed a revised diagnostic criteria for AE-IIPs, suggesting that it be classified as idiopathic or triggered. Many factors are known to trigger AE-IIPs, including surgery, infection, and drugs. However, it is unknown which AE-IIPs triggers have a worse prognosis. We aimed to investigate the prognosis of patients with various clinical types of AE-IIPs, particularly infection-triggered, non-infection triggered, and idiopathic AE-IIPs. METHODS: We retrospectively collected data from 128 chronic fibrosing IIPs (CF-IIPs) patients who were hospitalized by respiratory failure between April 2009 and March 2019 at Juntendo University Hospital. Among these patients, we evaluated 79 patients who developed AE-IIPs and 21 who developed pneumonia superimposed on CF-IIPs. Patients with AE-IIPs were classified into three types: idiopathic, infection-triggered, and non-infection-triggered AE-IIPs. We analyzed differences in patient characteristics, examination findings; level of serum markers, results of pulmonary function, and radiological findings, prior treatment for baseline CF-IIPs, and prognosis. We then evaluated the risk factor for early death (death within 30 days from the onset of AE-IIPs) associated with AE-IIPs. RESULTS: Among the patients who developed AE-IIPs, 34 were characterized as having idiopathic, 25 were characterized as having infection-triggered, and 20 were categorized as having non-infection-triggered AE-IIPs. Survival time for pneumonia superimposed on IIPs was significantly longer than that for any AE-IIPs. Survival time for bacterial pneumonia superimposed on CF-IIPs was significantly longer than that for AE-IIPs (for each idiopathic and all triggered IIPs). Thereafter, survival time for infection-triggered was significantly longer than for idiopathic or non-infection-triggered AE-IIPs. The mortality rate was significantly lower in infection-triggered AE-IIPs than in other types of AE-IIPs. Furthermore, the incidence of infection-triggered AE-IIPs in winter was significantly higher than that in other seasons. Moreover, the clinical AE-IIPs types and radiological findings at AE-IIP onset were significant risk factors for AE-IIPs-induced early death. CONCLUSIONS: Our findings suggest that patients with infection-triggered AE-IIPs can expect a better prognosis than can patients with other clinical types of AE-IIPs.

Age is an independent predictor in pathological diagnosis of sarcoidosis: a retrospective analysis of diagnosis by endobronchial ultrasound-guided transbronchial needle aspiration.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the current major modality for the diagnosis of sarcoidosis with hilar and mediastinal lymphadenopathy because of its higher diagnostic yield and safety; however, predictors for the pathological diagnosis of sarcoidosis by EBUS-TBNA remain uncertain. The objective of this study was to determine a novel predictor for the pathological diagnosis of sarcoidosis by EBUS-TBNA. METHODS: Patients with pathological and/or clinical diagnosis of sarcoidosis were identified from patients who underwent EBUS-TBNA between February 2010 and December 2017, retrospectively. We extracted data on age, sex, stage of disease, number of punctured lymph nodes, number of punctures per procedure and target lymph node, and size of punctured lymph node. Next, we divided patients into groups of pathological positive and negative by EBUS-TBNA, and multivariate logistic regression analysis was performed following univariate analyses to evaluate the efficacy of these parameters as a predictive factor of the pathological diagnosis of sarcoidosis by EBUS-TBNA. RESULTS: We selected 89 patients involving 115 mediastinal and hilar lymph nodes. The diagnostic yield of sarcoidosis by EBUS-TBNA was 74/89 (83.1%). There were no significant differences in the size of lymph node and number of punctures between the groups, there was a significant difference in age by univariate analyses. In addition, multivariate logistic regression revealed that age was significantly associated with pathological diagnosis of sarcoidosis by EBUS-TBNA [5 years = 1 unit, odds ratio (OR), 0.79; 95% CI, 0.64-0.97; P=0.03]. CONCLUSIONS: The diagnostic yield of sarcoidosis by EBUS-TBNA was higher in younger than older patients. Therefore, age may be a novel independent predictor for the pathological diagnosis of sarcoidosis by EBUS-TBNA.

Feasibility of complete surgical ligation on 72 dogs with singular extrahepatic congenital portosystemic shunt based on portal pressure and comparison of intraoperative mesenteric portovenography.

The relation between complete or partial ligation of extrahepatic portosystemic shunting and intraoperative mesenteric portovenography (IMP) was evaluated in 72 canines. Of the 72 dogs, 55 had complete ligation and 17 underwent partial ligation of abnormal vessels. IMP allowed evaluation of the number of intrahepatic portal branches and ratio of the diameter of cranial (CrPV) and caudal main portal vein (CaPV) at the shunt location. Nearly all cases in the complete ligation group and nearly half of the cases in the partial ligation group had three or more portal vein branches. CrPV/CaPV was 0.75 ± 0.24 in the complete ligation group and 0.29 ± 0.15 in the partial ligation group. CrPV/CaPV can be an effective new method for assessing IMP.