The incidence of drug-induced interstitial lung disease caused by epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors in patients with non-small cell lung cancer in presence and absence of vascular endothelial growth factor inhibitors: a systematic review.

Interstitial lung disease (ILD) or pneumonitis caused by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI) is a major concern in the treatment of non-small cell lung cancer (NSCLC). Whether the addition of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors can reduce the incidence of drug-induced ILD remains unclear. We conducted a systematic review to assess the incidence of ILD induced by EGFR-TKIs or ICIs in the presence or absence of VEGF/VEGFR inhibitors in relevant randomized trials between January 2009 and October 2023. The primary outcome was the odds ratio for the incidence of ILD in all patients worldwide and Asians. Secondary outcomes were the odds ratios (ORs) of the incidence at grade-3 or higher ILD in all patients worldwide and Asians. We identified 13 randomized studies, one sub-analysis in the EGFR-TKI group, and three randomized studies in the ICI group. In the EGFR-TKI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.54 (95% CI, 0.32-0.90; p = 0.02), which represented a significantly lower incidence than that without VEGF/VEGFR inhibitors. Contrarily, the OR of ILD incidence at grade ≥ 3 with VEGF/VEGFR inhibitors was 1.00 (95% CI, 0.43-2.36; p = 0.99). In all subjects in the ICI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.78 (95% CI, 0.51-1.21; p = 0.27). The systematic review demonstrated that the addition of VEGF/VEGFR inhibitors could reduce the incidence of drug-induced ILD at any grade caused by EGFR-TKI in patients with NSCLC but could not reduce that at grade ≥ 3. The ILD induced by ICIs remains undetermined owing to the limited number of randomized trials for which ILD data are available. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=409534, identifier CRD42023409534.

Atezolizumab and nintedanib in patients with non-small cell lung cancer and interstitial lung disease.

In patients with non-small cell lung cancer (NSCLC), pre-existing interstitial lung disease (ILD) is a risk factor for the development of pneumonitis induced by immune checkpoint inhibitors (ICIs). Anti-fibrotic agents, including nintedanib, reduce the potential for acute exacerbation of idiopathic pulmonary fibrosis (IPF). However, whether nintedanib can reduce the potential for ICI-induced pneumonitis is unknown. From among 140 patients with NSCLC treated with atezolizumab monotherapy at our institution, we retrospectively investigated 4 patients with pre-existing ILD treated concurrently with nintedanib. On computed tomography (CT), a usual interstitial pneumonia (UIP) pattern was present in one patient, probable UIP pattern in one patient, and indeterminate for UIP pattern in two patients. Of those four patients with pre-existing ILD, two achieved a partial response to ICI treatment, with response durations of 8.1 and 7.6 months. The other two patients experienced progressive disease. Notable adverse events included the development of non-symptomatic grade 1 pneumonitis in the patient with a probable UIP pattern and grade 3 lower gastrointestinal hemorrhage in another patient. None of the patients experienced a worsening of respiratory symptoms. In patients with NSCLC and pre-existing ILD, nintedanib might reduce the potential for ICI-induced pneumonitis and enhance the antitumor effect.

Unrealistic expectations and disclosure of incurability in patients with non-small cell lung cancer.

PURPOSE: Determining whether patients' unrealistic expectations of chemotherapy as a cure were associated with their perception of the disclosure of incurability. METHODS: This prospective study included consecutive patients with pretreated non-small cell lung cancer from four study sites. Patients and their oncologists were asked whether they perceived the disclosure of cancer incurability. Patients were also asked if they thought that chemotherapy was curative. We followed up on whether the deceased patients received specialized palliative care 14 months after their last enrollment. Multiple regression analyses were conducted to examine the association between the expectation of chemotherapy as a cure and patient/oncologist-reported perceptions of the disclosure of incurability. RESULTS: We analyzed 200 patients, 77 (38.5%) of whom had unrealistic expectations of a cure. Based on patients' perceptions, incurability was disclosed to 138 (69.0%) patients, and based on their oncologists' perceptions, incurability was disclosed to 185 (92.5%) patients (patient/oncologist agreements, κ = 0.19). Patients without a perception of the oncologist's disclosure of incurability-regardless of their oncologist's perception-were more likely to have unrealistic expectations of a cure than patients for whom both patient and oncologist perceptions were present. Patients who had unrealistic expectations of chemotherapy as a cure were shown to be significantly less likely to have received specialized palliative care, after adjusting for covariates (adjusted OR, 0.45; 95% CI, 0.23-0.91; p = .027). CONCLUSION: Oncologists' disclosure of incurability was not fully recognized by patients, and expectations of chemotherapy as a cure were associated with patients' perception of the disclosure of incurability.

Elements of End-of-Life Discussions Associated With Patients' Reported Outcomes and Actual End-of-Life Care in Patients With Pretreated Lung Cancer.

BACKGROUND: End-of-life discussions for patients with advanced cancer are internationally recommended to ensure consistency of end-of-life care with patients' values. This study examined the elements of end-of-life discussions associated with end-of-life care. MATERIALS AND METHODS: We performed a prospective observational study among consecutive patients with pretreated non-small cell lung cancer after the failure of first-line chemotherapy. We asked oncologists whether they had ever discussed "prognosis," "do not attempt resuscitation," "hospice," and "preferred place of death" with a patient at baseline. The quality of life (QOL) and depressive symptoms of patients were assessed using validated questionnaires at baseline and 3 months later. The end-of-life care that patients received was investigated using medical records. Oncologists' compassion and caregivers' preferences for hospice care were also assessed using questionnaires. Multiple regression analyses were conducted to examine the association between elements of end-of-life discussions and patient-reported outcomes as well as actual end-of-life care. RESULTS: We obtained 200 valid responses at baseline, 147 valid responses 3 months later, and 145 data points for medical care at the end-of-life stage. No element of the end-of-life discussion between the patient and their oncologist was significantly associated with patients' reported outcomes or actual end-of-life care. In addition, oncologists' compassion was significantly associated with improvement in both comprehensive QOL and depressive symptoms, and caregivers' preferences for hospice care and high educational level were significantly associated with hospice death. CONCLUSION: Oncologist-patient alliances and caregivers' involvement in end-of-life discussions may be influential in achieving optimal end-of-life care.

The effect of inheritance of IgE responsiveness on the susceptibility of mice to Trichinella spiralis infection.

IgE antibodies are likely involved in host protection. Trichinella spiralis is a helminth that induces protection through IgE antibodies. The present study examined T. spiralis susceptibility in high and low IgE responder mice, with a specific focus on the inheritance of IgE responsiveness, which controls IgE production specific for the IgE isotype and non-specific for antigens. Furthermore, low IgE responsiveness is inherited as a recessive trait under a single gene, which is not linked to the H-2 gene. This study determined the total IgE and anti-T. spiralis IgE antibody levels after T. spiralis infection in low IgE responder SJL/J mice were several times lower than those in high IgE responders, such as the BALB/c mice. An IgE-dependent susceptibility to T. spiralis, evaluated in mice treated with anti-IgE antibodies and in control mice, was observed in high IgE responder mice but not in low IgE responder mice. The inheritance of IgE responsiveness and susceptibility to T. spiralis was investigated using crosses of SJL/J with high IgE responders. All of the (BALB/c × SJL/J) F1 and half of the (BALB/c × SJL/J) F1 × SJL backcross progenies were high IgE responders after T. spiralis infection. Total IgE and antigen-specific IgE antibody levels were correlated and not linked to H-2. It should be noted that high IgE responders always exhibited low susceptibility, suggesting that the trait of IgE responsiveness functions as a trait of susceptibility to T. spiralis.

Prognostic Awareness and Discussions of Incurability in Patients with Pretreated Non-Small Cell Lung Cancer and Caregivers: A Prospective Cohort Study.

BACKGROUND: Although patients with advanced cancer often have poor prognostic awareness, the most effective communication approach for improving prognostic awareness is unclear. In addition, the association between prognostic awareness and preferences for future medical treatment remains unexplored. MATERIALS AND METHODS: We performed a prospective observational study of consecutive patients with advanced or post-operative recurrent non-small cell lung cancer whose disease had progressed after first-line chemotherapy, and their caregivers. We evaluated patterns of clinical discussions about incurability, prognostic awareness, and preference for future medical treatment at baseline and 3 months later. RESULTS: We obtained 200 valid responses to the questionnaires at baseline and 147 valid responses 3 months later. In addition, 180 caregivers returned valid responses. A total of 54% of patients and 51% of caregivers had accurate awareness at baseline, and 52% of patients had accurate awareness 3 months later. Multiple logistic regression analysis revealed that patients who were informed about incurability in recent and past discussions were significantly more likely to have accurate awareness 3 months later, compared with those who were only informed recently (adjusted odds ratio 5.08; 95% CI, 1.31-19.78; P = .019). Accurate awareness at 3 months was significantly negatively associated with preference for life-prolonging treatment at 3 months after adjusting for covariates (adjusted odds ratio 0.39; 95% CI, 0.17-0.90; P = .028). CONCLUSION: Patients with advanced cancer who had both recent and past discussions about incurability with their oncologists have more accurate prognostic awareness. Improving prognostic awareness could reduce the preference for life-prolonging treatment.

Risk factors for pneumonitis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors plus chemotherapy: A retrospective analysis.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy plus chemotherapy has become a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Pre-existing interstitial lung disease (ILD) is a risk factor for drug-induced pneumonitis caused by chemotherapy or ICI monotherapy. However, clinical data in patients with pre-existing ILD who received ICI therapy plus chemotherapy are limited. This study aimed to identify the risk factors for drug-induced pneumonitis in patients with NSCLC treated with ICIs plus chemotherapy. METHODS: We retrospectively reviewed the medical records of 160 consecutive patients who were diagnosed with NSCLC and treated with ICIs plus chemotherapy at Aichi Cancer Center Hospital between December 2018 and November 2020. Patients with a prior history of ICI treatment or thoracic radiotherapy were excluded from the analysis. RESULTS: Among 125 patients, pre-existing ILD was observed in 20 patients (16.0%). Drug-induced pneumonitis developed in 17 patients (13.6%), with a median time to onset of 19.3 weeks (range, 1.6-108.9 weeks). In multivariate logistic analysis, pre-existing ILD (odds ratio = 19.07, p = 0.0001) and PEM exposure (odds ratio = 5.67, p = 0.022) were identified as risk factors for the development of drug-induced pneumonitis. CONCLUSIONS: Pre-existing ILD and pemetrexed exposure are risk factors for drug-induced pneumonitis in patients with NSCLC.

Emerging therapies for non-small cell lung cancer harboring EGFR exon 20 insertion mutations: narrative review.

Background and Objective: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) are uncommon in non-small cell lung cancer (NSCLC). These mutations are generally resistant to first-generation EGFR tyrosine kinase inhibitors, unlike common EGFR mutations, including exon 19 deletions or exon 21 L858R point mutation. The development of effective targeted therapies for NSCLC harboring EGFR ex20ins has been eagerly anticipated over the years. Recently, the therapeutic landscape of this subgroup of EGFR-mutant NSCLC patients has rapidly evolved due to the emergence of new drugs. In 2021, several novel agents, such as amivantamab and mobocertinib, have been approved by the US Food and Drug Administration for patients with advanced platinum-resistant NSCLC harboring EGFR ex20ins. In this review, we mainly focus on emerging therapies targeting NSCLC with EGFR ex20ins, as well as important ongoing clinical trials. Methods: Searches were conducted in PubMed and supplemented with recent conference proceedings in November 30th, 2021. Key Content and Findings: Several novel emerging therapies showed favorable safety profile and promising anti-tumor activity in NSCLC patients with EGFR ex20ins in recent several clinical trials. Conclusions: There is still room for improvement in the treatment results of NSCLC harboring EGFR ex20ins. Future research should focus on the molecular heterogeneity in the size and location of distinct EGFR ex20ins, the mechanisms of acquired resistance to novel EGFR inhibitors, effective treatment that have good central nervous system penetrance, and the potential role of combination strategy.

Clinical features of patients with small cell lung cancer and idiopathic pulmonary fibrosis treated with chemotherapy or chemoradiotherapy.

BACKGROUND: The clinical features of patients with small cell lung cancer (SCLC) and idiopathic pulmonary fibrosis (IPF) have not been fully elucidated. PATIENTS AND METHODS: Data on 366 patients with pathologically confirmed SCLC who had been treated with chemotherapy or chemoradiotherapy were retrospectively analyzed to investigate the clinical features of SCLC with IPF. RESULTS: A total of 97 out of the 366 patients were diagnosed with interstitial lung disease (ILD), and 75 of them had IPF. For both the limited disease (LD) and extensive disease (ED) stages, the median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the patients with IPF compared with non-ILD patients. A multivariate analysis showed that poor performance status, ED stage, and the presence of IPF were associated with shorter OS. The response rate to first-line therapy was significantly lower in patients with IPF compared with the non-ILD patients. The rate of patients receiving fewer than three cycles of first-line chemotherapy was higher in patients with IPF, which was a factor of poor survival. In LD-stage patients with IPF, chemoradiotherapy was associated with longer PFS and OS compared with chemotherapy only. CONCLUSION: In patients with SCLC, the presence of IPF was associated with a lower response rate as well as shorter PFS and shorter OS. There are some cases that are suitable for chemoradiotherapy, even among patients with IPF.The reviews of this paper are available via the supplemental material section.

Efficacy of local therapy for oligoprogressive disease after programmed cell death 1 blockade in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non-small-cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD-1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty-eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option.

Efficacy and Safety Data of Osimertinib in Elderly Patients with NSCLC Who Harbor the EGFR T790M Mutation After Failure of Initial EGFR-TKI Treatment.

BACKGROUND/AIM: The aim of this study was to evaluate the safety and efficacy of osimertinib for elderly patients, since the data remain limited. PATIENTS AND METHODS: A total of 77 patients with advanced non-small cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation and treated with osimertinib were reviewed. Efficacy and safety indicators, such as EGFR-tyrosine kinase inhibitor (TKI)-related adverse events (AEs) and osimertinib-associated hematotoxicity, were evaluated in elderly patients (elderly group, EG; age, ≥75 years) by comparing them with younger patients (non-EG; aged <75 years). The frequency of AEs associated with osimertinib was compared with the initial EGFR-TKI treatment before osimertinib administration in the same patient cohort. RESULTS: Of the total 77 patients, 18 (23%) were assigned to the EG, whereas 59 (77%) were assigned to the non-EG. There were no significant differences in overall response rate and progression-free survival between the two groups. Regarding the safety of osimertinib, the EG had significantly more grade ≥2 paronychia than the non-EG (16.6% vs. 1.6%, p=0.04). Additionally, the maximum grade of EGFR-TKI-related AEs associated with osimertinib in the EG was significantly lower than that of the initial EGFR-TKI treatment (p=0.03). CONCLUSION: Osimertinib is a safe and effective treatment option for elderly patients with advanced NSCLC who harbor the EGFR mutation.

Histamine Released From Skin-Infiltrating Basophils but Not Mast Cells Is Crucial for Acquired Tick Resistance in Mice.

Ticks are blood-feeding arthropods that can transmit pathogens to humans and animals, leading to serious infectious diseases such as Lyme disease. After single or multiple tick infestation, some animal species develop resistance to tick feeding, leading to reduced risk of pathogen transmission. In mice infested with larval Haemaphysalis longicornis ticks, both mast cells and basophils reportedly play key roles in the manifestation of acquired tick resistance (ATR), but it remains ill-defined how they contribute to it. Here, we investigated their products responsible for ATR. Treatment of mice with antihistamine abolished the ATR while histamine or histamine H1 receptor agonist reduced tick-feeding even in the first infestation. In accordance with these, mice deficient for histamine production showed little or no ATR, indicating the crucial role for histamine in the expression of ATR. Adoptive transfer of mast cells and basophils derived from histamine-sufficient or deficient mice to recipient mice lacking mast cells and basophils, respectively, revealed that histamine produced by basophils but not mast cells is essential for the manifestation of ATR, in contrast to the case of local and systemic anaphylaxis where mast cell-derived histamine is the major player. During the second but not first tick infestation, basophils accumulated and made a cluster, surrounding a tick mouthpart, in the epidermis whereas mast cells were scattered and localized mainly in the dermis, more distantly from a tick mouthpart. This appears to explain why basophil-derived histamine is much more effective than mast cell-derived one. Histamine-sufficient, but not -deficient mice showed the thickened epidermis at the second tick-feeding site. Taken together, histamine released from skin-infiltrating basophils rather than skin-resident mast cells plays a crucial role in the manifestation of ATR, perhaps through promotion of epidermal hyperplasia that may inhibit tick feeding.

The response of common marmoset immunity against cedar pollen extract.

The in vivo model of pollinosis has been established using rodents, but the model cannot completely mimic human pollinosis. We used Callithrix jacchus, the common marmoset (CM), to establish a pollinosis animal model using intranasal weekly administration of cedar pollen extract with cholera toxin adjuvant. Some of the treated CMs exhibited the symptoms of snitching, excess nasal mucus and/or sneezing, but the period was very short, and the symptoms disappeared after several weeks. The CD4+CD25+ cell ratio in the peripheral blood increased in CMs quickly after the nasal administration of cedar pollen extract, but the timing was not parallel with the symptoms. IL-10 mRNA was enhanced in the peripheral blood mononuclear cells (PBMCs), suggesting CM-induced tolerance for cedar pollen administration. Similarly, Foxp3 mRNA was also detected in the PBMC. Additive sensitization of these CMs with Ascaris egg administration did not enhance chronic inflammation of type 1 allergy to induce the symptoms. These results suggest that the environmental immune cells develop transient allergic symptoms and subsequent immune-tolerance in the intranasally sensitized CMs.

Skin CD4+ Memory T Cells Play an Essential Role in Acquired Anti-Tick Immunity through Interleukin-3-Mediated Basophil Recruitment to Tick-Feeding Sites.

Ticks, blood-sucking arthropods, serve as vectors for transmission of infectious diseases including Lyme borreliosis. After tick infestation, several animal species can develop resistance to subsequent infestations, reducing the risk of transmission. In a mouse model, basophils reportedly infiltrate tick-feeding sites during the second but not first infestation and play a crucial role in the expression of acquired tick resistance. However, the mechanism underlying basophil recruitment to the second tick-feeding site remains ill-defined. Here, we investigated cells and their products responsible for the basophil recruitment. Little or no basophil infiltration was detected in T-cell-deficient mice, and adoptive transfer of CD4+ but not CD8+ T cells reconstituted it. Il3 gene expression was highly upregulated at the second tick-feeding site, and adoptive transfer of interleukin-3 (IL-3)-sufficient but not IL-3-deficient CD4+ T cells conferred the basophil infiltration on T-cell-deficient mice, indicating that the CD4+ T-cell-derived IL-3 is essential for the basophil recruitment. Notably, IL-3+ resident CD4+ memory T cells were detected even before the second infestation in previously uninfested skin distant from the first tick-feeding site. Taken together, IL-3 produced locally by skin CD4+ memory T cells appears to play a crucial role in basophil recruitment to the second tick-feeding site.

Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug-induced lung injury.

BACKGROUND AND OBJECTIVE: Drug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients. METHODS: Of the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis. RESULTS: At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO2 ratio < 300). There was a significant negative linear correlation between the PaO2 /FiO2 ratio and soluble TM in BALF (r = -0.448, P < 0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO2 ratio < 300). CONCLUSION: Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI.

Phase II Study of Carboplatin and Pemetrexed in Advanced EGFR-wild-type Non-squamous Non-small Cell Lung Cancer: The Central Japan Lung Study Group Trial 0906.

BACKGROUND: Several pre-clinical and clinical studies suggest a potential predictive role of epidermal growth factor receptor (EGFR) mutation in responsiveness to cytotoxic chemotherapy. The aim of this phase II study was to evaluate the efficacy and safety of pemetrexed-carboplatin combination as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to EGFR-wild-type cases. PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients received pemetrexed (500 mg/m(2)) and carboplatin (area under the curve=6) intravenously on day 1 every 3 weeks for three to six cycles. The objective response rate (ORR) was the primary end-point; secondary end-points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: A total of 54 patients were enrolled and 53 patients received therapy. No complete response was observed and partial response was observed in 19 (35.8%) cases, resulting in an ORR of 35.8% [95% confidence interval (CI)=23.1-50.2%]. Stable disease was observed in 20 (37.7%) patients and therefore the DCR was 73.6% (95% CI=59.7-84.7%). The median PFS was 5.4 months (95% CI=4.1-6.8 months) and the median OS was 12.7 months (95% CI=9.3-16.1 months). Treatment-related grade 3 or 4 hematological toxicities were neutropenia, leukopenia, anemia and thrombocytopenia in 35.8%, 11.3%, 30.2%, and 32.1% of patients, respectively. No grade 3 febrile neutropenia was observed, and grade 3 or 4 non-hematological toxicities were mild. There was no treatment-related death. CONCLUSION: The pemetrexed-carboplatin combination was effective and well-tolerated in patients with EGFR-wild-type non-squamous NSCLC (UMIN-CTR number: UMIN000003393).

Mean pulmonary arterial pressure as a prognostic indicator in connective tissue disease associated with interstitial lung disease: a retrospective cohort study.

BACKGROUND: Pulmonary hypertension (PH) can develop in connective tissue disease associated interstitial lung disease (CTD-ILD), and contributes to increased morbidity and mortality. However, except for systemic sclerosis and mixed connective tissue disease, the impact of mean pulmonary arterial pressure (MPAP) on survival in CTD-ILD has not been sufficiently elucidated. We hypothesized that pulmonary arterial pressure may be a prognostic factor in CTD-ILDs regardless of the kind of CTD. METHODS: We evaluated the survival impact of MPAP, which is measured using right heart catheterization, on survival of patients with CTD-ILD with various CTD backgrounds. We retrospectively analyzed data of consecutive CTD-ILD patients undergoing a pulmonary function test and right-heart-catheterization at the initial evaluation. RESULTS: We studied 74 patients (33 men and 41 women, mean age 62.8 ± 9.6, 24 with rheumatoid arthritis, 14 with systemic sclerosis, 14 with polymyositis/dermatomyositis, 11 with primary Sjögren's syndrome, and 11 with other diagnoses). Six patients exhibited pulmonary hypertension (MPAP ≥ 25 mmHg), and 16 (21.6 %) had mild elevation of MPAP (≥20 mmHg). The mean MPAP was 17.2 ± 5.5 mmHg. We did not observe a significant difference in MPAP among various CTDs. A univariate Cox proportional hazard model showed that MPAP has a significant impact on survival, while the type of CTD did not contribute to survival in our cohort. A multivariate Cox proportional hazard model showed MPAP (HR = 1.087; 95 % CI 1.008-1.172; p = 0.030) to be the sole independent determinant of survival. CONCLUSIONS: Mild elevation of MPAP is relatively common in CTD-ILD patients with various CTD backgrounds. A higher MPAP at the initial evaluation was a significant independent predictor of survival in CTD-ILD. MPAP evaluation provides additional information on disease status and will help physicians predict mortality in CTD-ILD.

Efficacy and Safety of Combined Carboplatin, Paclitaxel, and Bevacizumab for Patients with Advanced Non-squamous Non-small Cell Lung Cancer with Pre-existing Interstitial Lung Disease: A Retrospective Multi-institutional Study.

AIM: To investigate the efficacy and safety of carboplatin, paclitaxel, and bevacizumab (CPB) combination chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC) with pre-existing interstitial lung disease (ILD). PATIENTS AND METHODS: Twenty-five patients with non-squamous NSCLC with ILD who underwent CPB therapy between March 2007 and July 2013 were analyzed for treatment profiles. RESULTS: The median age was 67 (range=53-79) years and 96% were men. The triplet chemotherapy was repeated for a median of four cycles. The objective response rate was 72% (18/25), the median progression-free survival time was 7.2 months, and the median overall survival time was 8.5 months. The most frequent adverse event of grade 3 or more was neutropenia (72%, 18/25). Chemotherapy-induced acute exacerbation of ILD occurred in 12% of patients. CONCLUSION: CPB therapy may be an effective and feasible regimen even for patients with ILD, although clinicians should be concerned regarding neutropenia and acute exacerbation of ILD.

Lung-Dominant Connective Tissue Disease: Clinical, Radiologic, and Histologic Features.

BACKGROUND: Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. This study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD. METHODS: We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Patients were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed. RESULTS: The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan. After multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P = .002), who also had better survival than those with h-UIP (P = .031). In contrast, survival was not associated with HRCT scan pattern (P = .79). CONCLUSIONS: The major histologic patterns in LD-CTD were UIP followed by NSIP. Two-thirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP.

Second-line docetaxel for patients with platinum-refractory advanced non-small cell lung cancer and interstitial pneumonia.

PURPOSE: The role of second-line chemotherapy in patients with non-small cell lung cancer (NSCLC) and preexisting interstitial pneumonia (IP) previously treated with platinum-based chemotherapy remains uncertain. This study was conducted to elucidate the efficacy and tolerability of second-line docetaxel monotherapy for patients with platinum-refractory advanced (stage IIIB, IV, or relapse) NSCLC and preexisting IP. METHODS: A total of 35 patients (median age, 67 years) treated with docetaxel monotherapy in a second-line setting following first-line platinum-based chemotherapy between January 2002 and December 2013 were retrospectively reviewed. RESULTS: The overall response rate and disease control rate were 8.6 % [95 % confidence interval (CI) 0-17.9 %] and 37.1 % (95 % CI 21.1-53.1 %), respectively. The median progression-free survival and median overall survival periods were 1.6 months (95 % CI 1.2-2.0 months) and 5.1 months (95 % CI 3.2-6.7 months), respectively. The incidence of acute exacerbation (AE) of IP following docetaxel monotherapy was 14.3 % (5/35 patients). Of the five patients who developed AE of IP, three patients died. The toxicity of this regimen was substantial, with treatment-related deaths occurring in 5 (14.3 %) patients (AE of IP: 3, sepsis: 2). CONCLUSIONS: Docetaxel monotherapy has a poor activity and substantial risks when used for the treatment of platinum-resistant NSCLC with IP. Novel therapeutic approaches should be explored in this setting.