A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

BACKGROUND: Bevacizumab with platinum doublet therapy including paclitaxel + carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel + carboplatin led to Grade > 3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination in a Japanese population. METHODS: Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6 cycles of carboplatin (area under the concentration-time curve = 6 on Day 1) + nanoparticle albumin-bound paclitaxel (100 mg/m2 on Days 1, 8 and 15) + bevacizumab (15 mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel + bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. RESULTS: The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42 months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade ≥ 3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). CONCLUSIONS: All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

Directed induction of alveolar type I cells derived from pluripotent stem cells via Wnt signaling inhibition.

Alveologenesis is a developmental step involving the expansion of the lung surface area which is essential for gas exchange. The gas exchange process is mediated by alveolar type I (AT1) cells, which are known to be differentiated from alveolar type II (AT2) or bipotent cells. Due to the difficulty of isolating and culturing primary AT1 cells, the mechanism underlying their differentiation is not completely understood. We performed single-cell RNA sequencing (scRNA-seq) of fibroblast-dependent alveolar organoids (FD-AOs), including human induced pluripotent stem cell (hiPSC)-derived epithelial cells and fetal lung fibroblasts, and identified hiPSC-derived AT1 (iAT1) cells. A comparison of the FD-AOs and fibroblast-free alveolar organoids showed that iAT1 cells were mainly present in the FD-AOs. Importantly, the transcriptomes of iAT1 cells were remarkably similar to those of primary AT1 cells. Additionally, XAV-939, a tankyrase inhibitor, increased iAT1 cells in passaged FD-AOs, suggesting that these cells were differentiated from hiPSC-derived AT2 (iAT2) cells through the inhibition of canonical Wnt signaling. Consequently, our scRNA-seq data allowed us to define iAT1 cells and identify FD-AOs as a useful model for investigating the mechanism underlying human AT1 cell differentiation from AT2 cells in vitro.

Long-term expansion of alveolar stem cells derived from human iPS cells in organoids.

The stable expansion of tissue-specific stem cells in vitro has contributed to research on several organs. Alveolar epithelial type II (AT2) cells function as tissue stem cells in the lung, but robust models for studying human AT2 cells are lacking. Here we report a method for the efficient generation and long-term expansion of alveolar organoids (AOs) harboring SFTPC+ alveolar stem cells derived from human induced pluripotent stem cells (hiPSCs). hiPSC-derived SFTPC+ cells self-renewed, with transcriptomes and morphology consistent with those of AT2 cells, and were able to differentiate into alveolar epithelial type I (AT1)-like cells. Single-cell RNA-seq of SFTPC+ cells and their progenitors demonstrated that their differentiation process and cellular heterogeneity resembled those of developing AT2 cells in vivo. AOs were applicable to drug toxicology studies recapitulating AT2-cell-specific phenotypes. Our methods can help scientists overcome the limitations of current approaches to the modeling of human alveoli and should be useful for disease modeling and regenerative medicine.

Serum albumin level as a potential marker for deciding chemotherapy or best supportive care in elderly, advanced non-small cell lung cancer patients with poor performance status.

BACKGROUND: There have been few data on the chemotherapy in elderly advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS), and usefulness of chemotherapy for such patients remains unclear. The objective of this study was to identify factors that predicted the survival benefit of chemotherapy. METHODS: All consecutive elderly patients (≥75 years) with advanced NSCLC, Eastern Cooperative Oncology Group PS ≥2, EGFR mutation wild type/unknown, and newly diagnosed from January 2009 to December 2012 at a tertiary hospital were retrospectively reviewed. RESULTS: We enrolled 59 patients, and 31 patients received at least one chemotherapy regimen (chemotherapy group). However, 28 patients received best supportive care (BSC) alone (BSC group). The proportion of PS 2 and serum albumin levels was significantly higher in the chemotherapy group than in the BSC group. In the chemotherapy group, log-rank testing did not show statistically significant differences in overall survival (OS) between the single-agent therapy group and carboplatin-based doublet therapy group; however, the OS of patients receiving chemotherapy for only 1 cycle (early termination) was significantly shorter than patients receiving chemotherapy for ≥2 cycles. Hypoalbuminemia was not only a risk factor for the early termination of chemotherapy but also an independent prognostic factor in the chemotherapy group. A receiver operating characteristic curve analysis showed that the best cut-off value was 3.40 g/dL. In patients with serum albumin levels ≥3.40 g/dL, OS was significantly better in the chemotherapy group than in the BSC group (p = 0.0156), however, patients with serum albumin levels <3.40 g/dL exhibited poor prognosis regardless of the presence or absence of chemotherapy. CONCLUSION: In the elderly NSCLC patients with poor PS, serum albumin levels may help identify certain patient populations more likely to receive a survival benefit of systemic chemotherapy.

Interstitial lung disease in clinically amyopathic dermatomyositis with and without anti-MDA-5 antibody: to lump or split?

BACKGROUND: Interstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM-ILD) is often refractory and rapidly progressive. Although the anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody is associated with rapidly progressive ILD (RP-ILD), differences in clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD remain unclear. METHODS: To clarify the differences in the clinical features and prognosis between anti-MDA-5 antibody-positive and -negative cases, we retrospectively reviewed the medical records of patients diagnosed with CADM-ILD with and without anti-MDA-5 antibody at Kurashiki Central Hospital from January 2005 to September 2014. RESULTS: Anti-MDA-5 antibody was found in 10 of 16 patients (63%). The levels of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) at the first visit were significantly lower in positive patients than in negative patients, whereas the levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP), and the CD4(+)/CD8(+) ratio in the bronchoalveolar lavage (BAL) fluid were significantly higher in positive patients than negative patients. Subpleural ground-glass opacity (GGO) or irregular linear opacity was predominant in positive patients. Peribronchovascular consolidation was predominant in negative patients. Positive patients had significantly lower survival rates than negative patients, with all six fatal cases occurring in positive patients who died of refractory ILD within 92 days from the first visit despite intensive treatment. CONCLUSIONS: There are clear differences in the clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD. Low serum KL-6 and SP-D levels, high serum AST and γ-GTP levels, high CD4(+)/CD8(+) ratio in BAL fluid, and predominance of subpleural GGO or irregular linear opacity in HRCT may help to discriminate anti-MDA-5 antibody-positive CADM-ILD with poor prognosis.

Regulated activity of PP2A-B55 delta is crucial for controlling entry into and exit from mitosis in Xenopus egg extracts.

Entry into mitosis depends on the activity of cyclin-dependent kinases (CDKs). Conversely, exit from mitosis occurs when mitotic cyclins are degraded, thereby extinguishing CDK activity. Exit from mitosis must also require mitotic phosphoproteins to revert to their interphase hypophosphorylated forms, but there is a controversy about which phosphatase(s) is/are responsible for dephosphorylating the CDK substrates. We find that PP2A associated with a B55 delta subunit is relatively specific for a model mitotic CDK substrate in Xenopus egg extracts. The phosphatase activity measured by this substrate is regulated during the cell cycle--high in interphase and suppressed during mitosis. Depletion of PP2A-B55 delta (in interphase) from 'cycling' frog egg extracts accelerated their entry into mitosis and kept them indefinitely in mitosis. When PP2A-B55 delta was depleted from mitotic extracts, however, exit from mitosis was hardly delayed, showing that other phosphatase(s) are also required for mitotic exit. Increasing the concentration of PP2A-B55 delta in extracts by adding recombinant enzyme inhibited the entry into mitosis. This form of PP2A seems to be a key regulator of entry into and exit from mitosis.

Transient asymptomatic pulmonary opacities in a patient with MET exon 14 skipping non-small cell lung cancer: A case report.

Mesenchymal epithelial transition factor receptor (MET) tyrosine kinase inhibitors (MET-TKIs) have been approved for the treatment of non-small cell lung cancers with MET exon 14 skipping mutations. Transient asymptomatic pulmonary opacities (TAPOs) associated with epidermal growth factor receptor (EGFR)-TKIs have been reported. Here, we report a case wherein ground-glass opacities (GGOs) appeared during the course of treatment with tepotinib, a MET-TKI, but spontaneously resolved with drug withdrawal, after which treatment was resumed with a reduced dose. Although there have been no reports of TAPOs with MET-TKIs, the clinical and imaging findings of this case were consistent with TAPOs. For TAPOs occurring because of MET-TKI, the drug can be continued under careful observation even if GGOs appear.

Physiologic 18F-FDG muscle uptake in severe COPD: Implications for accurate lung cancer staging.

Recognizing physiologic 18F-fluorodeoxyglucose (FDG) uptake in severe COPD is crucial to avoid mistaking it for lung cancer metastasis. Correlating 18F-FDG avid lesions with co-registered computed tomography is essential for accurate lung cancer staging and preventing unnecessary interventions.

Concurrent trastuzumab deruxtecan-induced interstitial lung disease and COVID-19 in the treatment of advanced breast cancer.

Patients with cancer are at an increased risk of developing coronavirus disease 2019 (COVID-19) infection. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) against epidermal growth factor receptor 2 (HER2)-positive cancer, known to cause drug-induced interstitial lung disease (DILD), including drug-induced pneumonitis. A 60-year-old woman with breast cancer developed a fever during treatment with T-DXd and was diagnosed with COVID-19. The fever persisted for approximately 3 weeks, and chest computed tomography showed multiple consolidations with bilateral peripheral predominance. Since the clinical course was atypical for COVID-19 due to the long duration of the fever and the CT pattern was frequently seen in T-DXd-induced ILD, the patient was diagnosed with T-DXd-induced ILD, following which, prednisolone was started, leading to improvement in the symptoms and fading of shadows. Even in patients suspected of COVID-19 pneumonia, physicians should consider the possibility of DILD, particularly in patients undergoing cancer treatment.

Negative pressure pulmonary edema in a patient with COVID-19.

Negative pressure pulmonary edema (NPPE) should be considered in the differential diagnosis from an episode of asphyxia, and even if NPPE is diagnosed, the possibility of COVID-19 should be kept in mind under coronavirus pandemic conditions.

Epipericardial fat necrosis in a patient with sudden chest pain.

Epipericardial fat necrosis (EFN) may be considered in the differential diagnosis of chest pain. Clinicians should be kept in mind that EFN is self-limiting and is often followed up with imaging.

Core-shell hydrogel microfiber-expanded pluripotent stem cell-derived lung progenitors applicable to lung reconstruction in vivo.

Lung transplantation is the only treatment available for end-stage lung diseases; however, donor shortage is a global issue. The use of human pluripotent stem cells (hPSCs) for organ regeneration is a promising approach. Nevertheless, methods for the expansion of isolated hPSC-derived lung progenitors (hLPs) for transplantation purposes have not yet been reported. Herein, we established an expansion system of hLPs based on their three-dimensional culture in core-shell hydrogel microfibers, that ensures the maintenance of their bipotency for differentiation into alveolar and airway epithelial cells including alveolar type II (AT2) cells. Further, we developed an efficient in vivo transplantation method using an endoscope-assisted transtracheal administration system; the successful engraftment and in vivo differentiation of hLPs into alveolar epithelial cells (incorporated into the alveoli) was observed. Importantly, expanded hLPs in the context of microfibers were successfully transplanted into the murine lungs, opening avenues for cell-based therapies of lung diseases. Therefore, our novel method has potential regenerative medicine applications; additionally, the high-quality hLPs and AT2 cells generated via the microfiber-based technology are valuable for drug discovery purposes.

Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.

Mucociliary clearance is an essential lung function that facilitates the removal of inhaled pathogens and foreign matter unidirectionally from the airway tract and is innately achieved by coordinated ciliary beating of multiciliated cells. Should ciliary function become disturbed, mucus can accumulate in the airway causing subsequent obstruction and potentially recurrent pneumonia. However, it has been difficult to recapitulate unidirectional mucociliary flow using human-derived induced pluripotent stem cells (iPSCs) in vitro and the mechanism governing the flow has not yet been elucidated, hampering the proper humanized airway disease modeling. Here, we combine human iPSCs and airway-on-a-chip technology, to demonstrate the effectiveness of fluid shear stress (FSS) for regulating the global axis of multicellular planar cell polarity (PCP), as well as inducing ciliogenesis, thereby contributing to quantifiable unidirectional mucociliary flow. Furthermore, we applied the findings to disease modeling of primary ciliary dyskinesia (PCD), a genetic disease characterized by impaired mucociliary clearance. The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip. These findings suggest that the disease model of PCD developed here is a potential platform for making diagnoses and identifying therapeutic targets and that airway reconstruction therapy using mechanical stress to regulate PCP might have therapeutic value.

In Vitro Disease Modeling of Hermansky-Pudlak Syndrome Type 2 Using Human Induced Pluripotent Stem Cell-Derived Alveolar Organoids.

It has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases.

Chronological assessment of airway lesions in relapsing polychondritis by positron emission tomography.

A 40-year old woman presented with pyrexia, productive cough, and bilateral precordial pain. Positron emission tomography (PET)-computed tomography (CT) showed high, diffuse F-18 deoxyglucose accumulation in the tracheal, peribronchial, and bilateral costal cartilage. We diagnosed her with relapsing polychondritis (RP) based on McAdam's criteria. Airway lesions are a major prognostic indicator of RP, and so chronological assessment and control is essential. In this patient, PET-CT accurately reflected both the location and severity of the inflammation and helped to guide treatment decision-making and facilitated early detection of recurrence. However, its high cost is prohibitive to frequent use, making it necessary to comprehensively evaluate serum C-reactive protein levels, bronchoscopy, spirometry, and 3D-CT.

Identifying the Cause of the "Saturation Gap": Two Cases of Dapsone-induced Methemoglobinemia.

Diaphenylsulfone (DDS: Dapsone) is used for Pneumocystis pneumonia (PCP) prophylaxis, and methemoglobinemia has rarely been reported as a side effect of DDS. We herein report two cases of DDS-related methemoglobinemia in an 81-year-old man with organizing pneumonia and an 84-year-old woman with eosinophilic pneumonia under treatment with prednisolone. Both patients initially received trimethoprim/sulfamethoxazole for PCP prophylaxis and were switched to DDS due to side effects and subsequently exhibited a clinically unexplainable decrease in SpO2. Methemoglobinemia was diagnosed based on the findings of arterial blood gas analyses. In both cases, the methemoglobinemia improved after discontinuing DDS.