Clinical features of 26 cases of COVID-19-associated conjunctivitis.

PURPOSE: To explore the clinical features of COVID-19-associated conjunctivitis with the objective of preventing the spread of infection. STUDY DESIGN: Retrospective cohort study. METHODS: From March 2020 to March 2021, we retrospectively reviewed 26 (9.8%) consecutive COVID-19 patients with conjunctivitis among 282 COVID-19 cases admitted to our hospital. Clinical symptoms, onset date of conjunctivitis, time to patient recovery, and eye drop intervention were investigated. In addition, risk factors for developing conjunctivitis were statistically examined among 206 inpatients available for within 5 days of the onset. A multivariate analysis of conjunctivitis risk factors was performed. RESULTS: Among the 282 COVID-19 patients, 4 (1.4%) had conjunctival hyperemia as the primary symptom. The median time of onset was 4 days after the COVID-19 onset. Hyperemia was observed in all cases, but other ocular symptoms were rare. The median duration of hyperemia was 3 days. A multiple logistic regression analysis revealed that a young age (p=0.005) and current smoking habit (p=0.027) were independent risk factors for conjunctivitis after COVID-19. CONCLUSIONS: COVID-19-associated conjunctivitis is rare in the elderly and strongly associated with a history of smoking. It often occurs in the early stages of infection, and while hyperemia is recognized as a clinical symptom, other ocular symptoms are rare or non-existent. Many cases recover within a short time.

[Surgical Case of Bronchial Mucoepidermoid Carcinoma Safely Diagnosed by Enucleation Under the Bronchoscopy After Bronchial Arterial Embolization].

A 28-year-old male presented to our hospital with hemoptysis and his chest computerized tomography (CT) showed the right middle and lower lobe atelectasis due to the tumor of right intermediate bronchial trunk. To reduce the blood flow to the tumor, bronchial arterial embolization was performed and the tumor was resected using Cryoprobe with a flexible endobronchial scope. Thus, we could observe the tumor localization and diagnose before the surgical procedure. We performed the right sleeve middle lobectomy and the right lower lobe was safely preserved.

Comparison of self-reported symptoms in COVID-19 patients who had or had not previously received COVID-19 mRNA vaccination.

Although mRNA coronavirus disease 2019 (COVID-19) vaccines have been reported for high effectiveness against symptoms, it remains unclear whether post-vaccination infections are less symptomatic than infections in vaccine-naive individuals. We included patients with COVID-19 diagnosed by polymerase chain reaction tests during Japan's alpha and delta variant epidemics. COVID-19 symptoms at approximately 4 weeks were compared based on COVID-19 vaccination status. In total, 398 cases (372 symptomatic and 26 asymptomatic; 286 unvaccinated, 66 vaccinated with one dose, and 46 with two doses) were analyzed. The most common symptoms were fever (78.4%), fatigue (78.4%), cough (74.4%), loss of taste or smell (62.8%), and headache (59.8%). Post-vaccination infections were significantly less likely to be symptomatic. Possible confounder-adjusted odds ratios of two vaccine doses against fatigue, dry eyes and mouth, insomnia, fever, shortness of breath, unusual muscle pains, and loss of taste or smell were 0.18 (95% confidence interval [CI]: 0.09-0.38), 0.22 (95% CI: 0.08-0.59), 0.33 (95% CI: 0.14-0.80), 0.31 (95% CI: 0.15-0.63), 0.36 (95% CI: 0.16-0.76), 0.40 (95% CI: 0.19-0.82), and 0.44 (95% CI: 0.22-0.87), respectively. Post-vaccination infections after two mRNA COVID-19 vaccine doses show milder and fewer symptoms than infections in unvaccinated patients, highlighting the effectiveness of vaccination.

Absence of copy number gain of EGFR: A possible predictive marker of long-term response to afatinib.

Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is diverse even in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long-term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR-TKI, have been reported, but how to predict such long survivors has not been clarified. A multi-institutional prospective observational study, based on comprehensive genomic examination performed with next-generation sequencing of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long-term response to afatinib. Twenty-nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled in the study. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360. ctDNA was detected in 25 of the 29 samples. Median progression-free survival was shorter in patients whose tumors had EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome-editing lung cancer cell lines. HCC827 with EGFR amplification was relatively resistant to afatinib at concentrations below 0.5 nM, but genome-edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be a predictive marker of long-term response to afatinib. Comprehensive genomic analysis could lead to a more accurate prediction of EGFR-TKI efficacy.

A Randomized Phase 2 Study of 5-Aminolevulinic Acid Hydrochloride and Sodium Ferrous Citrate for the Prevention of Nephrotoxicity Induced by Cisplatin-Based Chemotherapy of Lung Cancer.

INTRODUCTION: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. METHODS: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. RESULTS: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m2, respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m2, respectively, p = 0.013). CONCLUSIONS: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.

Real-World Effectiveness of the mRNA COVID-19 Vaccines in Japan: A Case-Control Study.

The real-world effectiveness of the coronavirus disease 2019 (COVID-19) vaccines in Japan remains unclear. This case-control study evaluated the vaccine effectiveness (VE) of two doses of mRNA vaccine, BNT162b2 or mRNA-1273, against the delta (B.1.617.2) variant in the Japanese general population in the period June-September 2021. Individuals in close contact with COVID-19 patients were tested using polymerase chain reaction (PCR). A self-administered questionnaire evaluated vaccination status, demographic data, underlying medical conditions, lifestyle, personal protective health behaviors, and living environment. Two vaccine doses were reported by 11.6% of cases (n = 389) and 35.2% of controls (n = 179). Compared with controls, cases were younger and had a lower proportion who always performed handwashing for ≥20 s, a higher proportion of alcohol consumers, and a lower proportion of individuals living in single-family homes or with commuting family members. After adjusting for these confounding factors and day of PCR testing by multivariate logistic regression analysis, the VE in the period June-July (delta variant proportion 45%) was 92% and 79% in the period August-September (delta variant proportion 89%). The adjusted VE for homestay, hotel-based isolation and quarantine, and hospitalization was 78%, 77%, and 97%, respectively. Despite declining slightly, VE against hospitalization remained robust for ~3 months after the second dose. Vaccination policymaking will require longer-term monitoring of VE against new variants.

The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment.

BACKGROUND: EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified. METHODS: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas® ), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360® . Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed. RESULTS: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation. CONCLUSIONS: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M.

Acute Generalized Exanthematous Pustulosis Caused by Erlotinib in a Patient with Lung Cancer.

Acute generalized exanthematous pustulosis (AGEP) is a rare drug-related adverse skin reaction caused mainly by antibiotics. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used to treat lung cancer. A 69-year-old woman with primary lung cancer (adenocarcinoma, cT3N1M1b, stage IVB) developed erythema and multiple skin pustules on her abdomen and both thighs after 7 weeks of erlotinib treatment. She also had fever and general fatigue. Histological examination of a skin biopsy specimen showed intraepidermal pustules with neutrophil and eosinophil infiltration. She was diagnosed with erlotinib-induced AGEP. AGEP resolved by erlotinib discontinuation and systemic corticosteroid treatment. The lung cancer progressed when erlotinib was discontinued, so afatinib, a second-generation EGFR-TKI, was administrated without any skin adverse effects. Afatinib successfully decreased the lung cancer, and maintained the disease stable for 1 year. Although acneiform rash was the most common skin adverse event caused by EGFR, AGEP rarely occurred. The present case also demonstrated that it is possible to switch agents, from erlotinib to afatinib, even though they have the same pharmacological effects. Although AGEP is a rare drug-related skin disorder, physicians should be aware that erlotinib may induce AGEP.

Phase II trial of gefitinib plus pemetrexed after relapse using first-line gefitinib in patients with non-small cell lung cancer harboring EGFR gene mutations.

OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial. However, various clinical trials have suggested that EGFR-TKI beyond PD plus single-agent chemotherapy may be a possible treatment strategy. MATERIALS AND METHODS: This study was a single-arm phase II trial. Patients with EGFR-activating mutations (del19 and L858R) that progressed using first-line gefitinib treatment were enrolled and treated with gefitinib beyond PD plus pemetrexed 500 mg/m2 q3w. The primary endpoint was progression-free survival (PFS). Mutation-biased polymerase chain reaction quenching probe, which is the original method for detecting T790M mutations in cell-free plasma DNA, was used prior to treatment. RESULTS: Thirty-six patients were enrolled between May 1, 2013, and March 31, 2016. One patient was excluded before starting the treatment. Among the 35 patients, 15 patients had del19 mutations, and 20 patients had L858R mutations; 33 patients were evaluable for response by using radiographic findings. The median PFS was 6.7 months (95% confidence interval: 4.4-7.7 months). Nineteen patients were T790M positive. No significant difference in PFS was found in a subgroup analysis of EGFR mutation status and T790M positivity. All toxicities were tolerable. CONCLUSION: Gefitinib plus pemetrexed treatment following relapse using gefitinib in patients with Non-small cell lung cancer harboring EGFR mutations demonstrated preferable PFS with mild toxicity. This combination therapy may be considered for platinum-unfit patients without T790M with disease progression using first-line gefitinib. (This clinical trial was registered in UMIN-CTGR as UMIN000010709).

Severity and predictive factors of adverse events in pemetrexed-containing chemotherapy for non-small cell lung cancer.

Pemetrexed is a key anticancer agent for treatment of advanced non-small cell lung cancer (NSCLC). Pemetrexed is generally well tolerated, but individual-patient differences exist in severity of adverse events. Our study aimed to characterize the adverse events of pemetrexed that result in discontinuation of chemotherapy and to identify risk factors associated with those adverse events. We retrospectively studied the incidence of adverse events in 257 patients with NSCLC who received pemetrexed (P) with or without bevacizumab (B) and/or carboplatin (C): P, PB, CP, or CPB. Patients whose chemotherapy was discontinued were divided into two groups according to adverse events and disease progression. Grade 2/3 nausea, fatigue with P and PB, and rash with CP and CPB occurred more frequent in the adverse events group than in the disease progression group. Multivariate analysis indicated that grade 2/3 nausea [odds ratio (OR) 9.94; 95% confidence interval (CI) 1.46-67.37; p = 0.01] and fatigue (OR 10.62; CI 1.60-70.20; p = 0.01) with P or PB, and rash (OR 6.12; CI 1.34-27.88; p = 0.01) with CP or CPB, were independent risk factors for discontinuation of chemotherapy. Administration of dexamethasone at doses less than 4 mg after the day of pemetrexed administration was associated with nausea following P or PB (OR 11.08; 95% CI 1.02-119.95; p = 0.04). Grade 2/3 nausea and fatigue with P or PB, and rash with CP or CPB, were associated with discontinuation of chemotherapy.

Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study.

Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re-biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment.

The long-term survival of a patient with adenosquamous lung carcinoma harboring EGFR-activating mutations who was treated with gefitinib.

A 56-year-old woman diagnosed with squamous cell lung carcinoma after a transbronchoscopic examination underwent left upper lobectomy, which revealed a pathological diagnosis of adenosquamous carcinoma containing moderately differentiated squamous cell carcinoma and bronchioloalveolar carcinoma. The epidermal growth factor receptor (EGFR) exon 19 delE746-A750 mutation was detected in deoxyribonucleic acid (DNA) isolated from specimens of both components using microdissection. Treatment with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in a long-term tumor response lasting three years. Adenosquamous carcinoma is difficult to diagnose using transbronchoscopic procedures. Therefore, the examination of EGFR mutation status is important in order to determine the appropriate treatment, even in patients with non-adenocarcinoma.

Application of a highly sensitive detection system for epidermal growth factor receptor mutations in plasma DNA.

INTRODUCTION: : Detection of epidermal growth factor receptor (EGFR) mutations is indispensable to determine an appropriate lung cancer treatment. Although retreatment often prolongs survival, how to select the appropriate population for retreatment has not been clarified. METHODS: : We used novel methods to identify EGFR mutations: wild inhibiting polymerase chain reaction (PCR) and quenched probe system (WIP-QP) for exon 19 deletions and mutation-biased PCR and quenched probe system for L858R. After the detection limits were determined, we examined DNA isolated from lung cancer specimens and circulating plasma DNA samples of 39 adenocarcinoma patients whose primary tumors harbored EGFR exon 19 deletions or L858R. RESULTS: : Detection limit was 0.005 to 0.04 ng in genomic DNA and 0.1% to 0.3% in mutant plasmids. The results of cancer tissue specimens were identical to those with existing systems (nucleic acid-locked nucleic acid PCR clamp or cycleave PCR), except for two samples that showed both exon 19 deletions and L858R. One of the two samples was confirmed to harbor L858R mutation by allele-specific oligonucleotide PCR; the other one did not. Exon 19 deletions and L858R were detected in 44.7% and 8.7% of patients, using plasma DNA, among those who carried the identical abnormalities in primary tumors all of cases that evidenced pathological stage IV except for one patient, suggesting that EGFR mutations might be preferentially detected in plasma DNA obtained from patients in advanced stages. Serial monitoring of these mutations with T790M, a gate keeper mutation, demonstrated correlation with disease state. CONCLUSIONS: : Our novel detection systems for EGFR mutations could be useful not only at the beginning of treatment but also for monitoring using plasma DNA for deciding appropriate treatment, including rechallenge with EGFR-tyrosine kinase inhibitors.

A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA.

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are widely used to treat lung adenocarcinomas with EGFR-activating mutations. However, half of the patients acquire resistance because of the gatekeeper T790M mutation. Noninvasive mutation detection system is desired considering the difficulty in obtaining tissue specimens during disease progression. METHODS: Sixty-seven plasma DNA samples from 49 patients with lung adenocarcinoma and 30 healthy volunteers were evaluated. T790M in plasma DNA was determined using the mutation-biased polymerase chain reaction (PCR) quenching probe (MBP-QP) method. The method combines MBP and genotyping, the latter based on analysis of the melting curve of the probe DNA binding the target mutated site using a fluorescence QP system. RESULTS: The detection limit was two copies of control plasmid and 0.2 ng of genomic DNA. The mutant plasmid could be detected when it accounted for as little as 0.3% of a mixture of plasmids carrying EGFR exon 20 with or without T790M. The T790M mutation was detected in plasma DNA from 10 of 19 patients (53%) who acquired resistance, but not in nonresponders, patients responding to treatment, or those not treated with EGFR tyrosine kinase inhibitor. Other mutation detection systems, such as the nucleic acid-locked nucleic acid PCR clamp, the cycleave PCR technique, and allele-specific oligonucleotide PCR, detected T790M in three, four, and six patients, respectively, among 10 in which T790M was detected by the MBP-QP method. CONCLUSIONS: The MBP-QP method is simple, sensitive, and-intriguingly-reflective of clinical course, compared with the other three mutation-detection systems. Thus, the MBP-QP method is an ideal noninvasive monitoring system for detecting T790M in plasma samples.

A fully integrated, automated and rapid detection system for KRAS mutations.

KRAS mutations are detected in tumors of various organs, and they are also markers of resistance for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and monoclonal antibodies against the EGFR. Thus, the accurate and rapid detection of KRAS mutations is crucial, not only for screening, but also for the prediction of the efficacy of molecular-targeted therapy. The aim of the present study was to establish a novel automated detection system for KRAS mutations. One hundred and thirty-six lung adenocarcinoma patients were genotyped for KRAS mutations with both the conventional direct sequence (DS) method and with the newly developed quenching probe (QP) method that obtains data automatically within 60 min. The detection limit of the QP method using a control plasmid containing the KRAS mutation was 50 copies, and 10% mutant plasmid was detected in the mixture of wild-type and mutants. The results obtained by the QP and DS methods were identical in all but two of the 136 cases. The two differentially identified samples, which consisted of substantially fewer lung cancer cells, were positive according to the QP method but negative as determined by DS for KRAS mutations. These findings characterize the QP method as an accurate and rapid detection system for KRAS mutations.

[A case of mucormycosis of the thoracic wall in a non-immunocompromised man].

An 80-year-old man visited our hospital for the treatment of an anterior chest wall eruption from February 2007 and presented with dull pain in August 2007. He was referred to our department because chest CT showed the formation of an abscess from the subcutaneous area to the thoracic wall. Histological findings obtained from CT-guided biopsy revealed epithelioid granuloma without caseous necrosis, but both acid-fast bacteria and bacteriologic culture obtained from aspirated fluid samples were negative. Antituberculous therapy was selected because a tuberculous abscess was strongly suspected. However, the patient discontinued treatment soon after therapy began. He visited our hospital again for chest pain due to rupture of the abscess in October 2007. The pathological findings obtained from a second biopsy gave the same results, and antituberculosis therapy was restarted. However, his CT findings had worsened by August 2008, and a third biopsy was performed. Histopathologically, we diagnosed mucormycosis based on the findings of fungal hyphae, with broad, irregular branching at right angles. Thereafter, liposomal amphotericin B (L-AMB) was given intravenously and the abscess markedly improved. Excision was then performed, followed by adjuvant L-AMB administration, and there has been no recurrence to date.

Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Developing more effective NSCLC therapeutics will require the elucidation of the genetic and biochemical bases for this disease. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-ras-induced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined. METHODOLOGY/PRINCIPAL FINDINGS: We used genetic and pharmacologic approaches to modulate the activity of phosphatidylinositol 3-kinase (PI3K), a key mediator of oncogenic K-ras, in two genetic mouse models of lung adenocarcinoma. Oncogenic K-ras-induced BASC accumulation and tumor growth were blocked by treatment with a small molecule PI3K inhibitor and enhanced by inactivation of phosphatase and tensin homologue deleted from chromosome 10, a negative regulator of PI3K. CONCLUSIONS/SIGNIFICANCE: We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.

Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer.

Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.

Intratumoral epiregulin is a marker of advanced disease in non-small cell lung cancer patients and confers invasive properties on EGFR-mutant cells.

Non-small cell lung cancer (NSCLC) cells with activating epidermal growth factor receptor (EGFR) somatic mutations have unique biological properties, including high expression of the ErbB ligand epiregulin; however, the biological role of epiregulin in these cells has not been elucidated. To examine its role, we used an immunohistochemical approach to detect epiregulin expression in NSCLC biopsy samples and pharmacologic and genetic approaches to inhibit epiregulin in cultured NSCLC cells. In NSCLC biopsy samples, epiregulin was detected in 237 of 366 (64.7%) tumors, which correlated with nodal metastasis and a shorter duration of survival. In EGFR-mutant NSCLC cell lines, treatment with a small-molecule EGFR tyrosine kinase inhibitor diminished mRNA levels of the gene encoding epiregulin (EREG). The ability of EGFR-mutant NSCLC cells to invade through Matrigel in vitro was inhibited by treatment with an anti-epiregulin neutralizing antibody or by transfection with an EREG short hairpin RNA. Collectively, these findings show that epiregulin expression correlated with advanced disease, was EGFR dependent, and conferred invasive properties on NSCLC cells. Additional studies are warranted in NSCLC patients to evaluate whether epiregulin expression predicts the metastatic potential of primary tumors and whether anti-epiregulin treatment strategies are efficacious in the prevention of metastasis.

Hsp90 inhibitors cause G2/M arrest associated with the reduction of Cdc25C and Cdc2 in lung cancer cell lines.

PURPOSE: Hsp90, a molecular chaperone, is involved in folding, assembly, maturation, and stabilization of the client proteins which regulate survival of cancer cells, and thus Hsp90 inhibitors may be potential molecular targeting agents for cancer treatment. We investigated whether Hsp90 inhibitors have therapeutic value in lung cancer. METHODS: First, expression levels of Hsp90 in lung cancer cells were examined by western blotting and immunohistochemical analyses. Next, the effect of Hsp90 inhibitors, geldanamycin and 17-allylaminogeldanamycin (17-AAG), on lung cancer cell growth was examined. RESULTS: Remarkable high expression of Hsp90 protein in lung cancer cell lines and a more intense signal for Hsp90 by immunohistochemistry in males, patients with smoking index over 600, and squamous cell carcinoma were observed. Both Hsp90 inhibitors dose dependently inhibited the growth of lung cancer cell lines and induced G2/M arrest concomitant with decreased protein levels of Cdc25C and Cdc2. Moreover, combination of an Hsp90 inhibitor and irradiation had an additive effect on cell growth inhibition and reduction of Cdc25C and Cdc2 protein levels. CONCLUSION: Hsp90 inhibitor is thus a therapeutic tool for lung cancer based on its target proteins, which are involved in tumor progression and antiproliferative activity in lung cancer cells.