Survival benefit of combinatorial osimertinib rechallenge and entrectinib in an EGFR-mutant NSCLC patient with acquired LMNA-NTRK1 fusion following osimertinib resistance.

Acquired resistance to osimertinib is inevitable and heterogeneous despite its documented efficacy against EGFR-mutated non-small cell lung cancer (NSCLC). Subsequent therapeutic options assume the dominant form of the resistance mechanism; however, the more rare oncogenic driver, NTRK1 fusion, has also reportedly conferred osimertinib resistance. Nevertheless, clear-cut options when NSCLCs are driven by EGFR mutation and the subsequent NTRK fusion are lacking. This is a case of NSCLC wherein exon 19 deletion in EGFR (19del) and acquired LMNA-NTRK1 fusion were accompanied by the persistence of EGFR T790M. The patient underwent peritoneal metastasis after multiple targeted therapies: gefitinib, osimertinib, chemotherapy, and anlotinib plus docetaxel (in clinical trials). Osimertinib was subsequently re-administered with the NTRK fusion inhibitor entrectinib, resulting in remission of peritoneal metastases even after slow progression of pancreatic metastasis over the following 5 months. An extensive literature review to identify the efficacies of therapies for NTRK fusion as the means to acquired resistance to EGFR TKIs revealed that blocking both the EGFR mutation and the subsequent NTRK fusion can provide clinical benefits following EGFR TKIs resistance; however, the efficacy and safety of combination therapies must be further investigated. To precisely manage EGFR-mutated NSCLCs, it is also essential to identify the resistance mechanisms by repeating biopsies.

Compound heterozygous mutation of RTEL1 in interstitial lung disease complicated with pneumothorax and emphysema: A case report and literature review.

Interstitial lung diseases (ILDs) are common respiratory diseases with limited treatment options and poor prognoses. Early and accurate diagnosis of ILD is challenging and requires a multidisciplinary discussion. We report a 32-year-old patient admitted to our hospital with cough and increasing dyspnea on exertion. Computerized tomography scan of his chest demonstrated diffuse interstitial abnormalities, emphysematous changes, and a pneumothorax. Whole-exome sequencing (WES) and Sanger sequencing indicated a compound mutation of heterozygosity in RTEL1 gene c.2992C > T(p.Arg998*) and c.482T > C(p.Val161Ala). In-silicon analysis revealed the pathogenic nonsense mutation c.2992C > T, which introduced a premature stop codon in exon 30 of RTEL1. The patient is still alive with progressive dyspnea to now. We reviewed the pathophysiology of ILD patients carrying RTEL1 mutations and the roles of RTEL1 mutation in guiding treatment and prognostication in ILD.

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma.

OBJECTIVE: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. METHODS: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 µg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. RESULTS: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. CONCLUSIONS: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

Tripterygium polyglycosid attenuates the established airway inflammation in asthmatic mice.

OBJECTIVE: To investigate the effect of Tripterygium polyglycosid on establishing airway eosinophil infiltration and related airway hyperresponsiveness of asthmatic mice. METHODS: A mature murine asthmatic model was made with ovabulmin sensitized and challenged C57BL/6 mice. Forty mice were divided into four groups with 10 mice in each group: mice sensitized and challenged with saline (WS group), mice sensitized and challenged with ovalbumin (WO group), mice sensitized and challenged with ovalbumin and treated with Tripterygium polyglycosid (TP group) and Dexamethasone (DXM group). The mice were intraperitoneally injected with 20 µg chicken ovabulmin emulsified in injected alum on days 0 and 14, then were challenged with an aerosol generated from 1% ovabulmin on days 24, 25 and 26. Tripterygium polyglycosid was injected intraperitoneally at 50 mg/kg on days 25, 26 and 27 after ovabulmin challenge. Dexamethasone was administrated to mice at 2 mg/kg on day 21, 23 before ovabulmin challenge. The airway hyperresponsiveness, mucus production, eosinophils in parabronchial area and bronchoalveolar lavage fluid and the level of interleukin-5, granulo-macrophage clone stimulating factor in bronchoalveolar lavage fluid were measured as indexes of inflammation. RESULTS: Tripterygium polyglycosid treatment after ovabulmin challenge completely inhibited eosinophil infiltration in bronchoalveolar lavage fluid [(0.63 ± 0.34)× 10(4) vs. (75.0 ± 14.8)× 10(4), P<0.05] and the peribrochial area (12.60 ± 3.48 mm(2) vs. 379.0 ± 119.3 mm(2), P<0.05), mucus overproduction in airway (2.8 ± 1.7 vs. 7.1±5.6, P<0.05), and increased interleukin-5 levels in bronchoalveolar lavage fluid (28.8 ± 2.8 pg/mL vs. 7.5 ± 3.5 pg/mL, P<0.05). Meanwhile, Tripterygium polyglycosid treatment after ovabulmin challenge also partially inhibited airway hyperresponsiveness. The level of granulo-macrophage clone stimulating factor in bronchoalveolar lavage fluid didn't change with drugs intervention. CONCLUSIONS: The administration of Tripterygium polyglycosid could inhibit the established airway inflammation and reduce the airway hyperresponsiveness of allergic asthmatic mice. It provides a possible alternative therapeutic for asthma.

[The mechanism of airway inflammation in eosinophilic bronchitis and cough variant asthma].

OBJECTIVE: To explore the characteristics of airway inflammatory cells, cytokines and inflammatory mediators in eosinophilic bronchitis (EB) and cough variant asthma (CVA) patients and to elucidate the underlying mechanism of distinct airway inflammation between EB and CVA. METHODS: This study included 15 patients with EB (EB group), 15 patients with cough variant asthma (CVA, CVA group), 14 patients with bronchial asthma (asthma group) and 14 healthy controls (healthy group). Percentage of eosinophils (EOS) in sputum induced by hypertonic saline was detected by FACS. The percentage of CD(69)(+) EOS stimulated by interleukin-5 (IL-5) and interferon γ (IFN-γ) was also detected by FACS. The expression of leukotriene C4 synthase (LTC4S) and prostaglandin-endoperoxide synthase-2 (PTGS2) mRNA in sputum was measured by real-time PCR and the concentration of leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) in sputum was measured by ELISA. RESULTS: The percentage of EOS in induced sputum was 15.8 ± 3.2 (EB group), 13.0 ± 2.7 (CVA group) and 11.6 ± 4.5 (asthma group), respectively, which were significantly higher than 1.0 ± 0.4 in the healthy group. The difference was significant and the t value was 16.31, 15.23 and 14.21 respectively (P < 0.05). After stimulated by IL-5 and IFN-γ, the percentage of CD(69)(+) EOS in induced sputum was 1.5 ± 0.4 and 1.5 ± 0.5 (EB group), 1.4 ± 0.4 and 1.4 ± 0.3 (CVA group) and 1.42 ± 0.72 and 1.37 ± 0.46 (asthma group) respectively. There was no statistical significance between these 3 groups, but when compared with 0.4 ± 0.2 and 0.4 ± 0.1 in healthy group, the difference was significant (P < 0.05). The expression of IL-5 mRNA and protein in induced sputum of EB group, CVA group and asthma group were higher than the healthy group and the difference was all statistically different (P < 0.05), but there was no statistical significance between EB group, CVA group and asthma group. The expression of IFN-γ mRNA and protein in induced sputum of each group was not different when compared with healthy group (P > 0.05). The concentration of PGE2 in induced sputum of EB group was(839 ± 69) ng/L, which was higher than (33 ± 8) ng/L of CVA group, (25 ± 6) ng/L of asthma group and (24 ± 8) ng/L of healthy group (all P < 0.01). There was no statistical difference between CVA group, asthma group and healthy group. The expression of PTGS2 in induced sputum of EB group increased significantly; when compared with CVA group, asthma group and healthy group, the difference was significant (all P < 0.01). The concentration of LTC4 in induced sputum of EB group, CVA group and asthma group was all higher than the healthy group (all P < 0.05). The expression of LTC4S mRNA of EB group, CVA group and asthma group was also higher than the healthy group (all P < 0.05). The expression of LTC4S mRNA and LTC4 in the EB group was higher than that in the CVA group and the asthma group (P < 0.05). The value of LTC4/PGE2 in the CVA group and the asthma group was higher than that in the EB group (t = 8.7 and 13.1, P < 0.05). CONCLUSION: These data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and CVA (or asthma) may be due to the results of differences in PGE(2) production and an imbalance between the production of bronchoconstrictor LTC(4) and bronchoprotective PGE(2) lipid mediators.

[A retrospective study of 3 cases of severe asthma with fungal sensitization].

OBJECTIVE: to describe the clinical features and diagnosis of severe asthma with fungal sensitization (SAFS). METHODS: the clinical data of 3 patients of SAFS from this hospital were presented, and the related literatures reviewed. RESULTS: the 3 patients, 1 male and 2 females, aging 55, 52 and 61 years respectively, had a history of asthma for 4 - 40 years. All of them presented with severe asthma symptoms, and were found to have fungal sensitization by skin prick testing. Their serum IgE level was less than 1000 IU/ml. A. fumigatus was positive from sputum cultures. There were no radiological abnormalities such as pulmonary infiltrates and bronchiectasis by HRCT in all cases. The serum galactomannan (GM) was positive in 2 patients. After diagnosis, they received additional antifungal therapy for 4 - 22 months, respectively, and the prognosis was good. CONCLUSION: SAFS should be considered in patients with severe asthma and sensitization to fungi but without elevation of serum IgE. Adjunctive antifungal therapy is beneficial for asthma control.

Survival and prognostic factors analysis in surgically resected gastrointestinal stromal tumor patients.

BACKGROUND/AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract and predicting the clinical behavior and prognosis of GISTs has still been problem for both pathologists and clinicians. The aim of this study was to investigate the survival and prognostic factors of gastrointestinal stromal tumors after surgery. METHODOLOGY: Hematoxylin and eosin (H&E) stained histopathological slides of tumors from patients with GISTs were reviewed. Immunohistochemical staining was performed to demonstrate CD117, CD34, platelet -derived growth factor receptor (PDGFR-alpha) and Ki-67 protein expression. Clinicopathologic features (age, sex, tumor location and size, cell type, mitotic count, risk category, necrosis, surgical method, expression of CD117, CD34, PDGFR-alpha and Ki-67 protein) were evaluated by univariate and multivariate analyses in 135 patients with resected primary GISTs to identify independent prognostic factors. RESULTS: The overall disease-specific survival of 135 patients was 94.1% at 1 year, 76.3% at 3 years and 65.9% at 5 years. Multivariate analyses indicated that the tumor size, primary location, mitotic count, risk category, necrosis and Ki-67 index were independent significant predictors of survival (p < 0.05). Ki-67 index was strong poor predictors of survival as tumor size and mitotic count. CONCLUSIONS: Fletcher's biological behavior ranking method was a good approach to predict prognosis of GIST patients and had significant clinical value. It's better to combine other factors such as Ki-67 index and tumor primary location et al to predict prognosis accurately. Accurate prognostic prediction could provide evidence for postoperative adjuvant targeted therapy.

Secondary C-kit mutation is a cause of acquired resistance to imatinib in gastrointestinal stromal tumor.

C-kit gene gain of function mutations are important in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of KIT and achieves a partial response or stable disease in most patients with metastatic GIST, but there is increasing evidence of acquired resistance. We report a case of GIST with acquired resistance to imatinib during therapy and secondary c-kit mutation besides the primary mutation.

Gefitinib-induced hair alterations.

Human epidermal growth factor receptor (EGFR) is an attractive target for anticancer therapy. EGFR tyrosine kinase inhibitors are generally well tolerated and do not have the severe systemic side-effects usually seen with cytotoxic drugs. A specific adverse effect common to this class of agent is a papulopustular rash, usually on the face and upper torso. During prolonged treatment with EGFR inhibitors, changes of the hairs can be noticed. This report describes a rare case of a non-small-cell lung cancer with hair changes after several months of treatment with the EGFR inhibitor gefitinib. The patient's scalp hair grew more slowly and adopted a finer, more brittle and curly aspect. However, the eyelashes, eyebrows and hair of other parts of the face did not display similar changes. Little is known about the aetiology of this kind of hair alteration, and there are no clear evidence-based management recommendations. Histological data indicate that the hair alteration may be caused by EGFR inhibition in skin, although this has not been confirmed. Further studies are needed to investigate the reason for this phenomenon.