Glabridin and Anti-Non-Muscle Myosin IIA Therapy Disrupts Non-Small Cell Lung Carcinoma Motility

Lung cancer is the leading cause of cancer related death in the United States killing over 130,000 people each year. While a combination of chemo and radiation therapy may be effective, surgery is still required for many patients. Without surgery, the disease may progress and lead to metastases. We sought to determine if treatment with anti-non-muscle myosin IIA antibody would inhibit movement of the cells in the presence and absence of glabridin (an isoflavonoid compound shown to inhibit cell migration by inhibiting myosin). We compared inhibition by glabridin to that of an anti-non-muscle myosin IIA antibody and a combination therapy of both at 12 and 24 hours post wound creation. Cells that took up the anti-non-muscle myosin IIA antibody were greatly inhibited in motility and exhibited no significant change in wound healing. Glabridin treatment resulted in a dramatic increase in wound size within 12 hours and regeneration within 24 hours. The greatest decrease in motility was observed in cells treated with the combination of both glabridin and anti-non-muscle myosin IIA antibody. By 24 hrs, cell migration had halted due to death of the cells resulting from this combination. Further testing needs to be done to determine a safe mode of delivery of the combination therapy to ensure only local distribution. Controlled release drug delivery depot systems have been used as a means to provide local release of drugs intra-tumorally or adjacent to the cancerous tissue after surgical resection and have great potential.

Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

Relevance of EGFR gene mutation with pathological features and prognosis in patients with non-small-cell lung carcinoma

Objective:To study the relevance of EGFR gene mutation with pathological features and prognosis in patients with non-small-cell lung carcinoma.Methods:A total of 297 patients from July 2009 to May 2013 were chosen as objects.EGFR gene mutation were detected with fluorescence quantitative PCR.Relevance of EGFR gene mutation with clinical and pathological features was analyzed,and the prognosis of EGFR- mutant-patients and that of EGFR- wide type-patients was compared.Results:In 297 patients.136(45.79%) showed EGFR gene mutation.EGFR gene mutation had no significant relevance with age.gender,smoking history,family history of cancer and clinical stage(P>0.05);there was significant relevance between EGFR gene mutation and blood type,pathologic types,differentiation and diameter of cancer(P<0.05).The difference between prognosis of EGFR- mutant-patients and that of EGFR- wide type-patients was statistical significance(P<0.05).Conclusions:EGFR gene mutation has significant relevance with pathological features,the prognosis of EGFRmutant-paticnts is better than that of EGFR- wide type-patients.

Review of the treatment of metastatic non small cell lung carcinoma:A practical approach

In recent years,as we have a better knowledge and understanding of the biology of non small cell lung carcinoma(NSCLC),which leads us to targeting biomarkers driving the NSCLC carcinogenesis and metastatic potential,we now have an increased number of options to offer our patients with NSCLC.We also realize the importance of distinguishing squamous and non squamous histology to guide our treatment decisions of NSCLC.The palliative care concomitant with therapies from the very start of the treatment also showed an impact on survival.This review examines the treatment options in all lines of therapy for metastatic NSCLC that have been approved in Canada,the United States,or Europe.

Inhibitory Effect of MiR-449b on Cancer Cell Growth and Invasion through LGR4 in Non-Small-Cell Lung Carcinoma

Non-small-cell lung carcinoma （NSCLC） is one of the most frequently diagnosed malignancies worldwide. Previous studies have shown that microRNA-449b （miR-449b） functions as a tumor suppressor in many cancers. However, the role of miR- 449b in NSCLC is still unknown. In the present study, miR-449b was significantly down- regulated in NSCLC samples and cell lines. Bioinformatics analysis revealed that 3＇-UTR region of leucine rich repeat containing G protein-coupled receptor 4 （LGR4） mRNA had putative complementary sequences to miR-449b, which was further confirmed by the luciferase assay. Western blotting showed that restoration of miR-449b in NSCLC cells decreased the expression of LGR4. Interestingly, over-expression of miR-449b inhibited growth and invasion of NSCLC cells in vitro. Furthermore, ectopic expression of LGR4 reversed miR-449b-suppressed proliferation and invasion of NSCLC cells. Therefore, the data of the present study demonstrate that miR-449b inhibits tumor cell growth and invasion by targeting LGR4 in NSCLC.

The ^(18)F-FDG uptake in non small cell lung carcinoma correlates with the DNA-grading of malignancy

In order to evaluate correlation of glucose metabolism and DNA ploidity of tumors, the uptake of 18F-Deoxyglucose (FDG) by PET prior to surgery and the DNA cotent and DNA-grading of malignancy (DNA-MG) of Schiff-stained nuclei obtained from fresh tumor fragments by means of image cytometry were studied, and thereafter the correlation between standardized uptake value (SUV) and (DNA-MG) was analysed in forty-nine patients with histologically proven non-small cell lung carcinoma (NSCLC). As a result of the DNA histograms of these 49 patients, 46 (93.88%) were aneuploid and only 3(6.12%) were tetraploid. A linear correlation of the SUV versus the (DNA-MG) (r=0.336, p=0.024) was found, demonstrating that 18F-FDG PET as a non-invasive metabolic imaging technique, may also provide inforrnation correlated to malignant DNA patterns which may be valuable in malignant differentiation and prognostic prediction.

Alectinib-Induced Immune Hemolytic Anemia in a Patient with Lung Adenocarcinoma: Case Report and Literature Review

Alectinib is a selective Anaplastic Lymphoma Kinase (ALK) tyrosine kinase inhibitor used as standard therapy for ALK-rearranged lung adenocarcinoma. Hemolytic anemia is considered a rare but significant adverse event of alectinib. Here, we report the case of a 78-year-old female with advanced ALK rearrangement-positive lung adenocarcinoma who developed grade 4 drug-induced hemolytic anemia after receiving alectinib as first-line therapy. We discontinued alectinib treatment and switched to brigatinib. As a result, anemia improved without recurrence of lung adenocarcinoma over one year.

EGFR mutation identifies distant squamous cell carcinoma as metastasis from lung adenocarcinoma

Lung cancer metastasis is typically determined by histologic similarity between distant and primary lesions. Herein, we present a 70-year-old Japanese woman with an adenocarcinoma in her lung and a squamous cell carcinoma in her femur; both tumors had an identical epidermal growth factor receptor mutation, G719 S. This indicated that both tumors had a common origin, despite their histologic dissimilarity. The tumor in the femur was thus identified genetically as a lung cancer metastasis. This case suggests that genetic analysis can determine whether a distant lesion is a lung cancermetastasis, particularly when the histology differs from that of the primary lesion.

Pang Fuwan Uses Yao Medicine to Observe the Therapeutic Effects on the Physical and Mental Symptoms of Patients with Advanced Non-Small Cell Lung Cancer

Objective: Investigate the efficacy and safety of Yao Medicine in the treatment of advanced non-small-cell lung carcinoma, and explore the best therapeutic measure for clinical benefit. Methods: From July 2020 to July 2022, 84 patients with advanced non-small-cell lung carcinoma were selected and randomly divided into the Observation Group and control group, and the control group was treated with routine Western medicine, with 42 cases in each group. The activity of daily living (ADL) was assessed before and after treatment, meanwhile, the self-rating depression scale (SDS) and self-rating anxiety SAS (SAS) were used to assess the improvement of a bad mood, and quality of life SF-36 was used to assess the quality of life, to judge the efficacy and safety. Results: The effective rate of observation group was 91.67%. The effective rate of the control group was 76.19%. The effective rate of the observation group was significantly higher than that of the control group (P 0.05). There were no significant differences in the scores of SDS, SAS and quality of life between the two groups before treatment (P > 0.05), and after treatment, the scores of SDS, SAS and quality of life in the two groups were compared with those in the control group (P > 0.05), the scores of VAS, SDS and SAS decreased significantly, while ESCV, angle of straight leg elevation, ADL, physiological score, emotional score, social score and health status score increased significantly, the difference was statistically significant (P 0.05). Conclusion: Yao Medicine can improve the psychosomatic symptoms of patients with advanced non-small-cell lung carcinoma better, with better efficacy and higher safety.

Advances in adjuvant systemic therapy for non-small-cell lung cancer

Non-small-cell lung cancer remains a leading cause of death around the world. For most cases, the only chance of cure comes from resection for localised disease, however relapse rates remain high following surgery. Data has emerged over recent years regarding the utility of adjuvant chemotherapy for improving disease-free and overall survival of patients following curative resection. This paper reviews the clinical trials that have been conducted in this area along with the studies integrating radiation therapy in the adjuvant setting. The role of prognostic gene signatures are reviewed as well as ongoing clinical trials including those incorporating biological or targeted therapies.

ADJUVANT CHEMOTHERAPY FOLLOWING RADICAL SURGERYFOR NON-SMALL CELL LUNG CANCER:A RANDOMIZED STUDY

Objective: To evaluate the efficacy of adjuvant chemotherapy after radical surgery for non-small cell lung cancer (NSCLC). Methods: Seventy patients with NSCLC (stage I–III) undergone radical surgery were randomized into two groups: 35 patients received adjuvant chemotherapy with cyclophosphamide (CTX) 300 mg/m2, vincristine (VCR) 1.4% mg/m2, adriamycin (ADM) 50 mg/m2, lomustine (CCNU) 50 mg/m2 dl, cisplatin (DDP) 20 mg/m2, d1–5, for 4 cycles, and followed by oral Ftorafur (FT-207) 600–900 mg/d for 1 year (adjuvant chemotherapy group). The other 35 patients received surgical treatment only (surgery group). Results: The overall 5-year survival rate was 48.6% in the adjuvant chemotherapy group, and 31.4% in the surgery group, respectively. The difference between the two groups was not statistically significant (P>0.05). The 5-year survival rate of patients in stage III was 44.0% and 20.8% received surgery with and without adjuvant chemotherapy, respectively. The difference between the two groups was statistically significant (P<0.025). The 5-year survival rate of patients in stage I–II in the two groups was 60.0% and 54.5%, respectively (P>0.75). Conclusion: Postoperative adjuvant chemotherapy in NSCLC can improve survival, for those patients in stage III, it suggests significantly 5-year survival rate in the adjuvant chemotherapy group was higher than that in the surgery alone group.

Analysis of prognostic factors for overall survival in patients with advanced non-small cell lung cancer treated with second line chemotherapy

Aim: The aim of this study was to investigate prognostic factors for survival in patients with advanced NSCLC who receiving second-line chemotherapy. Methods: We retrospectively reviewed data of 116 patients with NSCLC receiving second-line treatments from October 2010 to December 2012 in Clinic for Lung Diseases of Clinical center Nis, Department for Pulmonary Oncology. Thirteen potential prognostic factors were chosen for analysis. Univariate analysis was conducted to identify prognostic factors associated with progression free survival and overall survival. Multivariate analysis included the prognostic significance factors in univariate analysis. Results: The univariate analysis for progression free survival (PFS) and overall survival (OS) was identified to have prognostic significance: performance status, smoking, weight loss, comorbidity, number of meta localization, first-line chemotherapy regimen and response to first-line chemotherapy. Nevertheless, multivariate Cox prortional hazard regression analysis showed that performance status (PFS: p = 0.000, OS: p = 0.000) weight loss ≥ 5% (PFS: p = 0.000, OS: p = 0.002), comorbidity (PFS: p = 0.001, OS: p = 0.012) and four places of meta localization (PFS: p = 0.021, OS: p = 0.021) were considered independent prognostic factors for both, progression free survival and overall survival. Conclusion: Performance status, weight loss ≥ 5%, comorbidity and higher number of meta localization were identified as prognostic factors for survival in advanced NSCLC patients receiving second-line chemotherapy treatment. These findings may help pretreatment prediction of survival and may facilitate in the future integration new agents into second-line treatment.

Sequential therapy according to distinct disease progression patterns in advanced ALK-positive non-small-cell lung cancer after crizotinib treatment

Objective: Crizotinib is recommended as the first-line therapy for advanced anaplastic lymphoma kinase(ALK)-positive non-small-cell lung cancer(NSCLC). Despite its initial efficacy, patients ultimately acquire resistance to crizotinib within 1 year. In such patients, the optimal sequential therapy after crizotinib treatment remains unknown. This study explored which sequential therapy option confers the greatest benefit.Methods: A total of 138 patients with advanced ALK-positive NSCLC resistant to crizotinib were studied. Based on patterns of disease progression of metastases, patients were divided into 3 groups: brain progression, non-liver progression, and liver progression. Sequential therapies included crizotinib continuation plus local therapy, nextgeneration ALK inhibitors(ALKi's), and chemotherapy. The primary endpoint was overall survival(OS) from the time of crizotinib resistance to death or last follow-up.Results: The 138 patients included 64 cases with progression in brain, 57 cases in non-liver sites and 17 cases in liver. A significant difference in OS was observed among the distinct progression pattern(median OS, 25.4 months in brain, 15.8 months in non-liver, and 10.8 months in liver, respectively, P=0.020). The difference in OS among sequential therapies was statistically significant in the non-liver progression group(median OS, 27.6 months with next-generation ALKi's, 13.3 months with crizotinib continuation, and 10.8 months with chemotherapy,respectively, P=0.019). However, crizotinib continuation plus local therapy seems to provide non-inferior median OS compared with next-generation ALKi's for patients with brain progression(median OS, 28.9 months vs.32.8 months, P=0.204). And no significant differences in OS were found in patients with progression in liver(P=0.061).Conclusions: Crizotinib continuation together with local therapy might be a feasible strategy for patients with progression in brain beyond crizotinib resistance, as well as next-generation ALKi's. Next-generation ALKi's tended to provide a survival benefit in patients with non-liver progression.

Weekly albumin-bound paclitaxel/cisplatin versus gemcitabine/cisplatin as first-line therapy for patients with advanced non-small-cell lung cancer:A phase II open-label clinical study

Objective: The aim of this trial was to compare both the efficacy and the safety of a weekly nanoparticle albumin-bound paclitaxel(nab-paclitaxel) plus cisplatin vs. gemcitabine plus cisplatin in patients with advanced non-small-cell lung cancer(NSCLC).Methods: A total of 84 participants received either 100 mg/m^2 nab-paclitaxel each week on d 1, 8 and 15 of a 28 day cycle, as well as cisplatin 75 mg/m^2 on d 1 every three weeks(nab-TP arm); or gemcitabine 1,000 mg/m^2 on d 1 and 8, plus cisplatin 75 mg/m^2 on d 1 every three weeks(GP arm). The primary end point was progression-free survival(PFS). The secondary end points were overall response rate(ORR) and overall survival(OS).Results: According to our analysis, the median PFS was 4.8 months for the nab-TP arm vs. 5.2 months for the GP arm(P=0.55). Analysis showed the median OS was 14.6 months for participants who were in the nab-TP arm vs. 15.1 months for those in the GP arm(P=0.94). Besides, nab-TP showed OS advantages over GP in patients harboring epidermal growth factor receptor(EGFR) mutation(26.7 vs. 15.3 months, P=0.046) and patients with a performance status of 0(23.5 vs. 14.7 months, P=0.020). It was found that incidences of drug-related grade 3 or 4 toxicities were comparable between the two treatment arms.Conclusions: Therefore, it can be seen that weekly nab-TP treatment has a similar efficacy and tolerability to GP treatment for patients who are undergoing their first-line treatment for NSCLC. It could be that survival differences among platinum doublets in the context of both EGFR mutation and performance status have the potential to be the basis for our further clinical trials.

Surgical strategies in the therapy of non-small cell lung cancer

Lung cancer represents the leading cause of cancer mortality worldwide. Despite improvements in preoperative staging, surgical techniques, neoadjuvant/adjuvant options and postoperative care, there are still major difficulties in significantly improving survival, especially in locally advanced non-small cell lung cancer(NSCLC). To date, surgical resection is the primary mode of treatment for stage?Ⅰ?and Ⅱ NSCLC and has become an important component of the multimodality therapy of even more advanced disease with a curative intention. In fact, in NSCLC patients with solitary distant metastases, surgical interventions have been discussed in the last years. Accordingly, this review displays the recent surgical strategies implemented in the therapy of NSCLC patients.

Stereotactic body radiation therapy for non-small cell lung cancer:A review

Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

The Therapeutic Effects of the Radiotherapy Plus TCM Treatment Observed in Senile Non-Parvicellular Lung Cancer Patients at the Late Stage

47 senile non-parvicellular lung cancer patients at stage Ⅲ or Ⅳ were randomly divided into a treatment group (26 cases) treated by radiotherapy plus traditional Chinese medicine (TCM) and a control group (21 cases) treated only by radiotherapy for observation of the therapeutic effects.The patients in the treatment group orally took Chinese medicine during and after the radiotherapy.There was no obvious difference in short-term therapeutic effects between the two groups,but the long-term curative effects in the treatment group was obviously superior to that in the control group (P<0.05 or P<0.01).Conclusion:radiotherapy plus TCM can prolong the survival period for senile non-parvicellular lung cancer patients.

A Phase Ⅱ Trial of Gefitinib as Maintenance Therapy after First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

Objective： To investigate the efficacy and safety of gefitinib as maintenance therapy for advanced non-small cell lung cancer （NSCLC） patients who obtained disease control （DC） after first-line chemotherapy in Chinese population. Methods： Chinese patients with advanced NSCLC treated with standard chemotherapy and obtained DC were assigned to receive gefitinib as maintenance treatment. The primary end point was overall survival time （OS）, the second end point was disease control rate （DCR） and progression-free survival time （PFS）. DCR included complete response （CR） plus partial response （PR） and plus stable disease （SD）. The impact of epidermal growth factor receptor （EGFR） mutation status on the treatment as exploratory point was also evaluated by denaturing high-performance liquid chromatography （DHPLC）. Results： Among 75 enrolled patients, the overall response rate was 37% and the DCR （CR ＋ PR ＋SD） was 66%. The median PFS and OS were 17.13 months and 26.13 months respectively, with 1- and 2-year survival rates 89.3% and 34.7%. Patients harboring somatic EGFR mutations obtained a prolonged median PFS and OS compared with EGFR wide type （25.1 vs. 13.0 months, P=0.019 and 33.37 vs. 25.57 months, P=0.014, respectively）. In COX regression model, only EGFR mutation status was the independently factor influencing both PFS and OS （P=0.029 and 0.017, respectively）, however, rash status was the predictor in terms of PFS （P=0.027）. Conclusion： Gefitinib produced encouraging survival when delivered as maintenance therapy in Chinese patients obtaining DC after first-line chemotherapy, especially for patients carrying somatic EGFR mutations. EGFR mutation is an independently predictive factor of survival.

Re-challenge chemotherapy with gemcitabine plus carboplatin in patients with non-small cell lung cancer

Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer(NSCLC),the patients′overall survival remains poor.Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC.NSCLC relapse has been attributed to acquired drug resistance,but the repopulation of sensitive clones may also play a role,in which case re-challenge may be appropriate.Here,we report the results of re-challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first-line setting and had either partial response or a progression-free interval of longer than 6 months.In this retrospective study,the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed.All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study.These patients were offered second-line treatment on confirmation of clear radiological disease progression.The overall response rate was 15%and disease control rate was 75%.The median survival time was 10.4 months,with 46%of patients alive at 1 year.These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy.