Metastatic Lung Cancer: Emerging Therapeutic Strategies.

Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based doublet chemotherapy, and other cytotoxic agents that offered significant survival advantage over best supportive care, until recently. Modest improvements were achieved with the addition of antibodies targeting the vascular endothelial growth factor, and the introduction of maintenance chemotherapy. Improvements in our knowledge of lung cancer biology have shifted the current treatment paradigm from being based on histology to one based on molecular biomarkers. Identification of potentially targetable driver mutations in a subgroup of these patients, pertaining to genes directing cell signaling pathways involved in proliferation and survival, has been the single most influential development in the treatment of lung cancer in the last two decades. Personalized medicine based on driver mutations offers enhanced efficacy at the expense of relatively minimal toxicity burden. Targeting the epidermal growth factor receptor pathway in patients with an activating mutation results in substantial improvement in patient outcome. Similarly, targeting ALK (anaplastic lymphoma kinase) fusion gene with first- and second-generation inhibitors results in improved efficacy over chemotherapy. For certain other mutations such as MET exon 14 and BRAF, promising inhibitory strategies are being investigated. In addition, the recent emergence of immune checkpoint inhibitors to reverse exhaustion of T cells has been a major breakthrough in rapidly changing the therapeutic landscape for lung cancer. This article reviews the role of systemic therapy in advanced stage lung cancer.

Spatial differences influence nitrogen uptake, grain yield, and land-use advantage of wheat/soybean relay intercropping systems.

Cereal/legume intercropping is becoming a popular production strategy for higher crop yields and net profits with reduced inputs and environmental impact. However, the effects of different spatial arrangements on the growth, grain yield, nitrogen uptake, and land-use advantage of wheat/soybean relay intercropping are still unclear, particularly under arid irrigated conditions. Therefore, in a three-year field study from 2018 to 2021, soybean was relay intercropped with wheat in different crop configurations (0.9 m, narrow strips; 1.8 m, medium strips; and 2.7 m, wide strips), and the results of intercropping systems were compared with their sole systems. Results revealed that intercrops with wide strips outperformed the narrow and medium strips, when the objective was to obtain higher total leaf area, dry matter, nitrogen uptake, and grain yield on a given land area due to reduced interspecific competition between intercrops. Specifically, at maturity, wide strips increased the dry matter accumulation (37% and 58%) and its distribution in roots (37% and 55%), straw (40% and 61%), and grains (30% and 46%) of wheat and soybean, respectively, compared to narrow strips. This enhanced dry matter in wide strips improved the soybean's competitive ability (by 17%) but reduced the wheat's competitive ability (by 12%) compared with narrow strips. Noticeably, all intercropping systems accumulated a significantly higher amount of nitrogen than sole systems, revealing that wheat/soybean relay intercropping requires fewer anthropogenic inputs (nitrogen) and exerts less pressure on the ecosystem than sole systems. Overall, in wide strips, intercropped wheat and soybean achieved 62% and 71% of sole wheat and soybean yield, respectively, which increased the greater total system yield (by 19%), total land equivalent ratio (by 24%), and net profit (by 34%) of wide strips compared to narrow strips. Our study, therefore, implies that the growth parameters, grain yields, nutrient accumulation, and land-use advantage of intercrop species could be improved with the proper spatial arrangement in cereal/legume intercropping systems.

Effect of Cadmium Toxicity on Growth, Oxidative Damage, Antioxidant Defense System and Cadmium Accumulation in Two Sorghum Cultivars.

Heavy metal stress is a leading environmental issue reducing crop growth and productivity, particularly in arid and semi-arid agro-ecological zones. Cadmium (Cd), a non-redox heavy metal, can indirectly increase the production of reactive oxygen species (ROS), inducing cell death. A pot experiment was conducted to investigate the effects of different concentrations of Cd (0, 5, 25, 50, 100 µM) on physiological and biochemical parameters in two sorghum (Sorghum bicolor L.) cultivars: JS-2002 and Chakwal Sorghum. The results showed that various concentrations of Cd significantly increased the Cd uptake in both cultivars; however, the uptake was higher in JS-2002 compared to Chakwal Sorghum in leaf, stem and root. Regardless of the cultivars, there was a higher accumulation of the Cd in roots than in shoots. The Cd stress significantly reduced the growth and increased the electrolyte leakage (EL), hydrogen peroxide (H2O2) concentration and malondialdehyde (MDA) content in both cultivars, but the Chakwal Sorghum showed more pronounced oxidative damage than the JS-2002, as reflected by higher H2O2, MDA and EL. Moreover, Cd stress, particularly 50 µM and 100 µM, decreased the activity of different antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). However, the JS-2002 exhibited higher SOD, POD and CAT activities than the Chakwal Sorghum under different Cd-levels. These findings revealed that JS-2002 had a stronger Cd enrichment capacity and also exhibited a better tolerance to Cd stress due to its efficient antioxidant defense system than Chakwal Sorghum. The present study provides the available information about Cd enrichment and tolerance in S. bicolor, which is used as an important agricultural crop for livestock feed in arid and semi-arid regions.

Nanoliposomal irinotecan plus fluorouracil and folinic acid: a new treatment option in metastatic pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with half of patients diagnosed in the metastatic setting. Until recently, patients after progression on front-line gemcitabine-based regimen had no standard second-line option, although flouropyrimidine-based regimens were frequently used in this setting. Encapsulation of chemotherapeutics in liposomal formulation is an effective way of prolonging drug deposition thereby enhancing cytotoxic efficacy. In a large phase III randomized trial on metastatic PDAC patients who progressed after gemcitabine-based chemotherapy, a novel nanoliposome-encapsulated irinotecan (PEP02, MM-398, nal-IRI, Onivyde, Merrimack, Boston, US) plus fluorouracil and folinic acid demonstrated a significant survival advantage compared to fluorouracil and folinic acid alone. This pivotal study led to the recent FDA approval of nanoliposomal irinotecan in patients with metastatic PDAC. In this article, we will review the literature regarding existing treatment options for metastatic PDAC, focusing specifically on nanoliposomal irinotecan in the clinical setting and its future implication.

Breast cancer resistance protein (BCRP) and excision repair cross complement-1 (ERCC1) expression in esophageal cancers and response to cisplatin and irinotecan based chemotherapy.

BACKGROUND: Esophageal cancer patients face a dismal outcome despite tri-modality management and median survival remains 15-18 months. Breast cancer resistance protein (BCRP) is an ATP-dependent efflux protein associated with chemotherapy resistance. The role of BCRP expression in esophageal cancer and normal esophageal cells is not known. Excision repair cross complement-1 (ERCC1) overexpression has been correlated with poorer response to cisplatin based chemotherapy. We examined the expression of BCRP and ERCC1 in patients with esophageal cancer and correlated it with survival in patients receiving irinotecan and cisplatin based chemotherapy. METHODS: With IRB approval, 40 cases of esophageal cancer diagnosed from 2004-2008, were stained for BCRP and ERCC1 expression by immunohistochemistry and scored by a pathologist blinded to clinical data. Baseline demographics, therapy given and survival data were collected and correlated with BCRP and ERCC1 expression. Fisher's exact test was used to determine association between BCRP and ERCC1 expression and demographics. Cox proportional hazards model was used for association of BCRP and ERCC1 with survival. RESULTS: On immunohistochemistry, 30/40 cancers (75%) expressed BCRP. Interestingly, down-regulation of BCRP expression in tumor compared with normal cells was seen in 40% of patients. ERCC1 positivity was seen in 15/30 cases (50%). Median overall survival (OS) was 19 months with no difference in survival between BCRP positive and negative patients (P=0.13) or ERCC1 positive and negative patients (P=0.85). Estimated hazard ratio (HR) of death for BRCP positive patients was 2.29 (95% CI: 0.79-6.64) and for ERCC1 positive patients was 1.09 (95% CI: 0.46-2.56). There was no association of BCRP and ERCC1 expression with disease stage, age, gender or histology. For patients who received cisplatin and irinotecan as first line chemotherapy, there was no difference in survival based on BCRP or ERCC1 status. CONCLUSIONS: BCRP expression is seen in a majority of esophageal cancers and normal esophageal mucosa. ERCC1 expression is seen in about half of the patients with esophageal cancer. Irinotecan based studies with esophageal and gastric cancer suggest response rates of 14-65%. Whether the 40% of tumors in our study found with down regulation of BCRP expression, constitute a majority of these responders needs to be prospectively validated in a larger data set. It should include markers such as ERCC1 predicting response to 5-fluorouracil and platinum based chemotherapy, to enable individualizing therapy for this cancer.