Risk factors and predictors of immune-related adverse events: implications for patients with non-small cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are now utilized as a standard of care treatment for multiple cancers, including in both the metastatic setting as well as in earlier stages of disease. The identification of unique immune-related adverse events (irAE) that occur during ICI treatment has led to intense research to identify potential risk factors and biomarkers that may assist in clinical decision making. Although initial studies in ICI were primarily in advanced stage disease, the use of ICI in earlier stages of disease as adjuvant therapies requires a better understanding of patient risk stratification to mitigate or prevent serious irAE. AREAS COVERED: In this review, we set out to describe the current state of research regarding potential risk factors for irAE in patients with non-small cell lung cancer, as well as explore the barriers to understanding irAE. We review data from irAE that occur in large phase 3 trials and prospective studies focusing on irAE, as well as the many retrospective studies that currently form the bulk of our understanding of irAE.

Drivers of genomic loss of heterozygosity in leiomyosarcoma are distinct from carcinomas.

Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.

Stem cell damage after chemotherapy- can we do better?

Therapy-related myeloid neoplasms are unintended and unwanted complications of cytotoxic chemotherapy and radiation. Unlike other environmental toxin-induced malignancies, exposure to the inciting agent is required to eradicate a primary and life-threatening cancer. In this review, we will focus on the biochemical mechanisms that lead to therapy-induced myeloid malignancy. This includes discussion of known mechanisms by which cytotoxic chemotherapy and radiation induce genetic mutations and promote evolution and expansion of malignant hematopoietic clones. Mechanisms by which the hematopoietic stem and progenitor microenvironment may be injured during the course of chemotherapy and radiation therapy will also be presented. While prevention strategies have not yet been brought into clinical testing or practice, there is active basic research relevant to prevention of t-MNs which is also included in our attempt to answer the question of whether we can do better to prevent stem cell injury after chemotherapy and radiation.

Assessing Fluid Responsiveness in Spontaneously Breathing Patients.

OBJECTIVES: The primary objective of this study was to test if fasting volunteers exhibit fluid responsiveness using noninvasive hemodynamic measurements. The secondary objective was to test a passive leg raise (PLR) maneuver as a diagnostic predictor of fluid responsiveness. METHODS: This was a quasi-experimental design involving healthy volunteers. Subjects were excluded for pregnancy and congestive heart failure. Following a 12-hour fast, subjects had baseline hemodynamic monitoring recorded using noninvasive, continuous pulse contour analysis. Subjects then had a PLR maneuver performed, followed by an intravenous bolus of crystalloid. A rise in stroke volume ≥ 10% from baseline with the bolus was considered consistent with fluid responsiveness, and the same rise with a PLR was consistent with a positive PLR maneuver. The primary outcome was the change in stroke volume with a fluid bolus. Univariate analysis assessed changes in hemodynamic parameters. Logistic regression analysis determined the test characteristics of the PLR in predicting subjects who were ultimately fluid responsive. RESULTS: Forty subjects completed the study. The mean change in stroke volume with a crystalloid bolus was 19% (95% confidence interval [CI] = 16% to 21%). Thirty-six (90%) subjects were fluid responsive. The mean PLR response for the overall cohort was 16% (95% CI = 12% to 19%), and 26 (65%) subjects had a positive PLR maneuver. The PLR was 72% sensitive (95% CI = 55% to 85%) and 100% specific (95% CI = 40% to 100%) for predicting the presence of fluid responsiveness. CONCLUSIONS: Noninvasive assessment of fluid responsiveness in healthy volunteers and prediction of this response with a PLR maneuver is achievable. Further work is indicated to test these methods in acutely ill patients.

MicroRNAs in breast cancer therapy.

Breast cancer is one of the most common type of cancers as well as a principal cause of cancer-related deaths in women worldwide. Although research has provided a better understanding and diagnosis of breast cancer, studies in breast cancer therapeutics are still far from satisfactory. Recent research on microRNAs (miRNAs) has implicated these tiny regulatory molecules in progression of breast cancer with the possibility of exploiting them as diagnostic and/or prognostic biomarkers. The loss of tumor suppressor miRNAs or overexpression of oncogenic miRNAs can lead to breast cancer tumorigenesis or metastasis. However, the next step - linking miRNAs to cancer therapeutics - is still under progression. The roles of miRNAs exhibit much potential in breast cancer therapy, but currently need to be further studied and evaluated in order to better understand how to apply laboratory results to clinical medicine. Here we provide an update on our current understanding of miRNAs as molecular targets for diagnosis, prognosis and therapy of breast cancers.

Erlotinib resistance in lung cancer: current progress and future perspectives.

Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.

The role of microRNAs in breast cancer migration, invasion and metastasis.

MicroRNAs (miRNAs) are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. Many miRNAs have been implicated in several human cancers, including breast cancer. miRNAs are known to regulate cell cycle and development, and thus may serve as useful targets for exploration in anticancer therapeutics. The link between altered miRNA signatures and breast cancer development and metastasis can be observed either through the loss of tumor suppressor miRNAs, such as let-7s, miR-30a/31/34a/125s/200s/203/205/206/342 or the overexpression of oncogenic miRNAs, such as miR-10b/21/135a/155/221/222/224/373/520c in breast cancer cells. Some of these miRNAs have also been validated in tumor specimens of breast cancer patients, underscoring their potential roles in diagnostics, as well as targets for novel therapeutics for breast cancer. In this review article, we will provide an overview and update of our current understanding of the mode of action of several of these well characterized miRNAs in breast cancer models. Therefore, better understanding of the gene networks orchestrated by these miRNAs may help exploit the full potential of miRNAs in regards to cancer diagnosis, treatment, and therapeutics.