Immunotherapy in Non-Small Cell Lung Cancer Patients with Brain Metastases: Clinical Challenges and Future Directions.

Immune checkpoint inhibitors have revolutionized the treatment landscape for patients with non-small cell lung cancers. Existing treatment paradigms for brain metastases in lung cancer patients leave patients with adverse neurocognitive function, poor quality of life, and dismal prognosis, thus highlighting the need to develop more effective systemic therapies. Although data are limited, emerging knowledge suggests promising activity and safety of immune checkpoint inhibitors in brain metastases in non-small cell lung cancer patients. This review aims to summarize the current data, highlight the challenges of incorporating immune checkpoint inhibitors in treating these patients, and identify areas for future research.

Strategies to Improve Participation of Older Adults in Cancer Research.

Cancer is a disease associated with aging. As the US population ages, the number of older adults with cancer is projected to dramatically increase. Despite this, older adults remain vastly underrepresented in research that sets the standards for cancer treatments and, consequently, clinicians struggle with how to interpret data from clinical trials and apply them to older adults in practice. A combination of system, clinician, and patient barriers bar opportunities for trial participation for many older patients, and strategies are needed to address these barriers at multiple fronts, five of which are offered here. This review highlights the need to (1) broaden eligibility criteria, (2) measure relevant end points, (3) expand standard trial designs, (4) increase resources (e.g., institutional support, interdisciplinary care, and telehealth), and (5) develop targeted interventions (e.g., behavioral interventions to promote patient enrollment). Implementing these solutions requires a substantial investment in engaging and collaborating with community-based practices, where the majority of older patients with cancer receive their care. Multifaceted strategies are needed to ensure that older patients with cancer, across diverse healthcare settings, receive the highest-quality, evidence-based care.

The Evolving Complexity of Treating Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2 (HER2)-Negative Breast Cancer: Special Considerations in Older Breast Cancer Patients-Part II: Metastatic Disease.

Breast cancer is a disease of aging, and the incidence of breast cancer is projected to increase dramatically as the global population ages. The majority of breast cancers that occur in older adults are hormone-receptor positive, human epidermal growth factor receptor-2 (HER2)-negative phenotypes, with favorable tumor biology; yet, because of underrepresentation in clinical trials, less evidence is available to guide the complex care for this population. Providing care for older patients with metastatic breast cancer, with coexisting medical conditions, increased risk of treatment toxicity, and frailty, remains a clinical challenge in oncology. In this review, we provide an overview of the current evidence from clinical trials and subanalyses of older adults with hormone receptor-positive, HER2-negative metastatic breast cancer, highlighting data on the safety and efficacy of oral therapies, including endocrine therapy alone or in combination with cyclin-dependent kinase (CDK) 4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. In addition, we note the significant underrepresentation of older and frail adults in these studies. Current and future directions in research for this special population, in order to address significant knowledge gaps, include the need to improve long-term adherence to hormonal and targeted therapy, prospective clinical trials that capture clinical and biological aging endpoints, and the need for a multidisciplinary approach with integration of geriatric and oncology principles.

Targeted Therapies in Non-small-Cell Lung Cancer.

The treatment landscape for non-small-cell lung cancer (NSCLC) has dramatically shifted over the past two decades. Targeted or precision medicine has primarily been responsible for this shift. Older paradigms of treating metastatic NSCLC with cytotoxic chemotherapy, while still important, have given way to evaluating tumor tissues for specific driver mutations that can be treated with targeted agents. Patients treated with targeted agents frequently have improved progression-free survival and overall survival compared to patients without a targetable driver mutation, highlighting the clinical benefit of precision medicine. In this chapter, we explore the historic landmark trials, the current state of the field, and potential future targets under investigation, in this exciting, rapidly evolving discipline of precision medicine in lung cancer.

Androgen Receptor and PI3K Pathway Activity in Ovarian Cancer.

We sought to evaluate androgen receptor (AR) and PI3K pathway activity in ovarian cancer cell lines and tissue and determine if either pathway was correlated with growth of ovarian cancers. AR expression and activity were quantified using immunohistochemistry (IHC) and RT-qPCR in six ovarian cancer cell lines and 51 tissue samples. Phospho-mTOR and AKT expression were quantified by IHC as well. Cell growth was assessed in the presence of AR modulating drugs and metformin. We found that despite robust AR expression and activity, no cell line was dependent on androgen for growth. However, metformin inhibited activity in five of the six cell lines. Patient tissues had large variation in AR expression and activity, as well as in expression of phospho-mTOR and AKT, but none of these variables correlated with progression-free survival (PFS). AR expression and activity did not predict the dependence of ovarian cancer cell lines on androgens for growth, and AR expression and activity did not correlate with PFS. This result suggests that AR expression as a criterion for patient selection for clinical trials evaluating molecules targeting AR may not predict response for ovarian cancer patients.

Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis.

OBJECTIVE: Neuromyelitis optica (NMO) is characterized by selective inflammation of the spinal cord and optic nerves but is distinct from multiple sclerosis (MS). Interferon (IFN)-ß mitigates disease activity in MS, but is controversial in NMO, with a few reports of disease worsening after IFN-ß therapy in this highly active disease. In systemic lupus erythematosus (SLE), IFNs adversely affect disease activity. This study examines for the first time whether serum IFN-α/ß activity and IFN-ß-induced responses in peripheral blood mononuclear cells (MNC) are abnormally elevated in NMO, as they are in SLE, but contrast to low levels in MS. METHODS: Serum type I IFN-α/ß activity was measured by a previously validated bioassay of 3 IFN-stimulated genes (RT-PCR sensitivity, 0.1 U/ml) rather than ELISA, which has lower sensitivity and specificity for measuring serum IFNs. IFN responses in PBMNC were assessed by in vitro IFN-ß-induced activation of phospho-tyrosine-STAT1 and phospho-serine-STAT1 transcription factors, and MxA proteins using Western blots. RESULTS: Serum IFN-α/ß activity was highest in SLE patients, followed by healthy subjects and NMO, but was surprisingly low in therapy-naïve MS. In functional assays in vitro, IFN-ß-induced high levels of P-S-STAT1 in NMO and SLE, but not in MS and controls. IFN-ß-induced MxA protein levels were elevated in NMO and SLE compared to MS. CONCLUSIONS: Serum IFN activity and IFN-ß-induced responses in PBMNC are elevated in SLE and NMO patients versus MS. This argues for similarities in pathophysiology between NMO and SLE and provides an explanation for IFN-induced disease worsening in NMO.

Biscationic bicephalic (double-headed) amphiphiles with an aromatic spacer and a single hydrophobic tail.

We report the synthesis and aggregation studies of a homologous family of biscationic "bicephalic" amphiphiles. Each of has a linear alkoxy chain and two trimethylammonium bromide headgroups connected to a benzene ring. Krafft temperatures (T(K)) in water were determined by differential scanning calorimetry (DSC) and conductivity. Critical micelle concentration (cmc) and ionization degree (alpha) values were determined by monitoring the conductivity of aqueous solutions as a function of concentration, and confirmed by monitoring the (1)H NMR chemical shift of the terminal methyl group as a function of concentration. Values for log(cmc) decrease linearly with increasing chain length, with a smaller dependence on chain length than for single-headed amphiphiles, consistent with literature reports on other bicephalic amphiphiles. Comparison to two related amphiphiles, each with a single headgroup reveals that the addition of a second head group results in an increase in cmc and a decrease of T(K). These effects are attributed to greater water solubility due to the incorporation of a second, hydrophilic headgroup. The effect on alpha is also discussed.