Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work is aimed at understanding the molecular basis of these resistance mechanisms, with exciting new studies evaluating novel agents and combination therapies to improve control of tumors with all forms of EGFR mutation. In this review, we first provide a discussion of EGFR-mutated lung cancer and the efficacy of available EGFR TKIs in the clinical setting against both common and rare EGFR mutations. Second, we discuss common resistance mechanisms that lead to therapy failure during treatment with EGFR TKIs. Third, we review novel approaches aimed at improving outcomes and overcoming resistance to EGFR TKIs. Finally, we highlight recent breakthroughs in the use of EGFR TKIs in non-metastatic EGFR-mutated lung cancer.

Background: High‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette–Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle‐invasive bladder cancer (MIBC). Patients who are BCG‐unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.Methods: To address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR‐NMIBC treated with immune‐related agents were retrieved from clinicaltrials.gov.Findings and Future Perspectives: Exploratory treatments for BCG‐Unresponsive HR‐NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs—pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec‐vncg—have been FDA approved for the treatment of BCG‐unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long‐term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR‐NMIBC is essential for the discovery of new targets and the development of effective treatments.

Treatment of solid malignancies has been revolutionized with the introduction of immune checkpoint inhibitors (ICIs) and their use is being expanded in therapy of different cancers. However, immune related adverse events (IRAEs) can occur during treatment. These side effects occur due to stimulation of the innate and adaptive immune system and can lead to serious complications. Recently, acral ischemia has been reported in some cases during treatment with programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors. Here, we discuss a case in which acral necrosis developed after initiation of a PD-1 inhibitor. We offer a review of the existing literature on the pathophysiology, clinical course and treatment outcomes. A 68-year-old female was diagnosed with stage IV non-small cell lung adenocarcinoma and was started on pembrolizumab. The patient developed sudden onset numbness and discoloration of fingertips bilaterally at week 25 after initiation of ICI treatment. Extensive workup to rule out hypercoagulable, autoimmune and vascular disease was unremarkable except for mild elevation of ANA and ESR. The symptoms quickly progressed into dry gangrene within four weeks and did not respond to medical or surgical treatment. Pembrolizumab was subsequently discontinued due to progression of metastatic disease. The patient refused further interventions and transitioned to hospice care where she expired after two months. Acral ischemia can develop during treatment of malignancies. This complication, although uncommon, canresult in digital amputation. Physicians should be aware of the possible progression of acral vascular necrosis when Raynaud’s like symptoms develop. Larger studies are needed to confirm the role of ICIs in the pathogenesis of acral vascular necrosis.

Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAF^V600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

Body composition refers to the proportional content of body fat mass and lean body mass that can lead to a continuum of different phenotypes ranging from cachectic/sarcopenic state to obesity. The heterogenetic phenotypes of body composition can contribute to formation of some cancer types and can sometimes lead to disparate outcomes. Both of these extremes of the spectrum exist in patients with non-small cell lung carcinoma (NSCLC). The discovery of new pathways that drive tumorigenesis contributing to cancer progression and resistance have expanded our understanding of cancer biology leading to development of new targeted therapies including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) that have changed the landscape of NSCLC treatment. However, in the new era of precision medicine, the impact of body composition phenotypes on treatment outcomes and survival is now being elucidated. In this review, we will discuss the emerging evidence of a link between body composition and outcomes in patients with NSCLC treated with TKI and ICI. We will also discuss suggested mechanisms by which body composition can impact tumor behavior and anti-tumor immunological response.