Yousef Zakharia

Pembrolizumab Therapy Triggering an Exacerbation of Preexisting Autoimmune Disease: A Report of 2 Patient Cases

Historically, metastatic melanoma was uniformly and rapidly lethal, and treatment options were limited. In recent years, however, checkpoint inhibitors have emerged as an accepted standard treatment for patients with advanced melanoma. In clinical trials, these agents have been largely well tolerated and have the potential to result in durable responses. Importantly though, one must recognize the unique side effect profile of these therapies, which can trigger or exacerbate underlying autoimmune disease. Whether this autoimmune activation is associated with a clinical response to therapy has been debated, and while not definitive, there is evidence in the literature of a possible association. The 2 cases presented describe this autoimmune phenomenon, along with a review of the existing literature on the relationship between response to immunotherapy and autoimmune side effects.

Ipilimumab: from preclinical development to future clinical perspectives in melanoma

The arsenal for the treatment of metastatic melanoma is limited. A new approach to therapy using checkpoint blockade has improved overall survival in this patient population. Ipilimumab a CTLA-4 monoclonal antibody is a first in class drug that has pioneered this revolution. In this review, the authors provide an account of the different stages that led to the development of ipilimumab, its approval in the clinical setting for the treatment of advanced melanoma and ongoing investigations of combinatorial immune therapy.

Spotlight on nivolumab in the treatment of renal cell carcinoma: design, development, and place in therapy

Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC); however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC.

Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development *

Selenium (Se)-containing molecules exert antioxidant properties and modulate targets associated with tumor growth, metastasis, angiogenesis, and drug resistance. Prevention clinical trials with low-dose supplementation of different types of Se molecules have yielded conflicting results. Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent. Further, Se pretreament offered selective protection of normal tissues from drug-induced toxicity, thereby allowing higher dosing than maximum tolerated doses. These enhanced therapeutic effects were associated with inhibition of hypoxia-inducible factor 1- and 2-alpha (HIF1α, HIF2α) protein, nuclear factor (erythyroid-derived 2)-like 2 (Nrf2) and pair-related homeobox-1 (Prx1) transcription factors, downregulation of oncogenic- and upregulation of tumor suppressor miRNAs. This review provides: 1) a brief update of clinical prevention trials with Se; 2) advances in the use of specific types, doses, and schedules of Se that selectively modulate antitumor activity and toxicity of anti-cancer drugs; 3) identification of targets selectively modulated by Se; 4) plasma and tumor tissue Se levels achieved after oral administration of Se in xenograft models and cancer patients; 5) development of a phase 1 clinical trial with escalating doses of orally administered selenomethionine in sequential combination with axitinib to patients with advanced clear cell renal cell carcinoma; and 6) clinical prospects for future therapeutic use of Se in combination with anticancer drugs.

Ovarian Cancer from an Immune Perspective

Despite major advances in the treatment of ovarian cancer over the past two decades, it is still an incurable disease and requires the development of better treatment strategies. In recent years, we have developed a greater understanding of tumor immunology and the interactions between tumors and the immune system. This has led to the emergence of cancer immunotherapy as the fourth treatment modality in cancer. In this article, we address the principles of immunotherapy and different approaches that have been investigated over the past decade and discuss the future of immune therapy in ovarian cancer.

Quality of Life Outcomes in Patients With Advanced Melanoma: A Review of the Literature

For patients with metastatic melanoma, the emergence of immune checkpoint inhibitors and targeted BRAF and MEK inhibitors has markedly enhanced clinical outcomes compared with chemotherapy. However, these novel agents are also associated with unique sets of adverse events, and increased overall survival can lead to prolonged exposure to some novel agents. Therefore, clinical evaluation of these therapies has now included the analysis of health‐related quality of life (HRQoL) in addition to more traditional efficacy and safety outcomes as a measure of patient perception of benefit. The current review focuses on HRQoL outcomes in clinical trials of immune checkpoint inhibitors and targeted therapies in patients with advanced and metastatic melanoma to inform healthcare providers about patient perception of HRQoL as a new perspective in treatment decision making.

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study

Introduction Epigenetic modifications play an important role in progression and development of resistance in V600EBRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with V600EBRAF positive metastatic melanoma with or without any prior treatment. Experimental Design The study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line. Results Fourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity. Conclusions The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in V600EBRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.

Non–Muscle Invasive Papillary Urothelial Carcinoma Metastatic to the Mandible:

Urothelial carcinoma, the most common histologic subtype of bladder cancer in the United States, most frequently presents as non–muscle invasive disease. Initially, therapy involves transurethral endoscopic resection and subsequent intravesical therapies with extended surveillance for high-risk disease. Even with the best treatments, recurrence and progression can occur. However, metastasis of non–muscle invasive bladder cancer to distant sites without evidence of progression or regional metastasis is rare. In this article, we present the case of a patient with high-grade papillary urothelial carcinoma who developed an unusual metastasis to the mandible, confirmed by GATA-3 immunostaining, over 4 years after initial transurethral resection. Prior to the development of metastatic disease, this patient had no evidence of local recurrence during maintenance Bacillus Calmette-Guerin intravesical therapy and concurrent surveillance. Positron emission tomography-computed tomography taken after presentation with mandibular metastasis did not show any evidence of regional metastasis. This case highlights an unusual location for distant metastasis of urothelial carcinoma occurring in a patient without evidence of muscle invasive disease or regional metastasis. We additionally highlight the utility of GATA-3 immunostaining in identifying urothelial carcinoma histologically.

Acute Flare of Bullous Pemphigus With Pembrolizumab Used for Treatment of Metastatic Urothelial Cancer

In the past decade, the resurgence of immunotherapy has changed the landscape of cancer therapy. Checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen-4, programmed death-1 on lymphocytes, and programmed death ligand-1 on tumors cells are currently utilized in the management of several cancers. These agents are double-edged sword with the positive effect being robust antitumor response but on the other side they can throttle up the normal immunologic homeostasis in a negative way, leading to adverse autoimmune toxicities. These adverse toxicities are frequent if patients have active autoimmune disorders. Here, we report a rare case of quiescent bullous pemphigoid which flared after initiation of pembrolizumab, a programmed death ligand-1 inhibitor.

Small bowel obstruction: a recurrence of melanoma during the second trimester of pregnancy

Background: The incidence of melanoma is on the rise in the United States and is particularly prevalent among women of childbearing age. Obtaining a complete history and understanding the unpredictable behavior of melanoma is essential to make the diagnosis of recurrent disease during pregnancy. Case: A 35-year-old G2P1 at 23 weeks and 1 days’ gestation with a remote history of (treated) cutaneous melanoma underwent an exploratory laparotomy for small bowel obstruction. Pathology was consistent with recurrent metastatic melanoma. Conclusion: Metastatic melanoma diagnosed during pregnancy is rare. There are no guidelines on how or when to proceed with treatment of metastatic disease or delivery of the fetus. Immunotherapy is changing the management of melanoma and is extending life expectancy. The significant survival benefits for mother with immunotherapy may outweigh the risks of preterm delivery for the baby. University of Iowa Carver College of Medicine, Iowa City, Iowa University of Iowa Hospitals and Clinics, Department of Internal Medicine, Iowa City, Iowa University of Iowa Hospitals and Clinics, Department of Obstetrics and Gynecology, Iowa