Widespread Hypertrophic Lichen Planus following Programmed Cell Death Ligand 1 Blockade.

Hypertrophic lichen planus (HLP) may not have the typical histological findings of lichen planus and often mimics squamous cell carcinoma (SCC). Distinguishing between the two can pose a diagnostic challenge. Here, we present a case of eruptive HLP mimicking SCC in the context of programmed cell death ligand 1 (PD-L1) immune checkpoint inhibition. A 73-year-old woman recently treated with durvalumab, an anti-PD-L1 antibody, presented to our clinic with diffuse hyperkeratotic papules and plaques previously thought to be eruptive SCC. The lesions did not respond to topical fluorouracil and continued to appear despite discontinuation of immunotherapy. Further histological analysis revealed intraepidermal epithelial proliferation with lichenoid inflammation. Subsequent treatment with topical corticosteroids significantly improved the size and number of lesions. The diagnosis of HLP was made based on histological features and response to topical steroids in the context of recent immunotherapy. This case reveals HLP as a potential adverse effect of PD-L1 inhibition and highlights the need for additional diagnostic assessment in patients presenting with eruptive hyperkeratotic lesions, especially on the lower extremities.

Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy.

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

Safe Transition to Pembrolizumab following Ipilimumab-Induced Guillain-Barré Syndrome: A Case Report and Review of the Literature.

BACKGROUND: Immune checkpoint inhibitors are novel therapies with indications for treating several solid cancers. They are associated with immune-related adverse events, which are generally well tolerated. Though rare, severe side effects may be life-threatening. One such adverse event is Guillain-Barré syndrome, which requires cessation of the immunotherapy and intravenous immunoglobulin and/or high-dose steroids to treat. No recommendations have been published regarding restarting cancer treatment after development of immunotherapy-induced Guillain-Barré syndrome. CASE PRESENTATION: A 71-year-old gentleman with recurrent, stage IIIB melanoma was started on ipilimumab (cytotoxic T lymphocyte antigen-4 inhibitor) for adjuvant treatment following radical neck dissection and radiation therapy. After completing his third cycle of ipilimumab, he developed rapidly progressive ascending paralysis. He was diagnosed with ipilimumab-induced atypical Guillain-Barré syndrome and was treated with intravenous immunoglobulin and corticosteroids. Ipilimumab was discontinued, and the patient was monitored via surveillance imaging, as there was no evidence of active disease at that time. Several months later, he was found to have recurrent disease involving the lung, requiring right lower lobectomy. Restaging revealed thoracic lymph node involvement, and he was then started on pembrolizumab (programmed cell death protein-1 inhibitor). He experienced a complete tumoral response to pembrolizumab, and he tolerated treatment well without recurrent weakness. CONCLUSIONS: Guillain-Barré syndrome is a rare but severe complication associated with immunotherapy. Our findings suggest that in patients with a history of ipilimumab-induced Guillain-Barré syndrome, pembrolizumab may possibly be a safe and effective alternative for cancer therapy.

Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib.

Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600-mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range.

Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors.

Recently, modulation of immune checkpoints has risen to prominence as a means to treat a number of solid malignancies, given the durable response seen in many patients and improved side effect profile compared to conventional chemotherapeutic agents. Several classes of immune checkpoint modulators have been developed. Here, we review current monoclonal antibodies directed against immune checkpoints that are employed in practice today. We discuss the history, mechanism, indications, and clinical data for each class of therapies. Furthermore, we review the challenges to durable tumor responses that are seen in some patients and discuss possible interventions to circumvent these barriers.

Targeting PD-L1 After Adjuvant Radiation in Subtotally Resected Primary Pineal Melanoma: A Case Report and Literature Review.

Primary melanoma of the pineal gland is a rare disease entity with an overall poor prognosis. Limited data exist to appropriately guide treatment decisions. Historical case reports have showed some success using a combination of surgical resection, radiotherapy, and chemotherapy, but long-term survival has been exceedingly rare. This report presents a female patient with a primary pineal melanoma who underwent subtotal resection followed by adjuvant focal radiation to the residual tumor. Immunohistochemistry identified a strong positivity for PD-L1 (70%). After radiation, systemic therapy with pembrolizumab was initiated with the plan to treat until progression. She has now completed 33 cycles of pembrolizumab without interruptions, complications, or disease progression. At the time of writing, the patient has had an excellent clinical outcome, with a durable near-complete response of >138 weeks. To our knowledge, this is the first patient with a pineal melanoma to be managed by targeting PD-L1. Furthermore, she has achieved the second longest overall survival and the longest progression-free survival reported in the literature.

Primary Malignant Melanoma of the Bladder Treated by Robotic Partial Cystectomy and Immunotherapy.

Background: Primary malignant melanoma (PMM) of the urinary tract is a rare entity, with only 28 cases reported in the literature. We present an interesting case of a 27-year-old Caucasian woman, with family history of melanoma, who initially presented with gross hematuria, and was subsequently found to have PMM of the bladder. Case Presentation: Initially diagnosis was made through transurethral resection of the bladder tumor with clinical suspicion of residual disease in the patient. Subsequently, she underwent robotic partial cystectomy with pelvic lymph node dissection followed by 1 year of pembrolizumab, a PD-1 checkpoint inhibitor. Subsequent imaging demonstrated no evidence of metastatic disease or local recurrence. Conclusion: This case report presents a unique management of a rare pathological diagnosis with the use of robotic partial cystectomy, and a PD-1 checkpoint inhibitor therapy that ultimately has led to a 2-year recurrence-free survival period for this young patient.

Molecular and Genomic Profiling to Identify Actionable Targets in Chromophobe Renal Cell Cancer.

Metastatic chromophobe renal cell cancer (chRCC) is a rare subtype of RCC with no standard treatment. We performed molecular profiling of 12 chRCC cases to identify alterations predictive of response to therapy. Tests included immunohistochemistry assays, fluorescence in situ hybridization, and next-generation sequencing. Analysis identified c-KIT overexpression in 6/9 (67%) samples analyzed, and loss of protein expression of RRM1 and MGMT in 11/12 (92%) and of PTEN in 7/12 samples (58%). Mutations of TP53, PTEN, APC, and VHL genes were identified. In summary, molecular profiling of chRCC identified alterations in genes and protein expression that might provide a mechanistic rationale for off-label use of approved therapies in advanced chRCC, and could guide the design of molecularly targeted clinical trials. PATIENT SUMMARY: In this study, we evaluated samples of a rare type of kidney cancer (chromophobe type) and identified potential genetic markers that could be used to individualize treatment and possibly improve treatment outcomes.

Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance.

Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.

Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab.

Background: To identify the optimal sequencing and timing of immunotherapy (IT) and stereotactic radiosurgery (SRS) for melanoma brain metastases (MBMs). Methods: The elapsed days between IT and SRS were correlated with local control (LC), regional brain control (RBC), time to CNS progression (TTPCNS), overall survival (OS), and radiation necrosis (RN). Logistic regression and Cox proportional models were used for statistical analysis. Results: Twenty-five patients with 58 MBMs underwent SRS and IT. Median follow-up was 22.7 mo (3.1-77.9 mo). A median of 2 SRS treatments of 21 Gy (range 16-24 Gy) and 4 cycles of Ipilimumab were delivered. SRS was delivered Before, After or Concurrently with IT in 9, 5, and 11 patients, respectively; 8/25 received SRS ≤30 d of IT and 17/25 were >30 d of IT. Median OS was 35.8 mo, 1- and 2-y OS was 83% and 64%, respectively, and LC was 94.8%. By timing, RBC and TTPCNS were significantly improved when SRS was delivered ≤30 d of IT (75% vs 23.5%, p = 0.03 and median not reached vs 5.7 mo, p = 0.02, respectively). By groups, Concurrent delivery improved TTPCNS (p = 0.04). The rate of RN was 20.7% (12/58 lesions) and RN was associated with improved OS (HR 0.21, p = 0.01). Conclusions: High OS was found for MBM treated with SRS and IT compared to historical reports. A significant association for improved RBC and TTPCNS was found when SRS was delivered concurrently and within 30 d of IT. Occurrence of RN was higher than SRS alone series but significantly associated with improved OS.

Limited Stage Aggressive Non-Hodgkin Lymphoma: What Is Optimal Therapy?

OPINION STATEMENT: The seminal SWOG trial S8736 trial established the success of a short course of chemotherapy followed by involved field radiation in treating limited stage aggressive NHL lymphoma. Addition of rituximab offered a surprisingly modest improvement in this disease subset. Radioimmunotherapy could hold a slight advantage over rituximab, but that should be investigated in a randomized trial setting. The role of radiation therapy continues to be widely debated, with interpretation complicated by different trial populations, methods of assessing risk, as well as by differences in timing and dose of radiation. Prolonged course of chemotherapy followed by radiation is certainly not justified in all patients with limited stage disease. Three to four cycles of R-CHOP followed closely by IFRT/ISRT, or six cycles of R-CHOP chemoimmunotherapy (based on the MInT trial) are acceptable options. PET/CT scans may further limit radiation to minority of patients who have residual PET-positive masses. PET/CT-directed treatment strategy is being tested in a US intergroup trial. There is evidence that localized DLBCL has a different biology as compared to advanced stage disease. This relates to propensity of limited stage disease to be proportionately more germinal center B-cell like (GCB) and to have late relapses beyond 5 years. Both biology and imaging need to be integrated in the study of limited stage disease without presumption that it should be approached the same as advanced stage disease.

A Rare Case of Primary Anterior Mediastinal Yolk Sac Tumor in an Elderly Adult Male.

Mediastinal germ cell tumors are extragonadal germ cell tumors (EGGCTs) commonly seen in children and young adults. They are more common in men. Clinically they are classified as teratomas, seminomas, and nonseminomatous germ cell tumors. Primary mediastinal yolk sac neoplasm is an extremely rare tumor. We present here a very rare case of primary yolk sac tumor of the anterior mediastinum in a 73-year-old male. Mediastinal germ cell tumors have a worse prognosis than gonadal germ cell tumors. Chemotherapy followed by adjuvant surgery improves overall response in EGGCTs. However, comorbidities can render treatment with chemotherapy and surgery challenging in elderly patients.

Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management.

Anticancer treatment has evolved enormously over the last decade. Drugs targeting receptor tyrosine kinases, VEGFR and EGFR have changed the treatment landscape of certain cancers and have shifted the theme of anticancer therapy toward personalized care. However, these newer agents also come with unique side-effect profiles not seen with conventional chemotherapy including serious cardiovascular adverse effects. Hence, meticulous understanding of the adverse effects is crucial in maximizing clinical benefits and minimizing detrimental effects of these newer drugs. We have reviewed the cardiovascular adverse effects of anti-VEGF therapy in this article.

Smoldering Multiple Myeloma: Emerging Concepts and Therapeutics.

Smoldering multiple myeloma (SMM) is a pre-malignant condition with an inherent risk for progression to multiple myeloma (MM). The 2014 IMWG guidelines define smoldering multiple myeloma as a monoclonal gammopathy disorder with serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10-60 % without any myeloma-defining events or amyloidosis. The risk for progression of SMM to MM vary based on clinical, laboratory, imaging, and molecular characteristics. Observation, with periodic monitoring is the current standard of care for SMM. Over last few years, research advances in SMM have led to the delineation of newer risk factors for progression and identification of a "high-risk" group that would potentially benefit from early treatment. This review focuses on advances in the SMM risk-stratification model and recent clinical trials in this patient population.

Poorly Differentiated Neuroendocrine Tumor of the Rectum Coexistent with Giant Rectal Villous Adenoma Presenting as McKittrick-Wheelock Syndrome.

McKittrick-Wheelock Syndrome is a rare disorder, noted for electrolyte and fluid depletion caused by secretory colorectal adenomas and carcinomas. We report here the first reported case of a 55-year-old man with a large rectal villous adenoma coexistent with a poorly differentiated neuroendocrine tumor of rectum presenting with McKittrick-Wheelock Syndrome. Palliative chemotherapy resulted in complete resolution of symptoms and improved quality of life.

Anti-PD-1 and PD-L1 therapy for bladder cancer: what is on the horizon?

Oncologic therapeutics has evolved enormously as we entered the 21st century. Unfortunately, the treatment of advanced urothelial cancer has remained unchanged over the last two decades despite a better understanding of the genetic alterations in bladder cancer. Pathways such as the PI3K/AKT3/mTOR and FGFR have been implicated in urothelial bladder cancer. However, targeted therapies have not shown proven benefit yet and are still considered investigational. Recently, researchers have been successful in manipulating the systemic immune response to mount antitumor effects in melanoma, lung cancer and lymphoma. Historically, intravesical Bacillus Calmette-Guérin immunotherapy has been highly active in nonmuscle invasive bladder cancer. Early data suggest that immune checkpoint inhibitors will soon prove to be another cornerstone in the treatment armamentarium of advanced bladder cancer.

Mixed germ cell testicular cancer with left ventricular metastasis presenting with embolic stroke and small bowel tumor seeding.

Testicular germ cell tumors (GCTs) metastasize in a very predictable fashion involving the retroperitoneal nodes first followed by hematogenous spread to distant organs like lungs, liver, and brain. Metastasis to heart is an extremely rare entity for GCT and fewer than 20 cases have been reported in the literature so far. We have summarized here a unique case of nonseminomatous germ cell tumor (NSGCT) with intracardiac metastasis resulting in systemic macroembolization to liver, spleen, brain, bowel and musculoskeletal tissues. This led to multiple adverse sequelae including ischemic stroke and bowel perforation.