Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation.

BACKGROUND: STK11 mutation (STK11m ) in patients (pts) with stage IV non-small cell lung cancer (NSCLC) is associated with inferior survival and poor response to immune checkpoint inhibitors (ICI). The significance of STK11m in stage III NSCLC pts treated with concurrent chemoradiation (CCRT) with or without consolidation ICI is unknown. METHODS: Stage III NSCLC patients who received CCRT and had known STK11 mutational status were included in this retrospective study. The data on the STK11m pts were collected from 4 cancer institutions. A cohort of pts with wild type STK11 (STK11w ) from the University of Iowa served as a comparison group. Patient demographics and clinical characteristics were collected. Cox regression models were used to explore the effect of STK11 mutation on survival. RESULTS: 75 pts with stage III NSCLC who had known STK11 mutational status were identified. 16/75 (21%) had STK11m . 5/16 with STK11 m did not receive CCRT so they were excluded from the analysis. The clinical and demographic characteristics for the 11 STK11m and 59 STK11w pts were not statistically different (STK11m vs. STK11w ): mean age: 57 vs. 64 yrs, non-squamous histology: 8/11 (73%) vs. 37/59 (63%), KRAS mutation: 3/11 (27%) vs. 11/59 (19%), TP53 mutation: 6/11 (55%) vs. 15/59 (25%), PD-L1 ≥50%: 1/8 (13%) vs. 10/32 (31%), and consolidation ICI 6/11 (55%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3-17) vs. 6 (range, 1-25) in the 17 pts with STK11w who received ICI (durvalumab). After adjusting for performance status and cancer stage, multivariable analysis showed that progression free survival (PFS) for the STK11m pts was significantly worse than STK11 w pts (HR =2.25; 95% CI, 1.03-4.88, P=0.04), whereas overall survival (OS) showed no significant difference for STK11m vs. STK11w patients (HR 1.47, 95% CI, 0.49-4.38, P=0.49). CONCLUSIONS: In stage III NSCLC patients who received CCRT, STK11m was associated with worse PFS compared to STK11w . Larger studies are needed to further explore the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.

Patient Characteristics and Survival Outcomes of Non-Metastatic, Non-Clear Cell Renal Cell Carcinoma.

BACKGROUND: Non-clear cell renal cell carcinoma (ccRCC) includes histologically and molecularly distinct subtypes such as papillary, chromophobe, collecting duct, and sarcomatoid RCC, with an incidence ranging from 20% to 25%. Oncologic outcomes and the role of adjuvant systemic therapy [vascular endothelial growth factor inhibitor (VEGFi) or immunotherapy] for non-ccRCC are not well-described. OBJECTIVE: To assess the incidence and survival outcomes of non-ccRCC subtypes in comparison to ccRCC. METHODS: The National Cancer Database was utilized to identify patients with non-metastatic RCC (T1-T4, N0-N1) between 2004 and 2015. The non-ccRCC cohort was further stratified by histologic subtype: papillary, chromophobe, sarcomatoid, and collecting duct RCC. Multivariable Cox regression models were used to compare overall survival (OS). RESULTS: The 5-year OS for chromophobe, papillary, clear cell, collecting duct, and sarcomatoid RCC was 91%, 82%, 81%, 44%, and 40%, respectively. After adjusting for clinicopathologic and treatment characteristics, there was no significant difference in OS between papillary RCC and ccRCC (p = 0.17). Patients with collecting duct and sarcomatoid subtypes were at over two times increased risk of death compared to patients with clear cell (p < 0.01 and p < 0.01, respectively). Conversely, patients with chromophobe RCC were at 36% decreased risk of death compared to ccRCC (p < 0.01). CONCLUSIONS: This hospital-based analysis confirms that collecting duct and sarcomatoid histologic subtypes are uncommon and associated with poor survival after surgery when compared to the other RCC subtypes. Further studies are needed to evaluate the role of neoadjuvant and adjuvant systemic therapies in these subtypes to improve oncologic outcomes.

Transformational Changes Between Non-Small Cell and Small Cell Lung Cancer-Biological and Clinical Relevance-A Review.

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non-small cell lung cancer and conversely, patients with non-small cell lung cancer have had transformation to small cell lung cancer or other non-small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.

Fibroblast Growth Factor Receptor (FGFR) Inhibitors in Urothelial Cancer.

Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns. IMPLICATIONS FOR PRACTICE: Dysregulated fibroblast growth factor receptor (FGFR) signaling is associated with several cancers, including urothelial carcinoma. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Most recently, erdafitinib was approved by the U.S. Food and Drug Administration for advanced urothelial carcinoma with FGFR gene alterations as the first molecularly targeted therapy. Additional ongoing clinical trials with other types of FGFR inhibitors have shown encouraging results. This review summarizes the oncogenic signaling of FGFR alterations, completed and ongoing clinical trials of FGFR inhibitors, and resistance patterns.

The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma.

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), as well as inhibitors of the mammalian target of the rapamycin (mTOR) pathway. Most recently, checkpoint inhibitors were shown to have excellent clinical efficacy. Although the patients are living longer, durable complete responses are rarely seen. Historically, high dose interleukin 2 (IL2) therapy has produced durable complete responses in 5% to 8% highly selected patients-albeit with significant toxicity. A durable complete response is a surrogate for a long-term response in the modern era of targeted therapy and checkpoint immunotherapy. Numerous clinical trials are currently exploring the combination of immunotherapy with various targeted therapeutic agents to develop therapies with a higher complete response rate with acceptable toxicity. in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy.

A case report and focused literature review of d-penicillamine and severe neutropenia: A serious toxicity from a seldom-used drug.

Prescribing d-penicillamine for Wilson's disease must be accompanied by vigilant monitoring, including a complete blood cell count with differential. For most, this should occur once or twice weekly during the first month of therapy and during periods of dose escalation, then every two weeks for six additional months, then monthly.

Current Landscape and the Potential Role of Hypoxia-Inducible Factors and Selenium in Clear Cell Renal Cell Carcinoma Treatment.

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) has led to the development of biologically-driven targeted therapies. Hypoxia-inducible factors (HIFs), angiogenic growth factors, von Hippel⁻Lindau (VHL) gene mutations, and oncogenic microRNAs (miRNAs) play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of vascular endothelial growth factor (VEGF) inhibitors, Mechanistic target of rapamycin (mTOR) inhibitors, and immunotherapeutic agents, which have significantly improved the outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC) inhibitors, selenium, and agents like PT2385 and PT2977 are being explored in various clinical trials as potential HIF inhibitors, to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in clear cell RCC (ccRCC) tumors.

Dabigatran-related leukocytoclastic vasculitis.

Dabigatran is a non-vitamin K antagonist oral anticoagulant that has been approved for atrial fibrillation and prevention of venous thromboembolism. Its use has been increasing in the USA since serum drug levels do not need monitoring. To date, no significant skin side effects have been reported other than 4 cases of non-specific skin lesion and 2 cases of leukocytoclastic vasculitis (LCV), which is a small vessel inflammatory disease that presents as palpable purpura in lower extremities. We present a man aged 57 years with chronic deep vein thrombosis who developed palpable purpura, petechiae, swelling in lower extremities, torso and distal upper extremities on the third day after dabigatran initiation. The present case highlights the potential risk for LCV with dabigatran use and provides insight into its management.