Immune checkpoint inhibitor therapy in biliary tract cancer (cholangiocarcinoma).

Biliary tract cancer (BTC) is a rare malignancy with overall poor prognosis. There are limited options regarding systemic therapy for this disease and historically only multi-agent chemotherapy regimens achieve meaningful responses that are often short lived. In the past several years immune checkpoint inhibitor (ICI) therapy has been established as an effective systemic therapy option in many solid tumors. The BTC tumor microenvironment (TME) including immune cells (T cells, macrophages, dendritic cells and natural killer cells) and immune checkpoint expression has been characterized. Findings have clinical implications that suggest that this entity is potentially amenable to immunomodulation, including via checkpoint inhibition. Single agent ICI studies have only been reported in the past few years and have mostly targeted the checkpoints PD-1 and PD-L1. As in other tumor subtypes patients with rare mismatch repair deficiency or microsatellite instability appear to have exquisite sensitivity to checkpoint inhibition. Abstracts and published studies suggest modest but real responses in all subtypes including objective response rates (ORRs) in the 5-20% range and meaningful disease control. They have paved the way for novel combination trials featuring a variety of treatment strategies and agents that look to enhance ICI efficacy and create long- term responders.

Antibody-Drug Conjugates in Bladder Cancer.

Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.

Complete metastasectomy for renal cell carcinoma: Comparison of five solid organ sites.

BACKGROUND AND OBJECTIVES: Patients with metastatic RCC can undergo metastasectomy to improve survival time. Our goal was to provide and compare characteristics and oncological outcomes of RCC patients who underwent complete metastasectomy at a single organ site. METHODS: A total of 138 RCC patients were identified as undergoing complete metastasectomy at a single organ site including adrenal, lung, liver, pancreas, or thyroid. Competing risk regression analysis was used to assess RFS and CSS adjusting for several covariates. RESULTS: In this highly selected cohort, RFS and CSS was 27% and 84% at 5 years following metastasectomy, respectively. Univariate analysis revealed that removal of multiple tumors, younger age, and a shorter interval between nephrectomy and metastasis was associated with worse RFS. Larger tumors and sarcomatoid histology at nephrectomy was associated with worse CSS. We found no evidence that metastases at the time of RCC diagnosis influenced recurrence or survival. Tumor size, number of metastases resected, and time from nephrectomy to first recurrence was significantly different, but recurrence rates were not found to be significantly different, when compared across all organ sites. CONCLUSIONS: These findings inform clinical and surgical management of select RCC patients with isolated metastasis to one of several organ sites. J. Surg. Oncol. 2016;114:375-379. © 2016 Wiley Periodicals, Inc.

Subcentimeter pulmonary nodules are not associated with disease progression in patients with renal cell carcinoma.

PURPOSE: Renal cell carcinoma most commonly metastasizes to the lung. Indeterminate pulmonary nodules develop preoperatively in half of the patients with localized renal cell carcinoma but clinical significance remains poorly defined. We determined whether the presence of indeterminate pulmonary nodules, or nodule size or number is associated with renal cell carcinoma outcomes. MATERIALS AND METHODS: We reviewed data on 1,102 patients with renal cell carcinoma in whom chest computerized tomography was done within 6 months before nephrectomy from 2002 to 2012. Patients with metastatic disease at presentation, benign tumors, pulmonary nodules greater than 2 cm or concurrent pulmonary disease were excluded, leaving 748 available for analysis. Study outcomes included lung metastasis, any distant metastasis or death from renal cell carcinoma. Cox proportional hazards models were used to assess whether the presence of indeterminate pulmonary nodules, or nodule size or number was associated with outcomes. Models were evaluated by comparing discrimination using the Harrell c-index. RESULTS: Indeterminate pulmonary nodules were present in 382 of 748 patients (51%). Median followup was 4.1 years (IQR 2.2-6.1). The presence of indeterminate pulmonary nodules was not associated with distant metastasis or death from kidney cancer. However, compared to subcm indeterminate pulmonary nodules the nodules greater than 1 cm were associated with metastatic disease after adjusting for tumor histology, stage and size (HR 2.48, 95% CI 1.08-5.68, p = 0.031). The outcome c-index increased slightly after adding nodule size to a predictive model adjusted for tumor characteristics. CONCLUSIONS: No evidence in the current study suggested that indeterminate pulmonary nodules less than 1 cm are associated with renal cell carcinoma progression, although large nodules significantly predicted metastatic disease. Patients with subcm indeterminate pulmonary nodules would be unlikely to benefit from extensive postoperative chest imaging surveillance, which should be reserved for patients with nodules greater than 1 cm.

iTriplet, a rule-based nucleic acid sequence motif finder.

BACKGROUND: With the advent of high throughput sequencing techniques, large amounts of sequencing data are readily available for analysis. Natural biological signals are intrinsically highly variable making their complete identification a computationally challenging problem. Many attempts in using statistical or combinatorial approaches have been made with great success in the past. However, identifying highly degenerate and long (>20 nucleotides) motifs still remains an unmet challenge as high degeneracy will diminish statistical significance of biological signals and increasing motif size will cause combinatorial explosion. In this report, we present a novel rule-based method that is focused on finding degenerate and long motifs. Our proposed method, named iTriplet, avoids costly enumeration present in existing combinatorial methods and is amenable to parallel processing. RESULTS: We have conducted a comprehensive assessment on the performance and sensitivity-specificity of iTriplet in analyzing artificial and real biological sequences in various genomic regions. The results show that iTriplet is able to solve challenging cases. Furthermore we have confirmed the utility of iTriplet by showing it accurately predicts polyA-site-related motifs using a dual Luciferase reporter assay. CONCLUSION: iTriplet is a novel rule-based combinatorial or enumerative motif finding method that is able to process highly degenerate and long motifs that have resisted analysis by other methods. In addition, iTriplet is distinguished from other methods of the same family by its parallelizability, which allows it to leverage the power of today's readily available high-performance computing systems.