Retroperitoneal drop metastases following robotic partial nephrectomy for renal cell carcinoma.

Rare retroperitoneal recurrence of clear cell renal cell carcinoma highlights the risk of tumor violation during surgery. A 61-year-old female with recurrent RCC in the retroperitoneum is presented six years after partial nephrectomy. Initial surveillance CT revealed a renal cyst and subsequent imaging confirmed clear cell RCC. Multiple small lesions indicated retroperitoneal recurrence. Surgical excision confirmed metastatic clear cell RCC. The proximity of the recurrence to the lower pole of the primary tumor suggests tumor violation as the cause. Respecting tumor boundaries during surgery is crucial to prevent metastasis and improve patient survival.

Chemical complementarity between tumor resident, T-cell receptor CDR3s and MAGEA3/6 correlates with increased melanoma survival: Potential relevance to MAGE vaccine auto-reactivity.

Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.

A comparison of immune receptor recombination databases sourced from tumour exome or RNAseq files: Verifications of immunological distinctions between primary and metastatic melanoma.

It became apparent several years ago that RNAseq and exome files prepared from tissue could be mined for adaptive immune receptor (IR) recombinations, which has given extra value to datasets originally intended for gene expression or mutation studies. For example, recovery of IR recombination reads from tumour specimen genomics files can correlate with survival rates. In particular, many benchmarking processes have been applied to the two sets of the IR recombination reads obtained from the cancer genome atlas files, but these two sets have never been directly compared. Here we show that both sets largely agree regarding several parameters. For example, recovery of TRB recombination reads from both WXS and RNAseq files representing metastatic melanoma was associated with a better outcome (p < .0004 in both cases); and T-cell receptor recombination read recovery, for both genomics file types, associated very strongly with T-cell gene expression markers. However, the use of CDR3 chemical features for survival distinctions was not consistent. This topic, and the surprising result that both datasets indicated that primary melanoma with recovery of IR recombination reads, in stark contrast to metastatic melanoma, represents a worse outcome, are discussed.

Electrostatic Complementarity of T-Cell Receptor-Alpha CDR3 Domains and Mutant Amino Acids Is Associated with Better Survival Rates for Sarcomas.

While sarcoma immunology has advanced with regard to basic, and even some applied topics, this disease has not been subject to more recent immunogenomics approaches. Thus, we assessed the immune receptor recombinations available from the cancer genome atlas (TCGA) sarcoma database via tumor sample exome and RNASeq files. Results indicated that recovery of T-cell receptor-alpha recombination reads (TRA) correlated with a better survival rate, with the expression of T-cell biomarkers, and with tumor sample apoptosis signatures consistent with the longer patient survival times. Furthermore, samples representing TRA complementarity determining region-3 (CDR3) net charge per residue (NCPR) based complementarity with the corresponding sarcoma mutanome had a better survival rate, and more granzyme expression, than samples lacking such complementarity. By specifically using RNASeq-recovered TRA CDR3s and related NCPR assessments, three genes, TP53, ATRX, and RB1, were identified as being key components of the mutanome-based complementarity. Thus, these genes may represent key immune system targets for soft tissue sarcomas. Also, several key results from above were reproduced with a pediatric osteosarcoma dataset, work that led to identification of MUC6 mutations as potentially linked to a strong immune response. In sum, TRA CDR3s are likely to be important prognostic indicators, and possibly a beginning tool for immunotherapy development strategies, for adult and pediatric sarcomas.

The Immune Microenvironment in Penile Cancer and Rationale for Immunotherapy.

Penile cancer is an extremely rare malignancy that accounts for approximately 1% of cancer deaths in the United States every year. While primary penile cancer can be managed surgically, advanced and metastatic forms of the disease require more aggressive management plans with systemic chemotherapy and/or radiotherapy. Despite the meaningful response to systemic treatments, the 2-year progression-free survival and disease-specific survival have shown disappointing results. Therefore, there is a crucial need for alternative treatment options with more favorable outcomes and a lower toxicity profile. There are currently extensive studies of tumor molecular biology and clinical trials with targeted molecular therapies, such as PD-1, PD-L1, and CTLA-4. In this review, we will describe the penile cancer microenvironment, and summarize the rationale for immunotherapy in penile cancer patients.

Chemical complementarity between immune receptor CDR3s and IDH1 mutants correlates with increased survival for lower grade glioma.

Focusing on highly specific aspects of the immune response is likely to answer a number of basic questions, and in some cases even resolve basic contradictions, in cancer immunology. For example, there are many cases, where chronic inflammation is associated with cancer development, and many other cases where an immune response represents an anticancer process. In this study, using bioinformatics algorithms, we examined the chemical relationships between the amino acid sequences of the complementarity-determining region-3 (CDR3) represented by immune receptors associated with lower grade glioma and isocitrate dehydrogenase-1 (IDH1) mutants. In particular, we developed a chemical complementarity scoring approach to classify tumors based on the complementarity of CDR3s and mutant IDH1 amino acids, relying on net charge per residue and hydropathy parameters. There was a strong correlation between the increased survival in low-grade glioma (LGG) and complementarity of IDH1 mutants to the CDR3 domain of the T-cell receptor beta chain (TRB). Similar results were obtained for TRB CDR3s and NRAS mutants in melanoma. Furthermore, the clear connection between increased survival rates and immune receptor-IDH1 mutant complementarities may also, partially, explain the better LGG prognosis for patients with IDH1 mutants.

Germline cytoskeletal and extra-cellular matrix-related single nucleotide variations associated with distinct cancer survival rates.

BACKGROUND: Human mutagenesis has a large stochastic component. Thus, large coding regions, especially cytoskeletal and extra-cellular matrix protein (CECMP) coding regions are particularly vulnerable to mutations. Recent results have verified a high level of somatic mutations in the CECMP coding regions in the cancer genome atlas (TCGA), and a relatively common occurrence of germline, deleterious mutations in the TCGA breast cancer dataset. METHODS: The objective of this study was to determine the correlations of CECMP coding region, germline nucleotide variations with both overall survival (OS) and disease-free survival (DFS). TCGA, tumor and blood variant calling files (VCFs) were intersected to identify germline SNVs. SNVs were then annotated to determine potential consequences for amino acid (AA) residue biochemistry. RESULTS: Germline SNVs were matched against somatic tumor SNVs (i.e., tumor mutations) over twenty TCGA datasets to identify 23 germline-somatic matched, deleterious AA substitutions in coding regions for FLG, TTN, MUC4, and MUC17. CONCLUSIONS: The germline-somatic matched SNVs, in particular for MUC4, extensively implicated in cancer development, represented highly, statistically significant effects on OS and DFS survival rates. The above results contribute to the establishment of what is potentially a new class of inherited cancer-facilitating genes, namely dominant negative tumor suppressor proteins.

When should fractional flow reserve be performed to assess the significance of borderline coronary artery lesions: Derivation of a simplified scoring system.

OBJECTIVES: To derive a simplified scoring system (SSS) that can assist in selecting patients who would benefit from the application of fractional flow reserve (FFR). BACKGROUND: Angiographers base decisions to perform FFR on their interpretation of % diameter stenosis (DS), which is subject to variability. Recent studies have shown that the amount of myocardium at jeopardy is an important factor in determining the degree of hemodynamic compromise. METHODS: We conducted a retrospective multivariable analysis to identify independent predictors of hemodynamic compromise in 289 patients with 317 coronary vessels undergoing FFR. A SSS was derived using the odds ratios as a weighted factor. The receiver operator characteristics curve was used to identify the optimal cutoff (≥3) to discern a functionally significant lesion (FFR≤0.8). RESULTS: Male gender, left anterior descending artery apical wrap, disease proximal to lesion, minimal lumen diameter and % DS predicted abnormal FFR (≤0.8) and lesion location in the left circumflex predicted a normal FFR. Using a cutoff score of ≥3 on the SSS, a specificity of 90.4% (95% CI: 83.0-95.3) and a sensitivity of 38.0% (95% CI: 31.5-44.9) was generated with a positive predictive value of 89.0% (95% CI: 80.7%-94.6%) and negative predictive value of 41.6% (95% CI: 35.1%-48.3%). CONCLUSIONS: The decision to use FFR should be based not only on the % DS but also the size of the myocardial mass jeopardized. A score of ≥3 on the SSS should prompt further investigation with a pressure wire.