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Eric Jonasch - Top 30 Publications

Phase 2 Trial of Capecitabine, Gemcitabine, and Bevacizumab in Sarcomatoid Renal-Cell Carcinoma.

Patients with sarcomatoid renal-cell carcinomas (sRCC) have poor outcomes and limited treatment options. Preclinical and clinical data suggest susceptibility to cytotoxic agents and vascular endothelial growth factor-targeted therapies. We designed a phase 2 trial to evaluate the efficacy and safety of capecitabine, gemcitabine, and bevacizumab in sRCC.

Effects of tamoxifen on urinary incontinence: Case report and review of literature.

Tamoxifen has been used in women with hormone receptor-positive breast cancer and has been shown to successfully reduce both recurrence and mortality. On the contrary, long-term use of tamoxifen has hormone-related urogenital side effects which decrease the quality of life of the patients.

Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation.

The immune profile of sarcomatoid renal cell carcinoma (sRCC), including the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) status, has not been well characterized.

HNF1B loss exacerbates the development of chromophobe renal cell carcinomas.

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell cycle checkpoint proteins RB1 and p27. Further, it altered the chromatin accessibility of Mad2l1, Bub1b and Rb1 genes and triggered aneuploidy development. Analysis of the TCGA database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC.

Recommendations for the Management of Rare Kidney Cancers.

The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations.

Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile and transcriptional landscape.

Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.<br /><br />Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes.  <br /><br />Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes.  The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer related genes, despite a higher mutational burden in S-.  Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC).  A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.  <br /><br />Conclusions: Sarcomatoid RCC segregates by parent subtype and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles.  These features prompt a more precise molecular classification of RCC with diagnostic, prognostic, and therapeutic implications.

Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer.

Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.

Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

Incorporating New Systemic Therapies in Kidney Cancer Treatment.

In 2017, pazopanib and sunitinib remain the mainstays of frontline therapy for advanced renal cell carcinoma. Independent review of frontline cabozantinib therapy may alter standard of care for patients at intermediate and poor risk. Multiple agents show a survival advantage in the second-line setting, including nivolumab, cabozantinib, and combination lenvatinib and everolimus. Selection of subsequent therapy will depend on patient disease status, comorbidities, and resource availability.

Outcomes of Patients with Renal Cell Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras.

We studied overall survival and prognostic factors in patients with sarcomatoid renal cell carcinoma treated with nephrectomy and systemic therapy in the cytokine and targeted therapy eras.

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT).

Interconnection: A qualitative analysis of adjusting to living with renal cell carcinoma.

Adjusting to cancer is an ongoing process, yet few studies explore this adjustment from a qualitative perspective. The aim of our qualitative study was to understand how patients construct their experience of adjusting to living with cancer.

Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era.

Bone metastases (BMs) occur commonly in patients with metastatic renal cell carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved the outcomes for patients with mRCC. However, data on the outcomes of mRCC patients with BMs treated with TKIs are limited. We describe the outcomes of patients with BMs treated with TKI therapy and compare them with the outcomes from a pre-TKI group.

Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs everolimus in advanced non-clear cell renal cell carcinoma.

No biomarkers are available to predict relative clinical benefit from targeted therapies in patients with non-clear cell renal cell carcinoma (nccRCC). To identify candidate predictive markers, we investigated a set of cytokines and angiogenic factors (CAFs) in previously untreated patients with nccRCC participating in the phase II ESPN trial comparing first-line sunitinib to everolimus. Pre-treatment concentrations of 30 CAFs were measured in plasma from 37 patients treated with everolimus (n=16) or sunitinib (n=21), and associated with progression-free (PFS) and overall survival (OS) after adjusting for potential confounders. High (>median) concentrations of soluble glycoprotein 130 (sgp130) were predictive of a longer PFS with sunitinib compared with everolimus (HR = 0.30; 95% CI: 0.11-0.85; P = 0.024). Significantly shorter PFS was noted, independently of treatment arm, in patients with high (>median) levels of IL-8 (HR = 3.13; 95% CI: 1.41-6.92), IL-13 (HR = 3.36; 95% CI: 1.49-7.58), and soluble tumor necrosis factor receptor II (HR = 2.21; 95% CI: 1.04-4.72). High IL-8 levels were also associated with significantly shorter OS (HR = 3.55; 95% CI: 1.55-8.14). Thus, using CAF profiling we identified candidate prognostic and predictive circulating biomarkers that can be used to inform therapeutic decisions in nccRCC.

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study.

To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS).

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

Pazopanib is associated with increased progression-free survival (PFS) in clear-cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non-clear-cell RCC, but data on outcomes in this setting are limited.

Dual Chromatin and Cytoskeletal Remodeling by SETD2.

Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy. These data now identify SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton and show a requirement for methylation in maintenance of genomic stability and the integrity of both the tubulin and histone codes.

Biphasic components of sarcomatoid clear cell renal cell carcinomas are molecularly similar to each other, but distinct from, non-sarcomatoid renal carcinomas.

Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid clear cell renal cell carcinoma (n=43) and non-sarcomatoid clear cell renal cell carcinoma (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid clear cell renal cell carcinoma (n=10) and advanced non-sarcomatoid clear cell renal cell carcinoma (n=155). The epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid clear cell renal cell carcinoma. Prognostic clear cell renal cell carcinoma gene expression profiles were shared by the biphasic components of sarcomatoid clear cell renal cell carcinoma and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid clear cell renal cell carcinomas using RNA-seq. Sarcomatoid clear cell renal cell carcinoma is molecularly distinct from non-sarcomatoid clear cell renal cell carcinoma, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the histological sarcomatoid component.

Autophagy degrades hypoxia inducible factors.

Hypoxia inducible factors are subjected to degradation by the ubiquitin-proteasome system (UPS), macroautophagy, and chaperone-mediated autophagy. The E3 ligases, ubiquitination, autophagy receptor proteins, and oxygen are determinants that direct hypoxia-inducible factors to different degradation pathways.

Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma.

In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019).

NCCN Evidence Blocks.

NCCN has developed a series of Evidence Blocks: graphics that provide ratings for each recommended treatment regimen in terms of efficacy, toxicity, quality and consistency of the supporting data, and affordability. The NCCN Evidence Blocks are currently available in 10 tumor types within the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). At a glance, patients and providers can understand how a given treatment was assessed by the NCCN Guidelines Panel and get a sense of how a given treatment may match individual needs and preferences. Robert W. Carlson, MD, CEO of NCCN, described the reasoning behind this new feature and how the tool is used, and Eric Jonasch, MD, Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and Vice Chair of the NCCN Kidney Cancer Panel, described its applicability in the management of metastatic renal cell carcinoma.

Treatment of Relapsed Germ Cell Tumors: Time For Something New?

Examination of moderators of expressive writing in patients with renal cell carcinoma: the role of depression and social support.

To identify groups most likely to benefit from an Expressive Writing (EW) intervention, we examined psychosocial variables as intervention moderators. We hypothesized that EW would be particularly effective for participants with high levels of depressive symptoms and social support at study entry.

The Role of Metastasectomy in Patients with Renal Cell Carcinoma with Sarcomatoid Dedifferentiation: A Matched Controlled Analysis.

Management of metastatic renal cell carcinoma with sarcomatoid dedifferentiation remains a therapeutic challenge with no standard treatment strategies. We evaluated whether metastasectomy has any survival benefit in patients with metastatic sarcomatoid dedifferentiation treated with radical nephrectomy.

The use of spine stereotactic radiosurgery for oligometastatic disease.

OBJECTIVE The authors investigated the outcomes following spine stereotactic radiosurgery (SSRS) for patients with oligometastatic disease of the spine. METHODS The study was a secondary analysis of 38 of 209 patients enrolled in 2 separate institutional Phase I/II prospective protocols and treated with SSRS between 2002 and 2011. Of these 38 patients, 33 (87%) were treated for a solitary spine metastasis, with no other history of metastatic disease. SSRS was prescribed to 24 Gy in 1 fraction (8%), 18 Gy in 1 fraction (18%), 16 Gy in 1 fraction (11%), 27 Gy in 3 fractions (53%), 30 Gy in 5 fractions (8%), or 20 Gy in 5 fractions (3%). Seventeen patients (45%) received prior conventional external beam radiation therapy. RESULTS The median overall survival (OS) was 75.7 months, and the 2- and 5-year OS rates were 84% and 60%, respectively. In multivariate analysis, patients who had prior spine surgery and a better Karnofsky Performance Scale score had an improved OS (HR 0.16, 95% CI 0.05-0.52, p < 0.01, and HR 0.33, 95% CI 0.13%-0.84%, p = 0.02, respectively), and those who had undergone prior radiation therapy had a worse OS (HR 3.6, 95% CI 1.2%-10%, p = 0.02). The 1-, 2-, and 5-year local progression-free survival rates were 85%, 82%, and 78%, respectively. The median time to systemic therapy modification was 41 months. Two patients (5%) experienced late Grade 3-4 toxicity. CONCLUSIONS Patients with oligometastatic disease of the spine treated with SSRS can experience long-term survival and a long time before needing a modification in systemic therapy. In addition, SSRS leads to excellent local control and minimal late toxicity.

Evaluation and management of pancreatic lesions in patients with von Hippel-Lindau disease.

von Hippel-Lindau (VHL) disease is a heritable cancer-predisposition syndrome with multiorgan involvement. Pancreatic lesions are detected in approximately two-thirds of patients with VHL disease at some point during their lifetime. In these patients, cystic pancreatic lesions are almost exclusively benign and, unless symptomatic, do not require surgical or endoscopic intervention; however, solid pancreatic lesions can often be recognized through imaging screens, and are commonly found to be nonfunctioning pancreatic neuroendocrine tumours (pNETs) with malignant potential. The natural history of these VHL-associated pNETs is variable, and lacks clinical or imaging features that predict disease progression or metastatic potential, and generally needs to be managed more conservatively than their sporadic counterparts. Treatment options for such lesions, which range from active surveillance to surgical intervention, can nevertheless be associated with considerable morbidity and even mortality. Of note, although several guidelines have been established for the management of tumours associated with VHL syndrome, none of these have specifically focused on pancreatic lesions. Thus, we aim to characterize the types of pancreatic lesions associated with VHL disease and their natural history, to identify particular lesions that necessitate treatment, and to define what forms of treatment should be undertaken.

Response to post-axitinib treatment in patients with metastatic renal cell carcinoma.

Axitinib is a potent inhibitor of the vascular endothelial growth factor (VEGF) receptor family with clinical activity in patients with metastatic renal cell carcinoma (mRCC). Given this biochemical potency, the clinical activity of subsequent treatment with targeted therapies in patients progressing on axitinib is of interest.

Key considerations in the treatment of von Hippel-Lindau disease.

Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations.

The genomic features underpinning renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) are not well understood, and at present, there are no specific or effective therapies for sRCC.