Surgical salvage in patients with advanced testicular cancer: indications, risks and outcomes

The purpose of this review is to present a comprehensive and updated review of the literature and summary of the indications, risks and outcomes related to salvage, desperation and late relapse surgery for advanced testicular cancer. After completing a thorough review of the current literature, this review has attempted to provide an overview of the indications for salvage, desperation and late relapse retroperitoneal lymph node dissection (RPLND) followed by a summary of the histopathologic and clinical outcomes regarding each. Recent literature, combined with a significant contribution from historical studies suggest that while testicular cancer is a relatively uncommon malignancy overall, it represents the most common solid organ malignancy for young men. Although a significant number of men are cured with a combination of first-line treatments, the remaining men are a diverse and often challenging cohort who require the benefit of expertise to improve their outcomes. The role of surgical strategies in the salvage, desperation and late relapse settings is unquestionable, although the most important question remains who will benefit. This often requires a multi-disciplinary approach at centers specializing in this disease process in order to recognize who should get surgery, what surgery to do and how to minimize the potential morbidity associated with the operation

Long-Term Oncologic Outcomes after Primary Retroperitoneal Lymph Node Dissection: Minimizing the Need for Adjuvant Chemotherapy

Objective: To analyze the oncological outcomes of men undergoing primary RPLND and characterize the use of adjuvant chemotherapy and template dissections. Methods: Retrospective review of Indiana University testis cancer database identified patients who underwent a primary RPLND between 01/2007 and 12/2017. Patients and providers were contacted to obtain information regarding adjuvant therapy, recurrence, and survival. Primary outcome was recurrence-free survival (RFS). Kaplan-Meier curves assessed survival differences stratified by pathologic stage, template of dissection, and use of adjuvant chemotherapy. Results: Overall, 274 patients were included. Most men presented with CS-I disease (214, 78%). A modified unilateral template was performed in 257 (94%) and bilateral template in 17 (6%). Overall, 148 (54%) and 126 (46%) of men had Pathologic Stage I (PS-I) and PS-II disease, respectively. Thirteen patients (10%) with PS-II disease were treated with adjuvant chemotherapy. With a median follow-up was 55 months, only 33 (12%) patients recurred. Of the 113 patients with PS-II disease who did not receive chemotherapy, 21 (19%) relapsed and 81% were cured were surgery alone and never recurred. No difference in RFS was noted between modified and bilateral template dissections. Conclusions: The use of adjuvant chemotherapy has been minimal over the past decade. The majority (81%) of men with PS-II disease were cured with RPLND alone and were able to avoid chemotherapy. Modified unilateral template dissection provided excellent oncologic control while minimizing morbidity

Towards high-throughput metabolomics using ultrahigh-field Fourier transform ion cyclotron resonance mass spectrometry

With unmatched mass resolution, mass accuracy, and exceptional detection sensitivity, Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FTICR-MS) has the potential to be a powerful new technique for high-throughput metabolomic analysis. In this study, we examine the properties of an ultrahigh-field 12-Tesla (12T) FTICR-MS for the identification and absolute quantitation of human plasma metabolites, and for the untargeted metabolic fingerprinting of inbred-strain mouse serum by direct infusion (DI). Using internal mass calibration (mass error ≤1 ppm), we determined the rational elemental compositions (incorporating unlimited C, H, N and O, and a maximum of two S, three P, two Na, and one K per formula) of approximately 250 out of 570 metabolite features detected in a 3-min infusion analysis of aqueous extract of human plasma, and were able to identify more than 100 metabolites. Using isotopically-labeled internal standards, we were able to obtain excellent calibration curves for the absolute quantitation of choline with sub-pmol sensitivity, using 500 times less sample than previous LC/MS analyses. Under optimized serum dilution conditions, chemical compounds spiked into mouse serum as metabolite mimics showed a linear response over a 600-fold concentration range. DI/FTICR-MS analysis of serum from 26 mice from 2 inbred strains, with and without acute trichloroethylene (TCE) treatment, gave a relative standard deviation (RSD) of 4.5%. Finally, we extended this method to the metabolomic fingerprinting of serum samples from 49 mice from 5 inbred strains involved in an acute alcohol toxicity study, using both positive and negative electrospray ionization (ESI). Using these samples, we demonstrated the utility of this method for high-throughput metabolomics, with more than 400 metabolites profiled in only 24 h. Our experiments demonstrate that DI/FTICR-MS is well-suited for high-throughput metabolomic analysis

Stable Isotope Biogeochemistry of Seabird Guano Fertilization: Results from Growth Chamber Studies with Maize (Zea Mays)

Stable isotope analysis is being utilized with increasing regularity to examine a wide range of issues (diet, habitat use, migration) in ecology, geology, archaeology, and related disciplines. A crucial component to these studies is a thorough understanding of the range and causes of baseline isotopic variation, which is relatively poorly understood for nitrogen (δ(15)N). Animal excrement is known to impact plant δ(15)N values, but the effects of seabird guano have not been systematically studied from an agricultural or horticultural standpoint.This paper presents isotopic (δ(13)C and δ(15)N) and vital data for maize (Zea mays) fertilized with Peruvian seabird guano under controlled conditions. The level of (15)N enrichment in fertilized plants is very large, with δ(15)N values ranging between 25.5 and 44.7‰ depending on the tissue and amount of fertilizer applied; comparatively, control plant δ(15)N values ranged between -0.3 and 5.7‰. Intraplant and temporal variability in δ(15)N values were large, particularly for the guano-fertilized plants, which can be attributed to changes in the availability of guano-derived N over time, and the reliance of stored vs. absorbed N. Plant δ(13)C values were not significantly impacted by guano fertilization. High concentrations of seabird guano inhibited maize germination and maize growth. Moreover, high levels of seabird guano greatly impacted the N metabolism of the plants, resulting in significantly higher tissue N content, particularly in the stalk.The results presented in this study demonstrate the very large impact of seabird guano on maize δ(15)N values. The use of seabird guano as a fertilizer can thus be traced using stable isotope analysis in food chemistry applications (certification of organic inputs). Furthermore, the fertilization of maize with seabird guano creates an isotopic signature very similar to a high-trophic level marine resource, which must be considered when interpreting isotopic data from archaeological material

Data Self-Recalibration and Mixture Mass Fingerprint Searching (DASER-MMF) to Enhance Protein Identification within Complex Mixtures

A novel algorithm based on Data Self-Recalibration and a subsequent Mixture Mass Fingerprint search (DASER-MMF) has been developed to improve the performance of protein identification from online 1D and 2D-LC-MS/MS experiments conducted on high-resolution mass spectrometers. Recalibration of 40% to 75% of the MS spectra in a human serum dataset is demonstrated with average errors of 0.3 ± 0.3 ppm, regardless of the original calibration quality. With simple protein mixtures, the MMF search identifies new proteins not found in the MS/MS based search and increases the sequence coverage for identified proteins by six times. The high mass accuracy allows proteins to be identified with as little as three peptide mass hits. When applied to very complex samples, the MMF search shows less dramatic performance improvements. However, refinements such as additional discriminating factors utilized within the search space provide significant gains in protein identification ability and indicate that further enhancements are possible in this realm

Effects of Valproic Acid and Dexamethasone Administration on Early Bio-Markers and Gene Expression Profile in Acute Kidney Ischemia-Reperfusion Injury in the Rat

<div><p>Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (saline) intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL) at 24 h was reduced (P<0.05) in VPA (2.7±1.8) and Dex (2.3±1.2) compared to Vehicle (3.8±0.5) group. At 3 h, urine albumin (mg/mL) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to naïve (uninjured/untreated control) (0.14±0.26) group. At 24 h post-IR urine lipocalin-2 (μg/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (9.61–11.36) compared to naïve group (0.67±0.29); also, kidney injury molecule-1 (KIM-1; ng/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (13.7–18.7) compared to naïve group (1.7±1.9). Histopathology demonstrated reduced (P<0.05) ischemic injury in the renal cortex in VPA (Grade 1.6±1.5) compared to Vehicle (Grade 2.9±1.1). Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI.</p></div

Histopathology of hematoxylin and eosin stained kidney sections.

<p>A, B, C = Renal cortex at 3 hours (h) post ischemia-reperfusion (IR); D, E, F = Renal outer medulla at 24 h post-IR; A, D = Vehicle (saline control); B, E = Valproic acid (VPA); C, F = Dexamethasone (Dex) treated animals. Three high power fields (400x) representing approximately 50 tubules from cortex and outer medulla of each kidney were evaluated for ischemic changes (injury), tubular necrosis and regenerative changes. Collectively kidney injury and regeneration were graded (0–4) based on the mean percentage of tubules affected: 0, None; 1, <25%; 2, ≥25 but <50%; 3, ≥50 but <75%; 4, >75–100%. Ischemic changes included nuclear condensation <b>(nc)</b>, cytoplasmic eosinophilia, individual cell necrosis and tubular dilation <b>(td)</b>; tubular necrosis <b>(tn)</b> included confluent cell necrosis or sloughing of the tubular epithelium; and regenerative changes included tubular dilation, cytoplasmic basophilia and contraction of the cytoplasm, as well as vesicular chromatin with nucleoli. Hemorrhage <b>(hg)</b> was predominant in the vehicle control group. G, H, I = represent Histopathology quantification: renal cortex (black bars ■) and renal outer medulla (white bars □). The histologic injury score was significantly (P<0.05) lower in the VPA treated group compared to the Vehicle control at 3 h post-IR (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126622#pone.0126622.t003" target="_blank">Table 3</a>).</p

Gene transcription analysis as determined by Affymetrix Gene Array Technology.

<p>The Venn diagrams presented show the number of transcriptomes expressed and overlaps in the kidneys of animals treated with valproic acid (VPA), dexamethasone (Dex) or untreated (None; Vehicle control) at 3, 24 and 120 hours (h) post ischemia-reperfusion (IR). All relative changes in gene expression are derived from comparison with naïve rats. Fewer genes were up-regulated in the VPA group compared to untreated Vehicle control group at 3 h post-IR. At 120 h post-IR only two genes were upregulated and none was downregulated in VPA treated animals. Specific gene expression information is presented in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126622#pone.0126622.s001" target="_blank">S1</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126622#pone.0126622.s006" target="_blank">S6</a> Tables</b>. The DNA microarray data have been deposited in NCBI’s Gene Expression Omnibus (GEO) repository and are accessible through Accession No. GSE58438 (<a href="http://www.ncbi.nlm.nih.gov/geo/" target="_blank">http://www.ncbi.nlm.nih.gov/geo/</a>).</p

Experimental design.

<p>Lewis rats were pre-medicated with Valproic acid (VPA; 150 mg/kg body weight) or Dexamethasone (Dex; 3 mg/kg/body weight) or saline (Vehicle control) intraperitoneally 30 minutes (min) prior to cross clamping left renal artery and inducing left renal ischemia. The cross clamp was removed after 45 min allowing kidney reperfusion, and at the same time a right nephrectomy was performed. Animals were sacrificed at 3, 24 and 120 hours post ischemia-reperfusion. Left kidney, blood and urine were collected for cellular and molecular analyses.</p

Comparisons of blood plasma and urine biomarkers (mean ± standard deviation) between time points (post kidney ischemia-reperfusion) in different treatment groups.^*

<p>*Creatinine and BUN (Blood Urea Nitrogen) were measured in blood plasma</p><p>Albumin, Lipocalin-2, Osteopontin, and KIM-1 (Kidney Injury Molecule-1) were measured in urine. <b>Normal/Naive,</b> plasma or urine drawn from naïve uninjured/untreated Wister rats served as base line. <b>VPA</b> (Valproic Acid), <b>Dex</b> (Dexamethasone) and <b>Vehicle</b> (saline control) treated groups at 3, 24 and 120 hour (h) reperfusion. Means with at least one common superscript (a, b or c) between 3, 24 or 120 h within each group (Vehicle, VPA or Dex) did not vary significantly (P>0.05).</p><p>Comparisons of blood plasma and urine biomarkers (mean ± standard deviation) between time points (post kidney ischemia-reperfusion) in different treatment groups.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126622#t001fn001" target="_blank">*</a>}</p