Kohli, Manish

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.

Abstract PURPOSE: Cell free circulating microvesicles (in particular, exosomes) contain proteins and nuclei acids that may serve as biomarkers for disease diagnosis and prognosis. The goal of this study was to identify exosomal microRNAs that may predict clinical outcome of patients with castrate resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: In discovery stage, we performed RNA sequencing using plasma exosomal RNAs derived from 36 patients with CRPC. We mapped the sequence reads to known miRbase (Release 19, 2043 entries) and normalized the miRNA abundance by sequence counts per million mappable reads. We applied Cox regression analysis to identify the miRNAs that were associated with overall survival of CRPC. In validation stage, we first examined an exosomal small RNA sequencing dataset consisting of 192 individuals with various health conditions. We used Normfinder and Bestkeeper to select most stably expressed miRNAs as candidates for normalization references. We then applied real-time qRT-PCR assays to test selected candidate reference miRNAs and survival-related miRNAs in additional 100 CRPC patients. From validated miRNAs, we constructed multivariate models to predict overall survival for this group of patients. RESULTS RNA sequencing generated over 6 million mappable reads per patient in the initial discovery cohort. Among these reads, ∼45% were mapped to known miRNAs for a total of 483 known and 275 novel miRNAs with normalized read counts ≥ 5. The median follow-up time for the 36 CRPC patients was 35.6 months during which 10 patients had died. Cox regression analysis identified four microRNAs (miR-1290, -1246, -375 and a predicted miRNA at chromosome 12) that were associated with overall survival (FDR<0.05). Of six selected candidate miRNAs, miR-30a/e-5p performed the best in their stability as endogenous references for real-time qRT-PCR. When normalized by these internal controls, we confirmed two of the three known miRs (miR-1290 and -375) showing significant association with overall survival in the validation cohort (p<0.001) with a median follow up time of 12.5 (range: 1-41) months at which time 28 patients had died. The median overall survival for patients with high (N=21) and low (N=40) expression in both miR-1290 and -375 was 7.2 (1-26.7) months and 15.3 (1-41) months, respectively (p<0.05). The miR-1290/-375-based prediction model consistently showed better predictive performance with AUC=72% than clinical variable-based model with AUC=64%. CONCLUSIONS: Plasma exosomal miRNAs provide an easily accessible resource for biomarker development in prognosis of advanced prostate cancer. Exosomal miR-1290 and miR-375 are associated with overall survival in CRPC patients. miR-30a/e-5p, especially the geometric mean of miR-30a/e-5p, are qualified endogenous references for real-time qPCR. Further confirmation of these findings is needed for prognostic and predictive biomarker in development of CRPC stage. Citation Format: Xiaoyi Huang, Tiezheng Yuan, Meihua Liang, Meijun Du, Shu Xia, Rachel Louise Dittmar, Zhifu Sun, Yan Lu, Stephen N. Thibodeau, Lisa Boardman, Manish Kohli, Liang Wang. Exosomal miR-1290 and miR-375 as prognostic markers in metastatic castrate resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 574. doi:10.1158/1538-7445.AM2014-574

A 73-year-old woman with a history of localised transitional cell cancer (TCC) of the bladder, resected 22 years prior, presented with tremor, gait unsteadiness and cognitive deficits. Basic neurological workup was negative and CT of the abdomen revealed recurrent TCC with a solitary pelvic metastasis. She was treated with surgical resection of her tumour and immunosuppression. Her symptoms resolved, and it was felt her presentation was consistent with paraneoplastic encephalopathy in the setting of bladder cancer metastasis. She has remained disease and symptom free over 5 years of follow-up. This case report reviews the mechanism, clinical features and treatment of paraneoplastic neurological syndromes, and discusses briefly the management of oligometastatic recurrent bladder cancer.

Abstract Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow up of 1.8 years (IQ range: 0.8-3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table. Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4174. doi:10.1158/1538-7445.AM2011-4174

Transitional cell carcinoma of the bladder (TCC) represents nearly 90% of genitourinary malignancies and typically presents with locally invasive symptoms. Metastasis to the central nervous system (CNS) is uncommon occurring in <5% of patients. When present, metastatic lesions are typically solid, isolated and located in the cerebrum. We report a case of a patient with a history of TCC who presented with lethargy and ataxia and was found to have a solitary cystic cerebellar lesion consistent with metastatic disease. Unfortunately, the prognosis for patients with TCC and CNS metastases is poor. Treatment options include debulking surgery, whole brain radiation, stereotactic radiosurgery and chemotherapy. Unfortunately, treatment may not appreciably extend survival and care is often supportive in previously reported cases. Though uncommon, TCC can metastasise to the CNS and should be considered in the differential diagnosis of patients, particularly those who were treated with aggressive surgery or combination chemotherapy previously.

Abstract Azadirachta indica, commonly known as neem, has gained worldwide prominence because of its medical properties, namely antitumor, antiviral, anti-inflammatory, antihyperglycemic, antifungal, and antibacterial activities. Despite these promising results, gaps remain in our understanding of the molecular mechanism of action of neem compounds and their potential for use in clinical trials. We investigated supercritical extract of neem leaves (SENL) for the following: molecular targets in vitro, in vivo efficacy to inhibit tumor growth, and bioactive compounds that exert antitumor activity. Treatment of LNCaP-luc2 prostate cancer cells with SENL suppressed dihydrotestosterone-induced androgen receptor and prostate-specific antigen levels. SENL inhibited integrin β1, calreticulin, and focal adhesion kinase activation in LNCaP-luc2 and PC3 prostate cancer cells. Oral administration of SENL significantly reduced LNCaP-luc2 xenograft tumor growth in mice with the formation of hyalinized fibrous tumor tissue, reduction in the prostate-specific antigen, and increase in AKR1C2 levels. To identify the active anticancer compounds, we fractionated SENL by high-pressure liquid chromatography and evaluated 16 peaks for cytotoxic activity. Four of the 16 peaks exhibited significant cytotoxic activity against prostate cancer cells. Mass spectrometry of the isolated peaks suggested the compounds with cytotoxic activity were nimbandiol, nimbolide, 2′,3′-dihydronimbolide, and 28-deoxonimbolide. Analysis of tumor tissue and plasma samples from mice treated with SENL indicated 28-deoxonimbolide and nimbolide as the bioactive compounds. Overall, our data revealed the bioactive compounds in SENL and suggested that the anticancer activity could be mediated through alteration in androgen receptor and calreticulin levels in prostate cancer. Mol Cancer Ther; 13(5); 1067–77. ©2014 AACR.

BACKGROUNDAngiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC.METHODSPatients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6‐month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor‐2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05).RESULTSA total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6‐month progression rate was 72% versus 64%. The median progression‐free survival (PFS) was 2.9 months (range, 0.5 months‐32.5 months) versus 2.7 months (range, 0.8 months −65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months‐22 months).CONCLUSIONSThe current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6‐month progression rate. Open‐label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib. Cancer 2014;120:692–701. © 2013 American Cancer Society.