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  • Author: Zhen Wang x
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Shulin Yu, Peng Wang and Zhen Chen

Background: Long RNAs have been recently identified in human blood exosomes, posing clinical implications. Whether exosomal long RNAs (exoLRs) could constitute key future biomarkers for noninvasive diagnosis, therapeutic evaluation, and prognosis in cancer remains unknown. The study aimed to explore the exoLR landscape of human blood exosomes and evaluate the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of pancreatic ductal adenocarcinoma (PDAC) based on exoLR profiling. Methods: A case-control study of 267 cases including 137 patients with PDAC and 39 with chronic pancreatitis (CP) plus 91 blood donors as healthy participants was conducted. The exoLR profile of pretreated blood samples was analyzed by exoLR-sequencing (exoLR-seq). Results: An average of 15,000 exoLRs were reliably detected for each sample through exoLR-seq, and 1,053 exoLRs were differentially expressed in PDAC. Based on these data, we constructed a diagnostic signature (d-signature) that showed high accuracy with an area under the curve (AUC) of 0.977 (95% CI: 0.958–0.996), a sensitivity of 92.42% (95% CI: 83.2%–97.49%), and a specificity of 95% (95% CI: 87.69%–98.62%) in a training cohort (n=146), which was further confirmed in a validation cohort (n=93). Notably, the combination of d-signature and CA19-9 yielded an AUC of 0.963 (95% CI: 0.909–1.017), with a sensitivity of 98.13% (95% CI: 93.41%–99.77%) and specificity of 94.59% (95% CI: 81.81%–99.34%). Additionally, we constructed a prognostic prediction model (exoLR p-signature) that effectively predicted prognosis and survival in patients with PDAC (P=9.838e-08). Conclusions: This study clearly demonstrated the value of exoLR profiling in cancer marker discovery and the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of PDAC.

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Jocelyn S. Chapman, Saurabh Asthana, Lindsay Cade, Matthew T. Chang, Zhen Wang, Charles J. Zaloudek, Stefanie Ueda, Eric A. Collisson and Barry S. Taylor

Cancer is currently classified and treated using an approach based on tissue of origin. Ambiguous or incorrect diagnoses, however, are common and often go unnoticed. Clinical cancer sequencing can provide diagnostic precision, therapeutic direction, and hereditary cancer risk assessment. This report presents a patient with an initial diagnosis of metastatic pancreatic adenocarcinoma (PDA), a disease with a dismal prognosis. Tumor sequencing revealed genomic abnormalities inconsistent with PDA, instead suggesting serous ovarian cancer. This molecular rediagnosis was further refined by the identification of a BRCA2 truncating mutation in the tumor, subsequently confirmed to be a germline event. These findings prompted the initiation of platinum-based chemotherapy, which produced a life-altering response, and referral to genetic counseling for her offspring. These results suggest that clinical tumor sequencing can simultaneously clarify diagnoses, guide therapy, and inform familial risk, even in patients with end-stage metastatic disease, making the case for the development of specific strategies to deploy sequencing coupled with big data in oncology to improve clinical cancer management.

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Thanh Ho, Irbaz Bin Riaz, Maheen Akhter, Saad Ullah Malik, Anum Riaz, Muhammad Zain Farooq, Safi U. Khan, Zhen Wang, M. Hassan Murad and Andrea Wahner Hendrickson

Background: Poly (ADP-ribose) polymerases (PARPs) are a highly conserved family of enzymes whose main function is to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) are increasingly used in cancers with deficiencies in homologous recombination. Clinical trials in breast and ovarian cancers have led to several FDA approvals in recent years, and their use in clinical practice is continuing to rise. It is thus necessary to assess their adverse event (AE) profile. Method: Literature search was performed using Ovid MEDLINE, EMBASE, CENTRAL, and Scopus (inception through October 26, 2018). Eligible studies were phase 3, randomized, controlled trials that compared single agent PARPi to placebo or standard treatment. Number of patients treated and AEs reported were recorded. Observed incidence of AE was reported with 95% CI. Heterogeneity was evaluated using Cochran Q statistic and I2 statistics quantified the proportion of heterogeneity not due to chance. Results: Databases revealed 869 references. Of these, 6 were eligible: 2 in breast cancer (OlympiAD, EMBRACA) and 4 in ovarian cancer (NOVA, ARIEL3, SOLO1, SOLO2). PARPi included niraparib (NOVA), olaparib (OlympiAD, SOLO1, SOLO2), rucaparib (ARIEL3), and talazoparib (EMBRACA). Of 1,685 patients who received PARPi, incidence of any AE, regardless of grade, was 98.5% (95% CI, 97.2–99.2%). Common AEs were: nausea (incidence rate, 68.9% and 95% CI, 58.7%–77.5%), fatigue (56.3%, 45.3%–66.8%), anemia (46.3%, 37.2%–55.8%), vomiting (33.7%, 29.5%–38.3%), neutropenia (24.7%, 15.3%–37.4%), headache (23.9%, 19.9%–28.4%), and reduced appetite (21.7%, 19.3%–24.3%). Myeloid neoplasms were rare (1.2%, 0.7%–1.9%). Incidence of grade 3 or higher AE was 44.3% (30.2%–59.5%) and often related to myelosuppression, specifically anemia (24.7%, 15.3%–37.4%), neutropenia (10.7%, 6.6%–16.9%), and thrombocytopenia (5.0%, 1.7%–14.0%). Incidence of serious AE was 24.3% (19.4%–29.9%); dose interruption occurred in 53.3% (41.2%–65.0%) and dose reduction occurred in 39.2% (23.6%–57.4%). 10% (7.4%–13.6%) of patients discontinued therapy due to AE. Death due to AE was rare; less than 1% (0.4%, 0.2%–0.8%) in all trials. Conclusion: Myelosuppression and gastrointestinal toxicities were the most commonly reported AE in 6 randomized phase 3 trials of PARPi for breast and ovarian cancers. Therapy was rarely discontinued due to AE. It remains to be seen whether these results will be reflected in clinical practice.

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Irbaz Bin Riaz, Saad Ullah Malik, Muhammad Husnain, Qurat Ul Ain Riaz Sipra, Warda Faridi, Farva R. Gondal, Thanh Ho, Siddhartha Yadav, Zhen Wang and Manish Kohli

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.