tbuckley/cabot-search huggingface dataset:
Circular RNA F-circSR derived from SLC34A2-ROS1 fusion gene promotes cell migration in non-small cell lung cancer
Authors: Ke Wu, Xun Liao, Youling Gong, Juan He, Jian-Kang Zhou, Shuangyan Tan, Wenchen Pu, Canhua Huang, Yu-Quan Wei, Yong Peng
Journal: Molecular Cancer (2019)

Cancer-associated chromosomal translocations are reported to generate oncogenic circular RNA (circRNA), contributing to tumorigenesis. The fusion gene SLC34A2-ROS1 (solute carrier family 34 member 2 and ROS proto-oncogene 1) plays an important role in non-small cell lung cancer (NSCLC) progression. However, whether SLC34A2-ROS1 gene can produce circRNA remains unknown. Here, we identified two novel circRNAs (F-circSR1 and F-circSR2) generated from SLC34A2-ROS1 fusion gene, while F-circSR1 has higher expression than F-circSR2. Functional studies through gain- and loss-of-function strategies showed that both F-circSRs promote cell migration in lung cancer cells, whereas they have little effect on cell proliferation. Using the minigene GFP reporter assay, we verified that the flanking complementary sequences with canonical splicing sites are essential for F-circSR biogenesis. Therefore, our findings demonstrate the oncogenic role of F-circSR in NSCLC and highlight its therapeutic potential.
The Sentinel Margin: Intraoperative <i>Ex Vivo</i> Specimen Mapping Using Relative Fluorescence Intensity
Authors: Stan van Keulen, Naoki Nishio, Andrew Birkeland, Shayan Fakurnejad, Brock Martin, Tim Forouzanfar, Kristen Cunanan, A. Dimitrios Colevas, Nynke S. van den Berg, Eben Rosenthal
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Despite major advancements in surgical oncology, the positive margin rate for primary head and neck cancer resection remains around 15%–30%. In particular, the deep surface margin is the most challenging to adequately assess. Inadequate margins are directly correlated to poor survival, and as such, mitigation of these rates is critical to improve patient outcomes. We have developed an ex vivo imaging strategy that utilizes fluorescence intensity peaks (relative to background signal) of an injected anti-EGFR antibody conjugated to a fluorescent probe to locate potential close or positive margins on the deep surface of the resected tumor specimen. Experimental Design: Twelve patients with head and neck cancer scheduled for surgery received systemic administration of a tumor-specific contrast-agent (panitumumab-IRDye800CW). After surgical resection, the tumor specimen was imaged using a fluorescence imager. The three highest fluorescence intensity-peaks on the deep surface of the specimen were isolated and correlated to histology to determine the margin distance at these regions. Results: Relative fluorescence peak intensities identified the closest margin on the deep surface of the specimen within 2.5 minutes. The highest intensity peak consistently (100%) detected the closest margin to the tumor. The difference in tumor margin distance between the first and second highest fluorescence intensity peak averaged 2.1 ± 1.4 mm. The tumor-margin difference between the second and third highest peak averaged 1.6 ± 0.6 mm. Conclusions: Fluorescence intensity peaks can identify the region on the specimen where tumor is closest to specimen's edge on the deep surface. This technique could have broad applications in obtaining adequate margins in oncological surgery.
Express-diagnosing of acute kidney injury among patients with the localized kidney cancer after partial nephrectomy under warm ischemia: A role of biomarkers.
Authors: Sergey N Dimitriadi, Oleg I. Kit, Elena M. Frantsiyants, A. V. Velichko, Dmitry A. Rozenko, Aleksandr V. Faenson, Elena V. Filatova, Dmitry A. Shvyrev, A. D. Rozenko, Ekaterina P. Omelchuk
Journal: Journal of Clinical Oncology (2019)

e16108 Background: The specialists consider partial nephrectomy (PN) under warm ischemia (WI) as a standard treatment option for localized renal cell carcinoma (RCC) patients. However, clinical use of the method is restricted by acute kidney injury (AKI) development among patients with high R.E.N.A.L. score, which usually demands long warm ischemia time (WIT). The purpose of the study consists in assessing of the diagnostic ability of cystatin С, IL-18, KIM-1, L-FABP and NGAL in express-diagnosing of AKI among patients with the localized kidney cancer after PN under WI. Methods: The sample of the examined patients consists data of the retrospective research of 100 cases with a localized RCC who underwent PN for elective indications using WI. The WIT was about 15-21 minutes. 24 hours prior to and 16 hours after the surgery, using the ELISA technique and standard test-systems the serum concentration of the following “early markers of AKI” was tested: cystatin С (BioVendor, Czech Republic), КIМ-1 (BCMDiagnostics, USA), NGAL (BCMDiagnostics, USA), L-FABP (Hycult Biotechnology, Netherlands), IL-18 (BenderMedsystems, USA). The WIT and diuresis rate were also registered. AKI was diagnosed based on the serum creatinine level measuring in accordance with the KDIGO guidelines. The clinical and laboratory data were processed using MS Excel software; the Wilcoxon test was used. Simultaneously the expert analysis of the data was carried out. Results: The AKI was registered in 24 patients having a preoperative serum cystatin С level higher than 1000 ng/ml. Another risk factor was WIT lasting 15-21 min. All patients with AKI had an increase of serum concentrations of all 3 following markers: cystatin С, NGAL and L-FABP by more than 10 per cent each (in relation to a preoperative level by each patient). In 5 patients (among the 24 ones) an elevation of creatinine serum concentration was registered just after 40 hours after the surgery – much later than the markers’ reaction appeared. Based on the expert analysis of the clinical and laboratory data the personified scale of early AKI diagnosing and its graphical representation in a form of three-dimensional model was developed. Conclusions: The new method allows diagnosing the AKI development after 16 hours in patients who underwent PN under WI on occasion of RCC. The method has good perspectives of clinical use as it allows identifying the AKI development before elevation of a serum creatinine concentration.
Refining the role of adjuvant chemotherapy in stage IB and IIA NSCLC.
Authors: Ranjan Pathak, Jessica R Hoag, Sarah B. Goldberg, Andres F Monsalve, Benjamin Resio, Daniel J. Boffa
Journal: Journal of Clinical Oncology (2019)

8519 Background: The role of adjuvant chemotherapy (AC) in stage IB (pT2aN0) and IIA (pT2bN0) non-small cell lung cancer (NSCLC) is currently unclear. Existing guideline recommendations are inconsistent, ranging from all tumors &gt;4 cm, to any patient with “high-risk features” (visceral pleural invasion (VPI), lymphovascular invasion (LVI), high grade, or sublobar resection). We used the National Cancer Data Base (NCDB) to clarify the role of AC in pT2N0 patients. Methods: The NCDB was queried for treatment-naïve, post-R0 resection, pT2N0 (AJCC 8 th edition) NSCLC patients between 2010 &amp; 2014. Patients treated with single-agent AC were excluded. Survival was calculated from 30 days after surgery to minimize immortal time bias. Multivariable Cox proportional hazards regression was used to estimate the association between AC and survival across tumor sizes (T2a: 3-4 cm and T2b: 4-5 cm to reflect guideline stratifications) and risk features. Results: Of the 10,127 patients identified, 1,856 (18%) received multi-agent AC. AC patients tended to be younger (median age 64 vs 70 yrs, p&lt;0.001), privately insured (40% vs 24%, p&lt;0.001), treated at a non-academic center (71% vs 66%, p&lt;0.001), and comorbidities-free (53% vs 48%, p&lt;0.001). In T2a patients (N=6,699), AC was not significantly associated with a mortality reduction, regardless of the presence of any high-risk features. In T2b patients (N=3,428), AC (N=931, 27%) was associated with a lower mortality (HR 0.77, 95% CI 0.65-0.9, p=0.001). However, in the absence of any high-risk features (N=1414, 41% of the 4-5 cm cohort), AC was not significantly associated with survival benefit (Table). Conclusions: The presence of high-risk features does not appear to support the guideline recommendations regarding the use of AC in stage IB patients with 3-4 cm tumors. On the other hand, the benefit of AC for 4-5 cm tumors may be limited to patients with at least one high-risk feature. [Table: see text]
Phase 1 of ABTL0812, a proautophagic drug, in combination with paclitaxel and carboplatin at first-line in advanced endometrial cancer and squamous cell lung carcinoma.
Authors: Lorena Farinas-Madrid, Purificación Estévez-García, Jose Alejandro Perez-Fidalgo, Joaquim Bosch-Barrera, Teresa Moran, Ernest Nadal, Victor Rodriguez Freixinos, Elisa Calvo, Alejandro Falcon, Paloma Martín-Martorell, Marisol Huerta Alvaro, Maria Pilar Barretina-Ginesta, Margarita Romeo, Marta Gil-Martin, Elena Garralda, Jordi Rodon, Jose M. Lizcano, Carles Domenech, Jose Alberto Alfon, Ana Oaknin
Journal: Journal of Clinical Oncology (2019)

3089 Background: ABTL0812 is a novel anti-cancer agent that induces a strong autophagy-mediated cell death by a dual mechanism. It inhibits the Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in squamous non-small cell lung carcinoma (Sq-NSCLC) and endometrial cancer (EC) has indicated drug efficacy as a single agent and potentiation of chemotherapy. Methods: A phase 1 clinical study was designed where ABTL0812 was administered orally in combination with 175 mg/m 2 paclitaxel/carboplatin AUC5 D1 every 3 weeks (P/C), and posterior ABTL0812 as a maintenance therapy until disease progression or unacceptable toxicity. The study included first-line patients (pts) with advanced Sq-NSCLC or advanced/recurrent EC. The design included a 3+3 de-escalation trial followed by an expansion cohort, where the starting dose of ABTL0812 was 1300 mg tid and if at least 2 pts experienced a DLT, the dose level would be de-escalated to 1000 mg tid. Safety and tolerability were the primary endpoints and preliminary efficacy according to RECIST v1.1 criteria and pharmacodynamic biomarkers (TRIB3 and CHOP an ER-stress biomarker, by qPCR in whole blood) were the secondary endpoints. Results: 16 EC and 5 Sq-NSCLC pts were enrolled. One DLT, a grade 4 neutropenia, appeared in the first cohort of 6 pts and no de-escalation was applied. Fourteen pts were included in an expansion cohort with the same dose level (1300 mg tid), and 1 DLT, a grade 3 febrile neutropenia, was observed. Therefore, the dose of 1300 mg tid was selected as RP2D in combination with P/C. Most frequent grades 2-4 AEs were neutrophil count decreased (n = 9, 43%), nausea (n = 5, 24%), fatigue (n = 4, 19%), followed by anemia, vomiting, dyspepsia, platelet count decreased, arthralgia and neurotoxicity (n = 2, 10% each). Seventeen pts (13 EC and 4 Sq-NSCLC) who completed at least two treatment cycles were evaluable for efficacy; 1 CR (EC), 8 PR (7 EC and 1 Sq-NSCLC), 7 SD (5 EC and 2 Sq-NSCLC) and 1 PD (Sq-NSCLC) were observed. Pharmacodynamic biomarkers showed increased TRIB3 and CHOP levels. Conclusions: The combination of ABTL0812+P/C was safe and tolerated, efficacy signals were observed, and biomarker modulation confirmed drug activity. The triple combination is currently being evaluated in both indications in a Phase 2 study. Clinical trial information: NCT03366480.
Antitumor efficacy of concurrent everolimus with hepatic transarterial bland embolization (evero-embo) in patients with metastatic well differentiated neuroendocrine tumor (NET).
Authors: Lowell Brian Anthony, Aman Chauhan, Jianrong Wu, Steven J Krohmer, Gaby Gabriel, Val R. Adams, Mark Evers, Susanne M. Arnold, Riham Khouli
Journal: Journal of Clinical Oncology (2019)

4115 Background: Hepatic transarterial embolization (HAE) is an effective loco-regional therapy for neuroendocrine tumor (NET) management. Systemic targeted therapies, such as everolimus and sunitinib, are typically held 2-4 weeks prior to and after procedures. The safety of concurrent use of everolimus with HAE has been previously reported (GI-ASCO). HAE induces anoxic injury while everolimus effects cell growth, proliferation and survival. Combining these two modalities may result in clinical synthetic lethality effectively debulking significant hepatic disease and/or delay progression. Historically bland HAE has a median hepatic PFS of ~9 months. In this study, the clinical efficacy of evero-embo is examined. Methods: A review of clinical and radiographic data was conducted for all sequential patients who underwent evero-embo between September 2016 and April 2018 at the University of Kentucky Markey Cancer Center. An independent radiologist performed RECIST measurements. Patients were required to have had systemic everolimus for ≥ 1 month prior to embolization in order to be included in this study and be on everolimus immediately post procedure. Patients with at least 12 months post procedure follow up were included for efficacy review. Results: A total of 51 HAEs with concurrent systemic everolimus were performed in 34 NET patients. Twenty one of 24 patients were noted to have a partial response. Rest had stable disease. Hepatic progression was not observed. Twenty-one of the 34 patients have had 12 or more months of follow up post procedure (median of 17 months). None of these 21 patients have had hepatic progression. Conclusions: Evero-embo results in a partial response rate of 62% and may have significant antitumor activity when compared to bland hepatic artery embolization in NET patients. With a median follow-up of 17 mos, hepatic progression has not occurred in any patient. Additional follow up is necessary to compare the median hepatic PFS of evero-embo to the historical drug-eluting bead HAE PFS.
Experience and impacts of remote telepathology consultation in improving cancer patients’ diagnosis and management in China.
Authors: Gang He, Mingfei Yan, Qingqing Wu, Ying Wang, Yujie Zhang, Jing Amanda Lu, Jiejun Wu, Xiaomei Li, Songqing Zhao, Ping Gu, Jameel Iqbal, Yue Hua Zhang
Journal: Journal of Clinical Oncology (2019)

e18337 Background: Over the past 4 years, we have conducted over 30 telepathology consultation cases from China covering a wide spectrum of cancers. Through our experience, we realized that the diagnostic accuracy and report integrity from Chinese pathologists is lower than US standards. which brings great concern about diagnosis, treatment and prognosis of cancer patients in China. Methods: Consultation cases were submitted by Chinese patients, their family members or physicians. Specifically, all clinical reports were sent for consultation including imaging studies, laboratory tests, pathology reports, and histology slides for review which covered a wide spectrum of malignant neoplasms, including lung, esophagus, stomach, colon, ovary, breast, prostate, neuroendocrine, melanoma, head/neck, and soft tissue sarcoma; for most cases (27/30) additional immunostaining or molecular tests were performed. All cases and reports were analyzed at top pathology institutions in the United States, including Memorial Sloan Kettering Cancer Center, Johns Hopkins Hospital, or Brigham Women’s Hospital/Beth Israel Medical Center. Following the review of the original materials, final diagnostic reports between the Chinese and US medical centers were compared for major discrepancies in diagnosis. Results: All consulted cases had major discrepancies in diagnosis (100%). Specifically, 75% of cases had improper cancer classifications or grading, 2 cases had improper quality control in immunostains rendering interpretation questionable; 3 cases lacked appropriate molecular tests; finally, 29/30 (97%) of cases lacked cancer staging based on CAP/AJCC/UICC TNM classification of cancer report protocols. Conclusions: Our consultation experiences demonstrated great discrepancies in malignant neoplasm diagnosis and reports among pathologists between the US and China. These findings raise concerns for Chinese patient’s clinical management and prognoses; moreover, they might help explain the observed difference in cancer patient's total 5-year survival between China and USA (40% vs 70%). These findings emphasize the importance of providing support and consultations for pathologists in China, especially those who practice in non-metropolitan, small county or rural local hospitals which lack updated information, technical and academic supports.
Prostate image-guided transperineal elastic-registration biopsy, a new diagnostic tool to refine the risk-stratification of prostate cancer and improve therapeutic decisions.
Authors: Pierre Graff-Cailleaud, Bertrand Covin, Daniel Portalez, Richard Aziza, Jonathan Khalifa, Mathieu Roumiguié, Bernard Malavaud
Journal: Journal of Clinical Oncology (2019)

e16595 Background: To evaluate image-guided Transperineal Elastic-Registration biopsy (TPER-B) in the risk-stratification of low-to-intermediate risk prostate cancer detected by Transrectal-ultrasound biopsy (TRUS-B) when estimates of cancer grade and volume discorded with multiparametric Magnetic Resonance Imaging (MRI). Methods: All patients referred for active surveillance or organ-conservative management were collegially reviewed for consistency between TRUS-B results and MRI. Image-guided TPER-B of the index target (IT) defined as the largest Prostate Imaging-Reporting Data System-v2 ≥3 abnormality were organized for discordant cases. Pathology reported Gleason grade, maximum cancer core length (MCCL) and total CCL (TCCL). Results: Of 237 prostate cancer patients (1-7/2018), 42 required TPER-B for risk-stratification. Eight cores were obtained [Median&amp;IQR: 8 (6-10)] including five (IQR: 4-6) in the IT. TPER-B of the IT yielded longer MCCL [Mean&amp;(95%CI): 5.4(3.9-6.9) vs. 2.5mm(1.9-3.1), p = 0.002] and TCCL [16.7(10.6-22.8) vs. 3.9mm(3.1-4.8), p = 0.0001] than TRUS-B of the gland. On TPER-B cores, longer TCCL [Mean&amp;(95%CI): 28.9mm(19.1-38.7) vs. 12.3mm(4.8-19.7), p = 0.02] were measured in Gleason score-7 than score-6 cancers (no cancers detected on IT TPER-B in 11 patients, all but one score 6 &lt; 4mm on TRUS-B). TPER-B cores of the IT upgraded 16/42(38.1%) patients. 21/42(50.0%) met University College London-definition 1 (Gleason score≥4+3 and/or MCL≥6mm) and 27/42(64.3%) definition 2 (Gleason score≥3+4 and/or MCL≥4mm), which correlate to clinically significant cancers &gt; 0.5mL and &gt; 0.2mL, respectively. Allocation to higher risk groups than anticipated from TRUS-B spurred adaptation of treatment protocols (active surveillance n = 15, prostatectomy n = 11, ionizing radiation n = 13, pending n = 3). Conclusions: Image-guided TPER-B of the index target provided more cancer material for pathology. Subsequent re-evaluation of cancer volume and grade switched a majority of patients towards higher risk groups and treatments with curative intent.
Naxitamab-based chemoimmunotherapy for resistant high-risk neuroblastoma: Preliminary results of HITS pilot/phase II study.
Authors: Jaume Mora, Brian H. Kushner, Miguel Angel Flores, Vicente Santa-María, Moira Garraus, Ellen M. Basu, Stephen S. Roberts, Alicia Castañeda, Maite Gorostegui, Nai-Kong V. Cheung, Shakeel Modak
Journal: Journal of Clinical Oncology (2019)

10025 Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m 2 /day intravenously (IV) plus temozolomide 150 mg/m 2 /day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m 2 /day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other &gt; grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.
NMR-metabolite-resonance signature to predict HR+ breast cancer patient response to CDK4/6 inhibitors.
Authors: Bo Zhang, Jason Warner, Christopher Pinto, Dejan Juric, Elizabeth ODay
Journal: Journal of Clinical Oncology (2019)

3043 Background: Advanced ER+ breast cancer patients have reported prolongation of stable disease when treated with a CDK4/6 inhibitor as a monotherapy or in combination with endocrine treatment. However ~20% of patients are intrinsically resistant and all patients eventually acquire resistance to these therapies. There is a critical need to identify biomarkers that accurately predict response and resistance to CDK4/6 inhibitors. ER-positivity, luminal patterns of gene expression, Rb function, overexpression of cyclin D1, cyclin E, CDK6 and low levels of p16 are biomarkers that do not accurately match clinical outcomes. Methods: We performed a retrospective study analyzing plasma-based metabolites from a baseline (pre-dose) and ~2 months post treatment of 21 women with estrogen-receptor-positive (ER+) metastatic breast cancer treated with CDK4/6 inhibitors. Results: By correlating the metabolite expression profiles to clinical outcomes we were able to identify a metabolic signature that could differentiate the CDK4/6 responders and resistant patients with a predictive accuracy of &gt; 90%. Further we were able to identify independent signatures predictive of response for individual CDK4/6 inhibitors palbociclib and ribociclib. Conclusions: The results of this study could lead to a paradigm shift in the administration of CDK4/6 inhibitors wherein prior to treatment and during treatment patient plasma is screened to determine whether that individual patient is responsive or resistant to a CDK4/6 inhibitor.