tbuckley/cabot-search huggingface dataset:
PU.1 and JDP2 expression in myelodysplastic syndromes to predict treatment response and leukemia transformation.
Authors: Kristian Boasman, Matthew Simmonds, Yogen Saunthararajah, Ciro Roberto Rinaldi
Journal: Journal of Clinical Oncology (2018)

7065 Background: Myelodysplastic syndromes (MDS) are malignant disorders leading to acute leukaemia (AML). Recent breakthroughs identified down-regulation of PU.1 in high risk MDS and AML, with work within NPM1 mutated AML cells showing PU.1 relocates in the cytoplasm causing differentiation arrest. Microarray analysis in PU.1 overexpressing K562, revealed Jun Dimerization Protein 2 (JDP2), downstream to PU.1 was significantly suppressed. In this study we investigated PU.1 and JDP2 expression during different stages of MDS progression/AML evolution and in patients responding to Azacitidine. Methods: Gene expression of PU.1 and JDP2, in total bone marrow and selected CD34+ cells, from 12 newly diagnosed MDS patients stratified according to IPSS-R (6-low, 3-intermediate, 3-high risk), 2 AML and 10 controls was undertaken. Samples were enriched for the mononuclear fraction by Ficoll separation and RNA analysed by RT-PCR for PU.1 and JDP2 expression. Protein expression was analysed by western blot. Results obtained were compared with Bloodspot MDS gene expression data. PU.1-knockdown was performed in K562 using PU.1 short interfering RNAs. Results: We revealed PU.1 and JDP2 are down regulated in MDS patients. PU.1 and JDP2 expression inversely correlates with disease progression, consistently reducing in IPSS-R groups. Investigating PU.1 and JDP2 expression data in MDS vs normal samples from a large Bloodspot pool confirmed our findings. To understand if JDP2 suppression is a direct result of reduced PU.1 we performed PU.1-knockdown. This revealed only a partial reduction in JDP2 expression suggesting a more complex regulatory mechanism. PU.1 and JDP2 expression levels in CD34+ cells, significantly and progressively reduces towards AML transformation. Furthermore, we demonstrated a significant upregulation in PU.1 and JDP2 expression in patients achieving a response to Azacitidine, suggesting PU.1/JDP2 could be targets of this drug. Conclusions: PU.1 and JDP2 expression correlates with patient’s prognosis and leukaemia transformation in MDS, highlighting a potential role as new diagnostic and prognostic markers in MDS.
Biases in assessment and reporting of health-related quality of life (QoL): A systematic review of oncology randomized phase III trials published between 2012 and 2016.
Authors: Laura Marandino, Anna La Salvia, Cristina Sonetto, Emmanuele De Luca, Daniele Pignataro, Clizia Zichi, Rosario F Di Stefano, Eleonora Ghisoni, Pasquale Lombardi, Annapaola Mariniello, Maria Lucia Reale, Elena Trevisi, Gianmarco Leone, Leonardo Muratori, Maddalena Marcato, Paolo Bironzo, Massimo Aglietta, Giorgio V. Scagliotti, Francesco Perrone, Massimo Di Maio
Journal: Journal of Clinical Oncology (2018)

e18719 Background: QoL assessment is relevant to evaluate benefit/risk ratio of cancer therapies and it is formally included in ASCO and ESMO scales of treatment value. However, its use as an endpoint in clinical trials is widely variable and quality of QoL reporting is heterogeneous. Aims of this study were: (i) to review QoL prevalence as endpoint in cancer randomized controlled trials (RCTs) published in major journals and (ii) to evaluate QoL reporting biases. Methods: All issues between 2012 and 2016 of 11 major journals where oncology RCTs are usually published were hand-searched for publications (pubs) of phase III trials in adult patients with solid tumors. Space allocated to QoL details was measured as number and % of rows in the Results section. Secondary QoL pubs were searched in PubMed. Time to secondary QoL publication was calculated according to Kaplan-Meier method, from the date of primary publication to the date of secondary QoL publication, if any, or to the date of last PubMed check. Results: 448 pubs were eligible (median Impact Factor [IF] 22.5); 323 (72.1%) were in advanced/metastatic pts. QoL was primary endpoint in 5 trials (1.1%), secondary/exploratory (expl.) endpoint in 230 trials (51.3%). In advanced/metastatic pts, QoL was primary endpoint in 4 trials (1.2%), secondary/expl. endpoint in 187 trials (57.9%). Out of 230 primary pubs of trials with QoL as secondary/expl. endpoint, QoL results were available in 140 (60.9%), with a median of 12 rows, corresponding to 9.2%, for QoL details in the Results section. Overall, with a median follow-up of 43 months, 72 secondary QoL pubs were found (median IF 6.0 vs. 26.5 of the respective primary publication). For trials with no QoL results in the primary publication, probability of secondary publication was 14.4%, 32.4% and 41.6% at 1, 2 and 3 years respectively (12.5%, 30.1% and 41.4%, respectively, in advanced/metastatic pts). Conclusions: QoL is not included as an endpoint in a relevant proportion of recently published phase III trials in solid tumors, even in metastatic patients. In addition, QoL results are subject to significant underreporting and delay in publication.
In-human activity and pharmacology of homemade silver nanoparticles in highly refractory metastatic head and neck squamous cell cancer.
Authors: Jasmine Singh, Farjana Fattah, Tam Burks, Jie Zheng, Xingya Jiang, Pamela Kurian, Sehresh Saleem, Jean Pearson, Saad A. Khan
Journal: Journal of Clinical Oncology (2017)

e17533 Background: Silver nanoparticles (SNPs) show high efficacy as targeted therapy against cancer cell lines, but have never been tested in patient clinical trials. We present the first in-human trial of SNPs in a cancer patient with a dramatic outcome. Methods: Homemade SNP solution is prepared by the patient with online instructions. Current from 3 9-volt batteries is passed across 99.99% pure silver-bar electrodes in distilled water, until the metal content of the water measures 0.09-0.15 parts per million. The manufacturer is a 77-year old male who developed multiple recurrences of nasal cavity squamous cell cancer. Over 2 years he progressed on platinum and taxane based-chemotherapy, radiation twice and 2 surgical resections. Large hepatic and pulmonary metastases were observed on PET, MRI and CT; he was initiated on hospice. Without informing his oncologist he subsequently began manufacturing and consuming the SNP solution. Results: The patient ingested 120 ml daily of the solution for 3 months leading to clinical recovery and complete resolution of cancer at all sites, persisting for 18 months. Electron microscopy of the silver solution revealed bimodal SNP size distributions; 3 &amp; 12 nm. Inductively coupled plasma mass spectrometry showed the basal blood silver ion concentrations of 32 ng/g. One hour after ingesting 60 ml of silver solution it rose to 46 ng/g. Urine showed no SNPs. Toxicities were not noted with this silver solution, with no evidence of myelosuppression, liver or kidney abnormalities on repeated testing. The patient underwent reconstructive surgery with excellent wound healing, and his performance status continues to improve. Conclusions: Ingestion of a SNP solution is associated with complete regression of highly refractory head and neck cancer in the absence of other anticancer therapy. Ingesting silver solution causes a noticeable and nearly immediate rise in blood silver concentration. Urinary excretion is not a major path of clearance from the body. Given these dramatic results that may be attributed to SNP in conjunction with strong preclinical data, further patient testing of SNP should be done to confirm its safety and efficacy in head and neck cancer.
Assessing DCE-MRI and DWI as treatment response biomarkers after SABR for primary renal cell carcinoma.
Authors: Hayley M Reynolds, Bimal Parameswaran, Diana Roettger, Mary Finnegan, Eddie Lau, Tomas Kron, Mark Shaw, Sarat Chander, Shankar Siva
Journal: Journal of Clinical Oncology (2018)

e16587 Background: Assessment of treatment response for renal cell carcinoma (RCC) is typically carried out using anatomical CT sized-based RECIST 1.1 criteria. Recently, our group completed a prospective pilot clinical trial delivering stereotactic ablative body radiotherapy (SABR) to patients with RCC (FASTRACK, trial number U1111-1132-5574). In this study, we assessed functional changes in tumours after SABR using dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted imaging (DWI) to see whether they may provide novel early treatment response biomarkers. Methods: DCE-MRI and DWI was acquired at baseline, and at two weeks and three months after SABR. DCE-MRI data was analysed using Dynamika software, which included computation of parametric maps by fitting signal intensity curves to the data, and pharmacokinetic maps using the extended Toft’s model. Apparent diffusion coefficient (ADC) maps were computed from DWI data using Siemens software, and statistics extracted. Tumour volume change after SABR was obtained using RECIST 1.1 tumour measurements from late follow-up CT (average 879 days, range 644-1241 days after SABR) and baseline CT. The change in each mean MRI parameter relative to baseline MRI for each tumour was correlated with the tumour volume change from CT. Results: Twelve patients were eligible for DWI analysis and a subset of ten for DCE-MRI analysis. RECIST 1.1 evaluation indicated 4 partial responders, 7 with stable disease, and 1 with progressive disease. The most promising DCE-MRI parameters correlating with tumour volume change were at three months after treatment and included the mean percentage of tumour voxels having washout contrast enhancement curve behaviour and the mean initial rate of enhancement (0.89, p = 0.001 and 0.78, p = 0.01 respectively). For DWI, the change in ADC kurtosis at two months after treatment was the most promising parameter (0.63, p = 0.03). Conclusions: Parameters from DCE-MRI and DWI show potential as early treatment response imaging biomarkers for SABR of RCC. A follow-up phase II clinical trial is now underway (FASTRACK II, trial number U1111-1170-4329) which will enable further assessment and validation of these potential biomarkers. Clinical trial information: U1111-1132-5574.
Colorectal cancer characteristics and outcomes after solid organ transplantation.
Authors: Amit Merchea, Kristopher P Croome, Faisal Shahjehan, Jordan Cochuyt, Zhuo Li, Dorin Colibaseanu, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2018)

e24131 Background: Individuals post-solid organ transplant can develop several secondary malignancies. We noted an increasing number of individuals seen over the last several years who developed colorectal cancers within a couple of years post-solid organ transplantation. The primary aim of this study was to describe the characteristics and outcomes of the patient population who developed colorectal cancer post-solid organ transplant. Methods: Data was gathered and merged from several registries at Mayo Clinic to identify all the patients who received a diagnosis of colon or rectal cancer and solid-organ transplant. Continuous variables were summarized as mean (standard deviation) and median (range), while categorical variables were reported as frequency (percentage). Time to colorectal cancer after transplant and overall survival after cancer diagnosis were estimated using Kaplan-Meier method. Results: 115 transplant patients were identified. The diagnosis of colorectal cancer was post-solid organ transplant in 65 patients. Final analysis was restricted to 63 patients. The mean age was 57-years. Majority had received a kidney transplant 28 (44.4%) followed by liver (36.5%). The median time to develop colorectal cancer was approximately 5 years [59.3 months (Range: 4.4-251.4 months)]. 15 (24.6%) were stage 4 at diagnosis and 13 (21.3%) had stage 3 colorectal cancer. Median overall survival was 30.8 months; 5-, 10- and 15-year survival was noted to be 42.5%, 18%, and 7.5%, respectively. None of the stage 4 patients were alive; while 46.3% of stage 3, 43% of stage-2 and 85% of stage-1 patients were alive at the 5-year mark. Patients post-transplant who received systemic chemotherapy, side effects (gastrointestinal) are a particular concern. Conclusions: Our study reports on one of the largest cohort of patients of colorectal cancer that developed the cancer post-solid organ transplant. Survival is extremely poor for advanced cases. However, long-term survivors are noted who developed the cancer at a relatively early stage. Colorectal screening recommendations may need to be revised post-solid organ transplant.
Will a national communication campaign to increase awareness of clinical trials work?
Authors: Holly A. Massett, David M. Dilts, Grace Miskin, Robert Bailey, Rebecca Ledsky, Nancy Atkinson, Andrea Denicoff, Rose Mary Padberg, Marin Allen, Karen Silver, Kelli Carrington, Shakun M. Malik, Lenora Johnson
Journal: Journal of Clinical Oncology (2016)

6537 Background: Two major barriers to patient clinical trial (CT) participation are lack of awareness of CTs and limited communication from physicians about available trials. Many call for a national communication campaign to increase public and physician awareness and interest in CTs. We present the results of a national survey assessing the impact of multiple message CT concept ads on individuals and primary care physicians (PCPs). Methods: National online survey in 2011 with PCPs (N = 171) and 3 categories of adults in the general public (healthy; ill with a serious chronic disease; or a caregiver; N = 541; oversampled for cancer). Individuals viewed 3 of 4 novel ads promoting CTs. Questions assessed attitudes and understanding of CTs, reactions to ads, and intentions to participate in (public) or recommend (PCPs) CTs before and after seeing the ads. Results: Prior to seeing ads, 65% of the public only had a general sense of CTs and 12% knew very little or nothing; only 36% said they were likely to consider a CT in the future. Top reasons to consider CTs were if earlier treatment did not work (64%) or their doctor recommended it (60%). Of PCPs, 59% said they were likely to suggest patients consider CTs. All ad concepts were rated positively ( = 3.7 to 4.3; 1 = very neg; 5 = very pos); though some were better received. Top strengths of ads were their appeal to the value of CTs and that “people like them” were in CTs; PCPs liked that viewers were encouraged to “talk with their doctors.” However, some responses differed across groups in the general public. After seeing the ads, the likelihood by the public to consider a CT nearly doubled (from 36% to 64%, p < .001) and 84% (increase by 25%, p < .001) of PCPs said they were likely to suggest CTs to patients. Conclusions: In general, ads were well received by all respondents and significantly increased the public’s consideration of CTs and PCPs’ likelihood of recommending CTs. The ads demonstrated the value of CTs, normalized CT participation, and proposed acceptable calls to action to talk with doctors and visit websites for more information. However, initial awareness of CTs is very low; any campaign would need to clearly and simply convey what a clinical trial is and care should be taken in selecting well-received ad concepts.
Correlation between comprehensive molecular profiling and clinical outcomes in patients with colorectal liver metastases.
Authors: Louise Catherine Connell, Francisco Sanchez-Vega, Taryn Mary Boucher, Rona D. Yaeger, Nikolaus Schultz, Andrea Cercek, Jaclyn Frances Hechtman, Nancy E. Kemeny
Journal: Journal of Clinical Oncology (2016)

e15114 Background: Genomic alterations in KRAS, NRAS, and BRAF have been associated with recurrence and survival for patients (pts) with liver metastatic colorectal cancer (mCRC). We used a multi-gene next generation sequencing (NGS) assay to evaluate the effect of genomic alterations on outcomes. Methods: A total of 253 pts with mCRC were identified from a prospectively maintained database of pts receiving hepatic arterial infusion (HAI) therapy and who had MSK-IMPACT analysis – a targeted exome capture NGS assay that includes 410 genes. Pts were separated into two groups: those who had complete resection of liver mCRC and were treated with adjuvant (ADJ) HAI (n = 136), and those with unresectable liver mCRC (METS) (n = 117). In the METS group, 63 pts had no extrahepatic disease and 54 pts had extrahepatic disease. All pts were treated with HAI plus systemic therapy. Clinicopathological data including progression free survival and overall survival (OS) were recorded. Results: For differences between METS and ADJ, pts with METS had enriched mutations in BRAF (12% METS vs. 3% ADJ, p = 0.006) and in SMAD4 (17.7 METS vs. 7.5% ADJ, p = 0.02). These mutations were associated with worse outcomes. BRAF mutations were associated with a lower OS (p = 0.01) in METS. All METS with no extrahepatic disease (n = 63) who had SMAD4 mutation developed hepatic progression (p = 0.02). The presence of a SMAD4 mutation was also associated with worse OS in ADJ (p < 0.001). SOX9 mutation was more common in ADJ (13%) vs. METS (6%). SRC was mutated only in ADJ and only in females. Altered genes in the ERK signaling pathway includingEGFR, KRAS, NRAS, HRAS and BRAF indicated worse OS in all subgroups receiving HAI (p = 0.0011 for the combined group, n = 253). Conclusions: Our study confirms the alteration spectrum previously described for liver mCRC. Novel findings include the higher prevalence of SOX9 mutation in ADJ and the exclusivity of SRC mutation in ADJ female pts, implying a positive prognostic effect. SMAD4 mutation correlated with worse OS in ADJ group and increased hepatic progression in METS group. Alteration of multiple genes in the MAPK pathway conferred a worse outcome, which may be relevant for targeted drug development.
Genomic characterization of variant histology muscle invasive bladder cancer (MIBC) to predict response to therapy.
Authors: Shilpa Gupta, Badrinath R. Konety, Elai Davicioni, Ewan Gibb
Journal: Journal of Clinical Oncology (2018)

e24290 Background: Molecular subtypes of MIBC have been discovered based on gene expression and impact of different subtyping methods on response of BC to neoadjuvant cisplatin-based chemotherapy (NAC) has been reported. We used gene expression profiling to study genomics and tx responses in variant-histology MIBC pts. Methods: In MIBC pts., tissue samples were profiled using genome-wide expression microarray and de-identified for GRID software analysis in R (v3.3.1). Each pt. was compared against a large reference cohort of pts. with UC who received the Decipher Bladder genomic subtyping classifier test (GenomeDx). We report the genomic and clinical response data from 2 pts. with sarcomatoid and small cell BC. Results: In the pt. with sarcomatoid variant, the UC component of tumor revealed low expression of basal and luminal urothelial markers (KRT5/6, KRT14, KRT20), but higher EMT activity typically seen with sarcomatoid tumors. There was robust expression of PD-L1 and PD-L2. Patient progressed rapidly on NAC, developing metastatic disease immediately after RC but achieved a rapid CR after 3 cycles of pembrolizumab, which may correlate with the robust expression of PD-L1 and PD-L2. In the pt. with primary small cell ca of bladder, genomic profiles were generated for TURBT and RC samples. TURBT profile revealed high proliferation and neuronal (NE) marker expression (TUBB2B, PEG10). Modest expression of basal (KRT5/6, KRT14) and EMT markers (ZEB1, VIM) suggested an underlying basal component. After cisplatin-etoposide, there was initial down-staging and the basal and EMT marker expression was undetectable in the RC sample, but the NE and proliferation markers remained high. The patient rapidly developed metastatic disease after RC but had a CR to 3 additional cycles of cisplatin-etoposide, suggesting the rapid proliferation of this tumor provided a target for etoposide via cell cycle inhibition. Conclusions: The genomic profiles from these cases provide clinically relevant information into development of genomic predictors of response and the selection of optimal therapy in variant histology MIBC. Ongoing work will provide further insights in these cohorts.
Role of sentinel lymph node biopsy using methylene blue dye for adequate intraoperative staging of medullary thyroid microcarcinomas: A single institution experience.
Authors: Nada Santrac, Ivan Markovic, Merima Goran, Marko Buta, Gordana Pupic, Radan Radoslav Dzodic
Journal: Journal of Clinical Oncology (2018)

e18116 Background: Management of lymph nodes (LN) in medullary thyroid carcinoma (MTC) is an ongoing debate. Many surgeons do prophylactic central and lateral neck dissections (LND). The aim of this study was to analyze usefulness of sentinel lymph node biopsy (SLNB) of jugulo-carotid regions, after methylene blue dye (MBD) mapping and frozen section analysis, for selecting true positive patients in clinically N0 (cN0) group of micro-MTCs for one-time LND. Methods: In a 10-year period, 17 cN0 patients were operated due to micro-MTCs (≤10mm), with serum calcitonin levels < 1000pg/ml. Surgical protocol included total thyroidectomy, prophylactic central neck dissection and SLNB of jugulo-carotid regions, after mapping with 1%-MBD. Sentinel-LNs were examined by frozen section. If benign, additional surrounding LNs from levels II-III were extirpated for standard pathohistology (sPH), with no further LND. If sentinel-LNs were malignant, one-time LND was performed. Results: One patient with calcitonin level of 221pg/ml had hereditary, bilateral micro-MTC, positive central-LNs and sentinel-LNs on both sides, so bilateral one-time LNDs were performed. Metastases were found in non-sentinel-LNs, as well. Remaining 16 patients had sporadic, unilateral micro-MTCs, without metastases in central-LNs, sentinel-LNs or non-sentinel-LNs. None of the patients had allergic reactions to MBD. Frozen section and sPH were 100% match. Overall accuracy of the method was 100%. Conclusions: This study is the first reported experience with SLNB of jugulo-carotid regions in MTCs using MBD, focusing on the subgroup of microcarcinomas. Dzodic’s method for LN staging in thyroid carcinomas can be precisely used for intraoperative assessment of lateral-LNs and optimizing initial surgery of micro-MTCs. cN0-patients with sentinel-LN metastases in lateral regions on frozen section can receive one-time LND, while those without benefit from less extensive surgery. All patients benefit from lower complication rate, since parathyroid glands remain non-colored after MBD-injection, which facilitates central neck dissection, even in less experienced surgeons’ hands.