tbuckley/cabot-search huggingface dataset:
VIOLETTE: A randomized phase II study to assess the DNA damage response inhibitors AZD6738 or AZD1775 in combination with olaparib (Ola) versus Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC).
Authors: Andrew Tutt, Christine Stephens, Paul Frewer, Andrew Pierce, Joon Rhee, Sarah Edgington, Lone Ottesen, Mei-Lin Ah-See, Simon J. Hollingsworth, Emma Dean
Journal: Journal of Clinical Oncology (2019)

TPS1112 Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.
Sequential treatment with pazopanib (PAZO) followed by nivolumab (NIVO) in patients with advanced or metastatic renal cell carcinoma (mRCC): Third interim results of the non-interventional study PAZOREAL.
Authors: Martin Boegemann, Jens Bedke, Martin Schostak, Christiane Hering-Schubert, Manfred Welslau, Jan Schleicher, Thomas Wolf, Alexander Petzoldt, Christian Doehn, Carsten Grüllich, Viktor Grünwald, Thomas Steiner, Anja Rogler, Sven Hanson, Dunja Klein, Tanja Medinger, Peter-Juergen Goebell
Journal: Journal of Clinical Oncology (2019)

4574 Background: Randomized clinical trials for the implementation of new therapies include only a selection of patients that are later treated with these new options. Thus, real-world evidence is urgently needed not only to monitor the translation of treatment approaches into routine practice but also to improve cancer treatment and survivorship care on a broader scale. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness [primary time on drug (TD)], tolerability, safety, and quality of life (QoL) in patients (pts) with mRCC, treated with 1 st L PAZO followed by 2 nd L NIVO or everolimus (EVE). Results: Between Dec. 2015 and Sep. 2017, 421 pts were enrolled and 402 pts started 1 st L PAZO treatment (Tx), 127 and 5 pts received NIVO and EVE as 2 nd L Tx, resp., 56 entered follow-up. At time of data-cut (08 Nov 2018) median TD was 6.6 months (95%CI 6.0-7.9) for 1 st L PAZO and 4.1 months (95%CI 3.2-5.8) for 2 nd L NIVO (all pts), 8.1 months (95% CI 6.6-9.5) for PAZO and 3.2 (2.7-6.5) for NIVO Tx for trial eligible pts (39.1% of 402 pts). Median TD for pts with or without prior nephrectomy was 7.6 vs 4.5 months, resp. The clinical benefit rate of 1 st L PAZO was 58.2 % (95% CI 53.3-62.9) based on investigator assessment. Median OS of PAZO was 29.5 months (95%CI 23.6-NA) for all pts, 28.2 months (95% CI 22.2-NA) for NIVO in 2 nd L. The most commonly reported AEs for PAZO Tx were diarrhea (35%), nausea (20.3%) and fatigue (17.5%). Most common PAZO-related grade 3/4 adverse events were hypertension (5%), hypertensive crisis (2.3%) and GGT increase (1.8%). QoL evaluated by EQ-5D-5L remained stable over different Tx lines. Conclusions: The interim results of the PAZOREAL study confirm a favorable overall survival in pts with mRCC treated with 1 st L PAZO in a real-world setting, good benefit-risk profile of PAZO and sustained QoL monitored over several treatment lines. In Germany NIVO as 2 nd L Tx is commonly applied after 1 st L Tx with PAZO.
Sorafenib as a postoperative adjuvant therapy in patients with hepatocellular carcinoma and microvascular invasion: A propensity score matching analysis.
Authors: Xiu-Ping Zhang, Zong-Tao Chai, Yu-Zhen Gao, Jin Ding, Wen-Ming Cong, Wan Yee Lau, Shuqun Cheng
Journal: Journal of Clinical Oncology (2019)

e14707 Background: There is an unmet need for the postoperative adjuvant therapy in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), which is associated with early recurrence after curative resection. This study aimed to investigate the role of Sorafenib as a postoperative adjuvant therapy in HCC patients with MVI after R0 liver resection (LR). Methods: Consecutive HCC patients with pathologically confirmed MVI who underwent R0 LR between January 2009 and December 2016 at the Eastern Hepatobiliary Surgery Hospital were retrospectively reviewed. Patients in the LR+sorafenib group (n = 581) received oral sorafenib (400 mg/d) at 1 weeks after R0 LR, while patients in the LR group (n = 147) only underwent R0 LR. Propensity score matching (PSM) was performed to balance the baseline characteristics between the two groups. Overall survival (OS) and recurrence-free survival (RFS) were followed up, and multivariate Cox regression analysis was performed. Results: After PSM, there were 113 patients in each group. The LR+sorafenib group demonstrated improved OS (median, 43.3 vs. 34.9 months; 1-year, 85% vs. 65%; 3-year, 66% vs. 51%; 5-year, 57% vs. 37%; log-rank P = 0.007) and RFS (median, 32.0 vs. 15.0 months; 1-year, 72% vs. 55%; 3-year, 47% vs. 36%; 5-year, 39% vs. 19%; log-rank P = 0.001) compared with the LR group after PSM. Multivariate Cox regression analysis indicated that R0 LR with postoperative sorafenib therapy was associated with better OS and PFS ( P &lt; 0.001). On subgroup analysis, similar survival benefits were observed for sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) 0-A, BCLC B and Child-Pugh A stages of disease. Conclusions: Sorafenib used as a postoperative adjuvant therapy in HCC patients with MVI after R0 LR was associated with significantly better survival outcomes than LR alone.
Cancer patients experiencing homelessness: What’s happening to them?
Authors: Brian Stewart Bingham, Benjin Facer, Camille Ivey, Evan Osmundson
Journal: Journal of Clinical Oncology (2019)

e18153 Background: Over three million people in the United States of America (USA) experience homelessness each year. Homeless patients have high rates of cancer risk factors, later stage diagnoses, and increased rates of cancer death. Despite this, little is known about the treatment of homeless patients with cancer. General recognition exists that homelessness is accompanied by socioeconomic challenges, but their effect on cancer treatment is unknown. This analysis identifies published data on cancer care in homeless populations and evaluates the difference in information volume related to screening and treatment. Methods: A PubMed, MEDLINE, and Web of Science search was performed using combinations of: “homeless, homeless persons, homelessness, street people, neoplasm, neoplasia, tumor, malignancy, cancer, screening, early detection of cancer, treatment, and therapy”. Each result was reviewed to identify primary research articles (excluded case reports and review articles) reporting data about cancer screening and/or treatment for homeless patients. For each included study, information was recorded including publication year, country, study type, patient numbers, and relevance to screening and/or treatment. Results: From this search, 61 publications were identified of which 29 were excluded due to inappropriate scope and/or publication type. In total, 32 publications were included for analysis. Most (81%) reported data from the USA and all were published in 1998 or later. Thirty (94%) reported data about cancer screening in homeless patients. In contrast, only two (6%) reported data about treatment and outcomes. Combined, these studies report screening data from over 8,000 patients compared to treatment data from less than 100. Only one publication reported utilization rates of different treatment modalities. Conclusions: This analysis highlights a disparity in published data about cancer screening and treatment for homeless patients. Little data exists regarding treatment and outcomes of homeless patients following a cancer diagnosis, with even less data about modalities, side effects, and follow-up. Future studies on treatment and outcomes of homeless cancer patients will identify barriers unique to this population and contribute to more evidence-based practices.
Early response assessment through multiparametric MRI based endpoints in a phase II multicenter study evaluating the efficacy of DPX-Survivac, intermittent low dose cyclophosphamide (CPA) and pembrolizumab combination study in subjects with solid tumors.
Authors: Diana Roettger, Faiq Shaikh, Sotirios Bisdas, Lisa Diana MacDonald, Stephan Fiset, Gabriela Nicola Rosu
Journal: Journal of Clinical Oncology (2019)

e14245 Background: Accurate assessment of tumor response to immunotherapy is challenged by pseudoprogression that mimics true progression. Conventional imaging and RECIST assessment do not adequately distinguish between them given their inability to account for changes in the tumor microenvironment. DPX-Survivac is a novel T cell activating therapy that triggers immune responses against tumors expressing survivin and is being studied in this trial in combination with CPA and pembrolizumab in several solid tumors. Multiparametric MRI approaches - dynamic contrast-enhanced MRI and diffusion-weighted imaging MRI are useful for accurate assessment of structural, perfusion and vascular assessment of the lesion and may identify pseudoprogression and compare to the RECIST-based assessment. Methods: The study will enroll up to 226 evaluable subjects in 5 different cohorts: ovarian cancer, HCC, NSCLC, bladder cancer and MSI-H cancer. These subjects will undergo initial imaging 28 days prior to treatment, to be assessed based on RECIST 1.1, and a pre-treatment tumor biopsy for quantitation of survivin and PD-L1 expression and MSI analyses. Treatment for 35 cycles or until disease progression. All patients will have CT images for RECIST 1.1 and iRECIST assessment. A subset of subjects will undergo mpMRI to calculate advanced imaging biomarkers. Results: MRI, clinical and patient-reported outcomes will be analyzed. Conclusions: This study will provide important evidence on the utility of mpMRI + CT-based assessment of response to immunotherapy and use it as an adjunct to the CT-based RECIST criteria by providing insight on how tumor lesions are impacted by treatment.
PIK3CA mutation as a prognostic factor in HPV-associated oropharynx cancer.
Authors: Brian T. Beaty, Gaorav Gupta, Colette J. Shen, Robert J Amdur, Jared Weiss, Juneko E. Grilley-Olson, Shetal Arvind Patel, Adam M. Zanation, Trevor Hackman, Brian Thorp, Jeffrey Blumberg, Samip Patel, Mark Christian Weissler, Wendell Gray Yarbrough, Nathan Christopher Sheets, Joel S. Parker, Neil Hayes, William M. Mendenhall, Roi Dagan, Bhishamjit S. Chera
Journal: Journal of Clinical Oncology (2019)

6011 Background: PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal SCC (OPSCC), with a prevalence of 20-30%. While PIK3CA mutations have been associated with adverse outcomes in cervical cancer, their prognostic significance in HPV-associated OPSCC remains unknown. We sought to elucidate the significance of PIK3CA mutations in a prospective cohort of HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Methods: Seventy-eight patients with HPV-associated OPSCC were prospectively enrolled on three protocols: LCCC 1121 (NCT03161821) or two phase II clinical trials of de-intensified CRT (NCT02281955 / NCT03077243). De-intensified regimen was 60 Gy IMRT with concurrent cisplatin (30mg/m 2 ). Next-generation sequencing of tumor samples was performed using a targeted panel-based assay (UNCSeq), including over 200 genes. We estimated disease-free survival (DFS) using the Kaplan-Meier method and compared treatment groups with two-sided log-rank test (Medcalc). Results: Sequencing was performed in 78 patients with a median follow-up of 24 months. Seventy-five patients received 60Gy; three patients received 70Gy. Ten patients had disease recurrence (2 regional only, 5 distant only, 3 regional and distant). Thirty-eight of 78 patients had at least one mutation identified (17 PIK3CA, 4 PTEN, 3 KRAS, 3 FBXW7, 3 FGFR3, 2 TP53, 2 prothrombin 20210, 1 NRAS, 1 BRCA1, 1 factor V Leiden, 1 FLT3, 1 RAD50, 1 PIK3R1). The most common site of PIK3CA mutation was the helical domain (E545K – 8/17, E542K – 2/17). Despite similar T/N staging and tobacco pack years, patients with WT-PIK3CA had significantly higher DFS (93%) compared with 65% for patients with PIK3CA mutations (p = 0.0009). Patients with mutations other than PIK3CA also had improved DFS relative to those with PIK3CA mutations (96% vs. 65%; p = 0.0147). Conclusions: PIK3CA mutation is associated with worse DFS in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with definitive CRT. These findings suggest that patients with PIK3CA mutations may not be suitable for de-intensified therapy and investigation of novel treatment strategies may be appropriate.
HPV test self collection versus CO-testing (2015-2018): New experience in a screening program in a northern province of Argentina, Tucumán.
Authors: Juan Jose Zarba, Silvia Victoria Holgado, Conrado Oscar Cinto, Veronica Ali, Maria Fernanda Arrieta, Adriana Beatriz Gonzalez, Claudia Veronica Abete
Journal: Journal of Clinical Oncology (2019)

e13063 Background: The benefits of population screening under the program in women at risk of uterine cervical cancer both methodsof detection, the search of lesions by gynecological cytology or the search for infection by oncogenic virus of the VPH family is widely demonstrated. Each of them has considerations to favor and others against. In Tucuman the two are applied since December 2014. Objective:to analyze partial results of the first stage of application of two methods under population screening program in women at risk of cervical cancer in Tucumán, Argentina. Methods: We analized the period December 2014 December 2018 of the files of the national register (SITAM: Sistema de Información de tamizaje- It is an on-line information system that allows the nominalized registration of women who access studies, diagnoses and treatments for the prevention of cervical cancer).49337samples from non-pregnant, aged 30 and older women without health insurance were included. 2 collection methods were applied: "Co-testing" (CT), cytological for PAP test and biological sampling for HPV Test ((T-HPV) and "Self-collected sampling" (SC) biological material for T-HPV. In cytology, Pap smear were stained with Papanicolaou and for the biological material, T-HPV Hybrid Capture was applied to detect 13 oncogenic HPV types. Bethesda System was used for cytological diagnosis. Results: until 2019 January, 49337 samples were processed, 7352 (14,8%) womenhave HPV oncogenic. Conclusions: the application of T-HPV to SC samples showed a interesting positivity,demonstrating once again T-HPV is an important strategy in the cervical cáncer prevention program.[Table: see text]
Prognostic significance of tartrate-resistant acid phosphatase expression in breast cancer.
Authors: Ming-Shen Dai, Hao-Chan Lo, Li-Jia Chen, Shun-Fu Tseng
Journal: Journal of Clinical Oncology (2019)

e12594 Background: Tartrate-resistant acid phosphatase (TRAP) is a metalloproteinase-like protein that is expressed in several primary and metastatic tumors, and its expression is positively correlated with the oncogenic process. Tartrate-resistant acid phosphatase is also a novel product of activated macrophage. We have previously demonstrated the clinical significance of TRAP expression in tumor-infiltrating macrophages and serum TRAP in patients with metastatic breast cancer (BC). Therefore, TRAP protein can potentially be a predictive and prognostic marker to evaluate disease progression and therapeutic response in breast cancer patients with bone metastasis. We aim to investigate the role of TRAP expression in breast cancer metastasis and survival. Methods: RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database. Estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, and TNBC subtypes were included in the analyses. The TRAP-overexpressed and -silenced breast cancer cells (MCF7, 4T1, MDA-MB-231) were used for validation. Survival data was also retrieved from the TCGA database to verify the prognostic biomarker. Results: Through TCGA database analysis, we found that TRAP expression correlated to the Ki-67 expression indicating the cancer cell proliferating activity. Additionally, TRAP expression positively correlated with mesenchymal markers (SNAIL, CDH1, MMP9, Fibronectin), and negatively correlated with epithelial markers (SMAD2, SOX10), implying that the TRAP expression is related to the breast cancer Epithelial-Mesenchymal-Transition process. This phenomenon was validated in TRAP-altered cell and confirmed inferior survival with TRAP-expressed breast cancer patients in TCGA database. Conclusions: Combining clinical TCGA data and cell-based analyses showed that TRAP expression was significantly associated with breast cancer proliferating activity, metastatic potential, and inferior survival. TRAP serves as a breast cancer prognostic biomarker and can be considered as a therapeutic target. Further investigation is warranted.
Case 2-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Daniel K. Podolsky, Carolyn C. Compton
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 55-year-old man was admitted to the hospital because of multiple gastric polyps and melena.He was well until seven years earlier, when occasional hematochezia prompted a sigmoidoscopic examination that revealed an internal hemorrhoid. One year later hematochezia recurred without symptoms, and a routine blood count showed that the hemoglobin was 12.5 g; the iron was 23 μg per 100 ml (4.1 μmol per liter). A barium-enema examination, with air contrast, was reported to be negative. An upper gastrointestinal series (Fig. 1) revealed coarse nodularity of gastric rugal folds, with a large mass along the greater curvature . . .
Apolipoprotein B as a New Link Between Cholesterol and Alzheimer Disease
Authors: Makoto Ishii
Journal: JAMA Neurology (2019)

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Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: An interim safety analysis.
Authors: Bertrand F. Tombal, Yohann Loriot, Fred Saad, Raymond S. McDermott, Tony Elliott, Alejo Rodriguez-Vida, Franco Nole, Beatrice Fournier, Laurence Collette, Silke Gillessen
Journal: Journal of Clinical Oncology (2019)

5007 Background: Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration resistant prostate cancer (mCRPC). The ERA223 trial (NCT02043678) was recently unblinded following the report of a significant increase in the fracture rates when abiraterone is combined with Ra223. Hence, FDA and EMA advised against this combination. The question whether mandated use of bone protecting agents (BPA), zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide/Ra223 combination is presently unknown. Methods: The phase III EORTC-1333-GUCG/PEACEIII (NCT02194842) trial compares enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients (https://www.eortc.org/research_field/clinical-detail/1333/). After the unblinding of ERA223, the trial was amended (v4.0, April 19, 2018) to mandate that all patients must start a BPA. We report the fracture rate in the safety population of 146 treated patients as of 28/01/2019. Results: Overall, 54.2% of the patients in the enza/Ra223 arm and 51.4% of the enza arm did not receive BPA; 18.0% in the enza/Ra223 arm and 27.0% in the enza arm did not use BPA at randomization, but started during protocol treatment according to the v4.0 amendment. 27.8% and 21.6% respectively, received BPA as of randomization. In total, 45.8% of enza/Ra223 patients and 48.6% of enza only patients receive bone protection on treatment. The fracture rate is reported in the table. Conclusions: There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports. This risk is significantly increased to 33% when Ra223 is added to enzalutamide. Strikingly, the risk is almost abolished by mandatory continuous administration of BPA starting at least 6 weeks before the first injection of Ra223, thus emphasizing the importance of treating mCRPC patients with BPA. Clinical trial information: NCT02194842. [Table: see text]