tbuckley/cabot-search huggingface dataset:
Prevalence of gastric cancer and premalignant changes in a Michigan cohort, 2013-2017.
Authors: Divyesh Reddy Nemakayala, Shilpa Tatineni, Ikponmwosa Enofe, Ling Wang, Heather Laird-Fick
Journal: Journal of Clinical Oncology (2019)

e15539 Background: Gastric cancer (GC) is uncommon in the US. Incidence varies by geography, race/ethnicity, sex, age, and socioeconomic status (SES). H. pylori is a risk factor for premalignant lesions and GC. Prior studies estimate risk of progression from premalignant to GC at 0.1-0.5% per year. US prevalence of premalignant lesions is unclear. This study describes the prevalence of premalignant lesions and GC in a large community-based sample. Methods: Patients aged ≥18 years undergoing EGD with gastric biopsy in Sparrow Health System were identified. Pathology reports were abstracted for sociodemographics, procedure information, and pathologic findings. Only patients with complete data were included for analysis. Statistical comparisons were assessed by chi-square tests or Fisher’s exact test in contingency tables for categorical variables, or t-tests for continuous variables as appropriate. Results: 4,111 patients were included for analysis. 3,783 (92.04%) had benign findings, 119 (2.90%) premalignant changes, and 31 (0.75%) gastric malignancies. 177 (4.31%) were H. pylori positive. Patients with benign (72.2%), premalignant (69.8%) and H. pylori-positive (69.5%) findings were often inpatients ( p&lt; 0.001 for all comparisons), but not patients with GC (58%, p= 0.37). Benign findings and H. pylori were more common in females (69.3%, p&lt; 0.001 and 59.9%, p&lt; 0.001, respectively). There were no sex differences for premalignant or malignant lesions. Patients with premalignancy and malignancy were older than those with benign findings (mean age 61.6 (SD = 14.8) vs 54.9 (SD = 16.1) years, p&lt; 0.001, and 69.9 (SD = 14.2) vs 54.9 (SD = 16.1) years, p&lt; 0.001, respectively). There was no age difference between patients with benign changes or H. pylori (mean age 54.9 (SD = 16.1) vs 56.4 (SD = 14.4) years, p= 0.24). There were no differences in SES by histological subtype. Conclusions: In a community sample, premalignant lesions and GC were uncommon and did not vary by sex or income. H. pylori infection was also uncommon and varied by sex. This may reflect actual burden of infection or protocols for testing biopsy specimens. Understanding local prevalence of premalignant changes could inform resource planning and surveillance strategies.
Training and validation study for sequential monitoring of CAMLs in circulation to predict ongoing progression in lung cancer patients undergoing definitive radiotherapy.
Authors: Daniel Adams, Jianzhong He, Yawei Qiao, Ting Xu, Hui Gao, James M. Reuben, Ritsuko Komaki, Zhongxing X. Liao, Ignacio Ivan Wistuba, Ashvathi Raghavakaimal, Cha-Mei Tang, Alexander Augustyn, Steven H. Lin
Journal: Journal of Clinical Oncology (2019)

3053 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of cancer patients that are prognostic for progressive disease. Further, it has been shown that changes in CAML size (i.e. enlargement above 50µm) can predict progression free survival (PFS) in thoracic cancers (e.g. lung). We enrolled 104 unresectable non-small cell lung cancer (NSCLC) patients, with an initial training set review of 54 patients, to determine if change in CAML size after radiation therapy was predictive PFS. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of chemo radiation, or radiation therapy. To achieve a 2-tailed 90% power (α = 0.05) we recruited a training set of 54 patients and validation set of 50 patients all with pathologically confirmed unresectable NSCLC: Stage I (n = 14), Stage II (n = 16), Stage III (n = 61) &amp; Stage IV (n = 13). Baseline (BL) blood samples were taken prior to start of therapy &amp; a 2nd blood sample (T1) was taken after completion of radiotherapy (~30 days). Blood was filtered by CellSieve filtration and CAMLs quantified. Analysis by CAML size of &lt; 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate &amp; multivariate analysis. Results: CAMLs were found in 95% of samples averaging 2.7 CAMLs/7.5mL sample at BL, with CAMLs ≥50 µm having reduced PFS (HR = 2.2, 95%CI1.3-3.8, p = 0.003). At T1, 18 patients had increased CAML size ≥50 µm with PFS (HR = 4.6, 95%CI2.5-8.3, p &lt; 0.001). In total, ≥50 µm CAMLs at BL was 76% accurate at predicting progression within 24 months while ≥50 µm CAMLs at T1 was 83% accurate at predicting progression. Conclusions: In unresectable NSCLC patients, enlargement of CAMLs during treatment is an indicator active progression. We identify that a single ≥50 µm CAML after induction of radiotherapy, in our training set and confirmed in our validation set, is an indicator of poor prognosis. We suggest that changes in CAML size during therapy may indicate the efficacy of therapy and could potentially help shape subsequent therapeutic decisions.
A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.
Authors: Antonio Jimeno, Mateusz Opyrchal, Jennifer Robinson Diamond, Christos Fountzilas, Bradley Corr, Ildiko Bezi, Hui Wang, Rudolf Kwan, Jay Zhi, David Cutler, Patrick McKay Boland
Journal: Journal of Clinical Oncology (2019)

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x10 9 /L, platelets ≥ 100x10 9 /L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m 2 . Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m 2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m 2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]
ATALANTE-1 randomized phase III trial, OSE 2101 versus standard treatment as second- or third-line in HLA-A2 positive advanced non-small cell lung cancer (NSCLC) patients.
Authors: Enriqueta Felip, Giuseppe Giaccone, Rafal Dziadziuszko, Fabrice Denis, Teresa Moran, Didier Debieuvre, Manuel Cobo, Domenico Galetta, François Roger Vanel, Giampiero Romano, Anne Madroszyk, Christos Chouaid, Francois-Regis Ferrand, Werner Hilgers, Federico Cappuzzo, Philippe Masson, Nir Peled, Berangere Vasseur, Jordi Remon, Benjamin Besse
Journal: Journal of Clinical Oncology (2019)

TPS9121 Background: New treatment strategies are needed for advanced NSCLC patients who progress on treatment with immune checkpoint inhibitors (ICI). Tedopi (OSE2101) is a neoepitope vaccine restricted to HLA-A2 positive patients (45%) targeting five tumor-associated antigens frequently expressed in lung cancer cells, ACE, HER2, MAGE2, MAGE3 and P53. Previously, in a phase II trial (Barve et al. JCO 2008), Tedopi showed a median overall survival (OS) of 17.3 months with a manageable safety profile in advanced NSCLC patients. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard of care (SoC) treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy. Methods: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements; progressive disease to platinum-based chemotherapy (ChT) with sequential or concurrent ICI; HLA-A2 positivity (blood test); ECOG PS 0-1; with treated and asymptomatic brain metastases,, are randomized 2:1 to receive 5mg Tedopi subcutaneously Q3W for 6 cycles, then Q8W for the reminder of the year and finally Q12W, or SoC treatment with: docetaxel 75 mg/m 2 Q3W or pemetrexed 500 mg/m 2 Q3W (in non-squamous and pemetrexed-naïve patients). Treatment continues until progression, intolerable toxicity or consent withdrawal, in both arms. Patients are stratified by histology, best response to first line, and line rank of ICI. Tumor assessment is performed every 6 weeks (RECIST 1.1). Primary endpoint is OS. Secondary end points are PFS, ORR, DCR, and duration of response, quality of life and safety. This is a superiority study with a hazard ratio of 0.7, two-sided alpha 5% and power 80%, after 278 events are observed. An independent analysis (1year OS rate) is planned in the first 84 patients treated with Tedopi. Last trial review by the DMC in June 18 suggested that the trial continues as planned. Translational research will be performed evaluating pharmacodynamic markers of efficacy such as immunogenicity response against Tedopi vaccine neoantigens, as well as parameters in liquid and tissue biopsies. End January 19, 87 patients (51 Tedopi, 36 Soc) have been enrolled. Clinical trial information: NCT02654587.
Biofabricated tumor microenvironments for studying colorectal cancer <i>in vitro</i> and <i>in vivo</i>.
Authors: Mahesh Devarasetty, Samuel Herberg, Anthony Dominijanni, Ethan Willey-Shelkey, Aleksander Skardal, Shay Soker
Journal: Journal of Clinical Oncology (2019)

e14689 Background: Microenvironmental mechanics have a tremendous effect on the progression, phenotype, and therapeutic response of cancer cells positioning it as a high-potential target for novel therapeutic development. Laboratory modeling of the microenvironment and its multitude of effects is imperative for developing new avenues of anti-cancer therapy that can target non-traditional vectors such as the extracellular matrix (ECM) and stromal cells. Researchers have developed in vitro models of the tumor microenvironment (TME) to meet this need. While in vitro modeling is an important step in therapeutic development, there are few studies that validate in vitro generated results to gold-standard in vivo models, and further, to patient-derived data. Previously, we have developed a model of the colorectal tumor microenvironment and found a connection between collagen ultrastructure and cancer cell phenotype. Using this characterized organoid model, we implant bioengineered TMEs into mice to track long-term growth and progression of cancer and compare our results to clinical biopsies. Methods: Tumor organoids are produced by combining stromal cells and type I collagen. Cancer cell spheroids are embedded into the organoid for long term observation. Organoids are either observed in vitro or implanted subcutaneously into mice for in vivo tracking. Results: Organoids retain structure and viability during long term culture in vitro and in vivo, and embedded cancer cells respond significantly differently depending on the architecture of the surrounding TME. Cancer cells assume a mesenchymal, invasive, and proliferative phenotype in unorganized TMEs, and revert to an epithelial phenotype in an ordered TME. In addition, analysis of biopsied tissue, across tumor grade, demonstrates a correlation between cancer cell phenotype and microenvironmental architecture. Conclusions: In all this is the first study to establish a connection between TME micro-structure and cancer cell phenotype consistently across three distinct research modalities. These results have the potential to pave the way for utilizing bioengineered microenvironmental models as therapeutic development platforms and for targeting TME micro-structure to control colorectal cancer cell progression.
Cell-free DNA in uveal melanoma: Results from the first-in-human trial of mivebresib (ABBV-075).
Authors: Sapna Pradyuman Patel, Meredith Pelster, Rosa Mostorino, Johannes E. Wolff, Cyril Ramathal, Xiaotian Chen, Beibei Hu, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2019)

e14526 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Cell free DNA (cfDNA) is a non-invasive mechanism for monitoring malignancy in UM patients. BET proteins activate transcription of oncogenic genes, and mivebresib (ABBV-075) is a potent pan-BET inhibitor. In the first-in-human phase 1 study, safety and pharmacokinetics of mivebresib were assessed in patients with advanced cancer (NCT02391480). We compared cfDNA mutational dynamics with the survival of UM patients treated with mivebresib. Methods: Adult patients with metastatic solid tumors and ≥1 line of prior treatment were treated with mivebresib on a schedule of daily; 3 days/week; or 4 days on, 3 days off. Two mL of plasma cfDNA (≥10ng) in 5 patients (3 progressive disease [PD], 2 stable disease [SD]) were sequenced with a targeted 63-gene panel (68 Kb) to ≥800X unique depth after barcode-based error-suppression and genomic alterations discovered in all patients. Results: As of May 2018, 10 UM patients received ≥1 dose of mivebresib with median 8.1 weeks (range, 3.6–39.6) of treatment. The median age was 55 years (range, 37–73). 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each). 9 patients were evaluable, 4 achieved a best response of SD and 5 PD (RECIST v1.1). The mean pretreatment cfDNA concentration was 21.0 ng/mL (N = 5 with plasma available). cfDNA levels increased in two patients by 0.6% (SD) and 64.4% (PD). In PD patients, elevated cfDNA concentration (32.7 ng/mL [PD] vs 3.5 ng/mL [SD]) was associated with shorter progression-free survival and overall survival. At baseline, the cfDNA mutational load (median mutant molecules/mL plasma) of pathogenic (COSMIC) mutations with AF ≥1% was highest in PD (893.9; range, 78-4951.5) vs SD patients (53.1; range, 9.3-606.2) and negatively correlated with the patient’s survival (R 2 = 0.531). In 1 PD patient, multiple TP53 (C23G, V203M) and CDKN2A (A148T, L63P) mutations were acquired by the time of progression. Conclusions: These data suggest cfDNA as a potential marker for survival of UM patients. Further investigation of BET inhibition in this population is warranted. Clinical trial information: NCT02391480.
Detection of subthreshold microsatellite instability in breast cancer: An ongoing investigation.
Authors: Joshua Z. Drago, Alicia Latham, Shanu Modi, Pedram Razavi, Zsofia Kinga Stadler, Mark E. Robson
Journal: Journal of Clinical Oncology (2019)

1089 Background: Microsatellite instability (MSI) and mismatch repair deficiency (MMRd) can occur sporadically in solid tumors across histologic subtype and predict clinical response to immune checkpoint blockade (ICB). MSIsensor uses next generation sequencing to report the percentage of unstable microsatellites in a given tumor sample as a score. While scores of ≥10 and &lt; 3 have excellent sensitivity/specificity for MSI/MMRd, intermediate scores of 3-10 are of unknown clinical significance, and may include patients with MSI-like genomic signatures who would be overlooked by historical assays. Methods: MSIsensor testing was performed on primary or metastatic tumor specimens from 2,371 patients with breast cancer. Scores of 3-10 were considered MSI-Indeterminate (MSI-I). Concurrent somatic mutations were determined using the MSK-IMPACT assay. Results: Of the 2,371 patients tested, 147 were found to have MSI-I tumors. Ninety-nine (67.3%) were metastatic specimens, and 48 (32.7%) were primary specimens. Of the MSI-I patients, 64 (43.5%) were estrogen receptor positive, 57 (38.8%) were triple negative, and 24 (16.3%) were HER-2 amplified. Somatic TP53 mutations were detected in 109 (74.1%) MSI-I patients, including 54 (94.7%) triple negative patients. Fourteen MSI-I patients were found to have somatic mutations in MMR genes ( MLH1, MSH2, MSH6, PMS2 or EPCAM), but no germline mutations were found. Of the 99 patients with MSI-I metastatic disease, 15 received ICB as part of their clinical care, exhibiting a median progression-free-survival (PFS) of 3 months. Of the 4 patients who demonstrated a PFS of &gt; 6 months on ICB, 2 were found to have somatic mutations in MMR genes. Conclusions: We introduce a subpopulation of breast cancer patients whose tumors exhibit genomic signs of microsatellite instability without meeting the classic criteria for MSI/MMRd as previously defined in colon and endometrial cancers. A subset of these patients may exhibit the properties of MSI/MMRd at the epigenetic and protein-expression levels, and thus potentially benefit from ICB.
The role of necroptosis in cancer biology and therapy
Authors: Yitao Gong, Zhiyao Fan, Guopei Luo, Chao Yang, Qiuyi Huang, Kun Fan, He Cheng, Kaizhou Jin, Quanxing Ni, Xianjun Yu, Chen Liu
Journal: Molecular Cancer (2019)

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy. The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated. Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.
Cervical cancer screening in incarcerated women: An experience from the first cervical cancer screening campaign in a southern Thailand correctional facility.
Authors: Ingporn Jiamset, Siwat Sakdejayont, Nanthiya Rattanakhot, Krantarat Peeyananjarassri, Arunee Dechaphunkul, Patrapim Sunpaweravong
Journal: Journal of Clinical Oncology (2019)

6572 Background: Cervical cancer is one of the most preventable cancers, not only presence of effective HPV vaccination but also simple and robust screening methods such as Pap test. Nevertheless, there were some women at risk whom were unable to access screening cause of incarceration. Hence, in 2018, together with Songkhla Woman Correctional Institute, we launched a cancer screening campaign including clinical breast exam, mobile mammography and Pap test. This is the first report of cervical cancer screening result demonstrated the essential of cervical cancer screening in these disadvantaged women. Methods: Due to the regulation of the jail, we had to limited bring-in tools, allowed staffs and operating-time, therefore we used a pre-screening questionnaire, included 5 items: HIV infection, number of partner, parity, age at first sexual intercourse and number of term baby and each of them scored as 2 for “high-risk” and 1 for “low-risk”, total score ranged from 5 to 10. We ranked and chose the volunteer participants, who have HIV infection and/or with highest risk score, to undergo Pap test. Results: Of the 1328 questionnaire responders, Their mean risk score was 7.3 (SD= 1.3). HIV infected participants number were 34 (2.5%). Of the 200 screened-participants, None of them had ever received HPV vaccination before, and all participant did not have Pap test since imprisonment. (mean 53.8 m, range 13-236 m, SD 36.7). Their score ranged between 8 to 10, 42.5% of them had score level 8, 54.5% had score level 9 and 3% had score level 10. Mean age was 37.7 years. 10 (5%) of them had abnormal Pap test; 1 of them showed ASC-US, 1 was LSIL, 1 was ASC-H, 5 of them showed HSIL and 2 of them showed squamous cell carcinoma and small round cell carcinoma. Final histopathological test resulted in 6 of cervical intraepithelial neoplasia (CIN) I, metaplasia and cervicitis, 3 were diagnose CIN III and 1 diagnosed microinvasive carcinoma. Incidence of cervical cancer was higher than normal population in this region. (0.5% vs 0.02%). Conclusions: Incarcerated women were at high risk of cervical cancer compared to normal population. Unfortunately, in many places, they were unconditionally inaccessible to the cervical cancer preventive healthcare system for years. Social should increase awareness to decrease this health disparity.