tbuckley/cabot-search huggingface dataset:
Mechanistic study of the superior anti-cancer properties of a first-in-class small molecule targeting PCNA.
Authors: Long Gu, Robert Lingeman, Min Li, Robert Hickey, Yilun Liu, Linda Malkas
Journal: Journal of Clinical Oncology (2019)

e14636 Background: Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was predominantly expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interdomain connector loop of PCNA that is known to be a major binding site for many of PCNA’s interacting proteins. A cell permeable peptide harboring the L126-Y133 sequence inhibited PCNA function in cancer cells and selectively kills cancer cells and xenograft tumors. Methods: Based on these observations, we sought small molecules targeting this peptide region of PCNA as potential broad-spectrum anti-cancer agents. Results: Our effort led to a drug candidate, AOH1996, which selectively kills a broad range of cancer cells at high nanomolar concentrations, but is not associated with significant toxicity to non-malignant cells. It also works synergistically with DNA damaging chemotherapeutic drugs, such as cisplatin and irinotecan, to selectively kill cancer cells. This compound is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it doesn’t cause significant toxicity at 2.5 times its effective dose. Mechanistically, AOH1996 competes with T3, a known PCNA ligand, for binding to PCNA. However, the mechanism by which AOH1996 exerts its effect on cancer cells may not be identical to what have been reported for the T3 analogs. In particular, we found that AOH1996 interferes with the association of PCNA and MCM7 to euchromatin, leading to DNA replication stress, blockade of homologous recombination-mediated DNA repair, and induction of apoptosis in cancer cells. Conclusions: These findings demonstrated the potential of this compound as a novel therapeutic agent warranting clinical investigation for cancer treatment. We have started planning a phase 1 clinical study for this compound.
Case 27-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, F.J. Stafford-Brady, D.W. Oldach
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 59-year-old woman was admitted to the hospital because of a sore throat, fever, and profound weakness.She was well until one month earlier, when facial palsy developed and resolved in about one week. Six days before entry a sore throat appeared, without fever or other symptoms. A physician prescribed penicillin taken by mouth, but the sore throat worsened and the patient began to feel progressively weaker, with difficulty in walking. Three days before admission she came to this hospital, where examination showed that the temperature was 38.7°C. Erythema without an exudate was noted over the left . . .
Survival analysis and clinical characteristics of forty-eight patients with alpha-fetoprotein-positive gastric cancer treated by integrated Chinese and western medicine.
Authors: Wenting He, Tong Zhang, Yanhong Xuan, Hongliang Zhang
Journal: Journal of Clinical Oncology (2019)

e15550 Background: Alpha-fetoprotein-producing gastric carcinoma (AFPGC) is a special type of gastric cancer, which has characteristics of strong invasiveness, prone to liver and lymphnode metastasis, easy misdiagnosis and worse prognosis. According to the literature, the survival of AFPGC was 4-14 months (m). There is no report about integrated Chinese and Western Medicine on the AFPGC patients. This study is to explore the effect of integrated Chinese and Western Medicine on the survival and clinical characteristics of patients with AFPGC. Methods: 398 consecutive patients with gastric cancer admitted to Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine from Jan 2012 to Jun 2018 were retrospectively collected. All patients were diagnosed by pathology. And on the basis treatment of conventional Western Medicine combined with Chinese Medicine for more than 3 m. Follow-up up to Dec 31th 2018. The median follow-up time was 11.1 m. According to the results of serum alpha-fetoprotein chemiluminescence assay, AFPGC was found in 48 out of 398 patients. The median overall survival (mOS) and clinical characteristics of AFPGC patients were analyzed. Results: Among 48 patients with AFPGC, 1 case (2.1%) in stage Ⅰ, 1 case (2.1%) in stage Ⅱ, 8 cases (16.7%) in stage Ⅲ, 36 cases (75.0%) in stage Ⅳ, and 2 cases with unknown stages; 35 cases (72.9%) received chemotherapy, 22 cases (45.8%) received local treatment, including palliative radiotherapy and hepatic artery chemoembolization, and 4 cases (8.3%) received targeted therapy. At the end of follow-up, 40 patients died, with the mOS of 16 m, 27.5 m in stage Ⅰ-Ⅲ and 14 m in stage Ⅳ, which was significantly longer than reported in the literature. Compared with non-AFPGC patients, tumor metastasis and serosal invasion of higher incidence ( 75.0% vs 38.9, x 2 = 22.3, p &lt; 0.0001; 75.0% vs 38.9%, x 2 = 17.5, p = 0.0015 ). The incidence of liver and/or lymph node metastasis is higher (52.1% vs 17.4%, x 2 = 25.1, p &lt; 0.0001; 33.3% vs 15.7%, x 2 = 7.7, p = 0.0054 ). The incidence of pleuroperitoneal and omental metastasis is higher (33.3% vs 11.7%, x 2 = 13.0, p = 0.0003 ). Conclusions: Integrated Chinese and Western Medicine can significantly prolong the survival of patients with AFPGC. AFPGC seem to be more prone to tumour metastasis, serosal invasion, liver metastasis, lymph node metastasis, pleuroperitoneal and omental metastasis. However, limited by the sample size, whether the above factors are independent prognostic factors for AFPGC is still not conclusive.
Phase 3 international trial of adjuvant whole brain radiotherapy (WBRT) or observation (Obs) following local treatment of 1-3 melanoma brain metastases (MBMs).
Authors: Gerald Fogarty, Kari Dolven-Jacobsen, Rachael L. Morton, George Hruby, Anna K. Nowak, Janette L. Vardy, Katharine J. Drummond, Haryana M. Dhillon, Catherine Mandel, Richard A. Scolyer, Brindha Shivalingham, Mark R. Middleton, Bryan H. Burmeister, Serigne Lo, Claudius H. Reisse, Elizabeth J. Paton, Victoria Steel, Narelle C. Williams, John F. Thompson, Angela M. Hong
Journal: Journal of Clinical Oncology (2019)

9500 Background: The role of adjuvant WBRT in MBMs is controversial. This trial compares WBRT with Obs after local treatment of 1-3 MBMs. Methods: The primary endpoint is distant intracranial failure (DIF) within 12 months of randomization. The a priori neurocognitive function (NCF) endpoint is Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months. Secondary endpoints include local failure (LF), overall survival (OS) and global quality of life (QoL). Analyses were conducted on intention-to-treat basis with nominal two-sided significance level 5%. Drug therapy was allowed. Effective drugs became available during trial and their impact was analysed. Results: Of 586 eligible patients (pts), 215 consented from 31 sites in 3 countries (Australia, UK and Norway) between 2009 and 2017. Eight (0.04%) who withdrew or had no data collected were excluded. 107 randomized to Obs and 100 to WBRT. Mean age 62 years, 67% males, 61% with single MBM of mean size 2cm, 67% had extracranial disease at randomization. The two arms were well matched. NCF was completed by English speakers; 50 WBRT and 70 Obs at baseline, declining to 26 and 35 respectively at 4 months. Within 12 months, 54 (50.5%) Obs had DIF compared with 42 (42.0%) WBRT pts (OR 0.71; 95%CI 0.41-1.23; p = 0.222). There was no difference in LF (p = 0.100) or OS (log-rank p = 0.861). 53% (Obs) and 59% (WBRT) pts were alive at 12 months. There was no significant between-group difference in mean intervention effect on global QoL (p = 0.083). Pts who received T-cell checkpoint inhibitors and/or mitogen-activated protein kinase (MAPK) pathway inhibitors and WBRT before or within 12 months of randomization had DIF rate 29% compared with Obs and no systemic therapy had 44%, but was not significant (p = 0.228). Obs had greater relative improvement from baseline in HVLT-R at every timepoint. At 4 months, Obs had 20.9% improvement from baseline in HVLT-R-delayed recall compared to 2.7% decline in WBRT; overall adjusted average intervention effect 23.6% (95%CI 9.0, 38.2; p = 0.0018). There was no difference in time to cognitive failure or in proportions with global cognitive impairment. Conclusion: This level one evidence shows WBRT does not improve outcomes in MBMs. This practice-changing trial justifies the recent move away from WBRT that occurred during the course of the trial. Clinical trial information: NCT01503827.
Impact on gemcitabine plus cisplatin in unresectable hilar cholangiocarcinoma patients according to effective biliary drainage: A multicenter study.
Authors: Jingu Kang, Jong-Chan Lee, Min Jae Kim, Se Yeol Yang, Sang Myung Woo, Jae Hyup Jung, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2019)

e15658 Background: Hilar cholangiocarcinoma (HC) is known to have a poor prognosis due to cholangitis and lack of effective chemotherapeutic regimen. Since 2010, gemcitabine plus cisplatin (GP) is recommended as first-line chemotherapy in cholangiocarcinoma. However, it is still unclear whether GP is effective on HC. We aimed to evaluate the impact on GP in unresectable HC patients according to effective biliary drainage (EBD). Methods: From 2010 to 2016, 112 patients with unresectable HC confirmed by biopsy at three tertiary referral hospitals in Korea were enrolled. 38 patients received GP [cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter), each administered on days 1 and 8, every 3 weeks]. 74 patients received best supportive care (BSC). The EBD group was defined as a total bilirubin decrease of less than 2 mg/dl within 2 weeks after the first drainage procedure or 50% reduction than pre-procedure total bilirubin. Overall survival (OS) was evaluated in GP group and BSC group according to EBD achieved using the Kaplan–Meier survival curve and the log-rank test. Results: When compared with the BSC group (n = 74), the GP group (n = 38) obtained a benefit in OS (median OS, 6.14 vs 12.7 months, p &lt; 0.001). Moreover, patients with EBD experienced significantly longer OS compared with ineffective biliary drainage (IEBD) patients (median OS, 8.03 vs 5.01 months, p &lt; 0.005). GP chemotherapy was beneficial for OS in IEBD group (p &lt; 0.001) as well as in EBD group (p &lt; 0.005). In the multivariate analysis, GP chemotherapy (HR 0.33, 95% CI 0.21–0.52, p &lt; 0.001), EBD (HR 0.60, 95% CI 0.40–0.91, p &lt; 0.001) and 2 more metastatic site (HR 3.21, 95% CI 1.66–6.18, p &lt; 0.001) were significant prognostic factors. Conclusions: GP chemotherapy provides longer survival in HC, regardless of effective or ineffective biliary drainage.
Persistent radiation-induced alopecia in patients with central nervous system tumors and head and neck sarcomas.
Authors: Gregory S. Phillips, Danielle Novetsky Friedman, Sabrina Trelles, Oluwaseun Kukoyi, Morgan Freret, Azael David Freites Martinez, Robin H. Unger, Joseph J. Disa, Leonard H. Wexler, Kathryn Beal, Suzanne L. Wolden, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2019)

e23072 Background: Persistent radiation-induced alopecia (pRIA), or incomplete hair regrowth 6 months following radiotherapy (RT) completion, poses a significant quality of life burden, but its clinical characteristics and management outcomes are not well understood. Methods: Retrospective database query of patients with primary central nervous system tumors or head and neck sarcomas evaluated at an oncodermatology clinic and diagnosed with pRIA between 1/1/11 and 9/19/18. Clinical data and standardized clinical photographs were analyzed. Alopecia was graded according to the CTCAE v5. Results: Sixty-two patients with pRIA were identified (mean [SD] age, 33 [19]; 75% female; 18 &lt; 21 years at pRIA diagnosis). The most common diagnoses were medulloblastoma (20, 32%) and glioblastoma multiforme (17, 27%). Mean duration between RT and pRIA diagnosis was 3.1 years (95% CI, 2.3-4.2). Additional cancer therapies included surgery (57, 92%), cytotoxic chemotherapy (35, 57%), and combination cytotoxic + targeted therapy (24, 39%). Cancer type, age, number of chemotherapy agents, and duration between RT and pRIA diagnosis were significantly associated with alopecia type: mixed pattern (localized and diffuse) alopecia was predominant in younger patients with medulloblastoma exposed to greater number of agents (p &lt; .005). Alopecia grade 2 ( &gt; 50% hair loss) was predominant in patients that received concurrent chemotherapy and RT (p = .046). Among 22 patients treated with 5% minoxidil topical solution, a response was noted in 16 (73%) (Table). One patient receiving hair transplantation and one receiving scalp reconstruction had complete resolution of pRIA. Conclusions: Concurrent chemotherapy with RT may be a risk factor for grade 2 pRIA. Topical minoxidil may provide some benefit in pRIA; however, prospective trials are needed to assess efficacy. Procedural interventions should be considered as a viable therapeutic option in a subset of patients. [Table: see text]
Effect of patient age on efficacy of FOLFIRI plus cetuximab vs bevacizumab in 1st-line treatment of metastatic colorectal cancer: An analysis of FIRE-3 (AIO KRK 0306).
Authors: Volker Heinemann, Dominik Paul Modest, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Florian Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian A. Lerchenmuller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Swantje Held, Andreas Jung, Thomas Kirchner, Sebastian Stintzing
Journal: Journal of Clinical Oncology (2019)

3541 Background: FIRE-3 compared 1 st -line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. The subgroup of extended RASwt patients consisted of 400 patients. The median age of patients treated in FIRE-3 was 64 years. Analyses of efficacy of doublet-chemotherapy in patients &gt;70 years have shown inconsistent results. Methods: In this exploratory analysis, patients were grouped into cohorts with 65 years and 70 years as a cut-off for age-related analysis of the FIRE-3 study population. ORR was compared using Fisher´s exact test, Survival analyses were done using Kaplan-Meier estimation and median survival times were compared using log-rank testing. Results: Within the RAS wt population, patients older than 70 years had a significantly shorter OS when compared to patients ≤70 years of age in both arms (p= 0.02 for cetuximab arm, p= 0.02 for bevacizumab arm). Patients ≤65 years and ≤70 years had a significantly longer OS when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab (p= 0.01 and 0.02 respectively). The OS benefit of cetuximab treated patients compared to bevacizumab treated patients was consistent for patients ≤65 years (p=0.005) and patients ≤70 years (p= 0.009) of age. In patients older than 70 years, however, comparable efficacy of bevacizumab and cetuximab was observed. This effect of age on outcome appears to be affected by sidedness. RAS wt population (n=400). Conclusions: In the overall RAS wt population, younger patients have a significant OS benefit when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab, while this was not the case in patients older than 70 years.[Table: see text]
The targetable mutation landscape of Chinese patients with non-small cell lung cancer.
Authors: Jun Li, Cuiyun Zhang, Jiuzhou Zhao, Zhizhong Wang, Bing Wei, Rui Sun, Harry J.M. Groen, Jie Ma, Yongjun Guo
Journal: Journal of Clinical Oncology (2019)

e13018 Background: In recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has been substantially improved by targeted therapies against specific molecular aberrations, i.e. tyrosine kinase inhibitors (TKIs) for Epidermal Growth Factor Receptor ( EGFR) etc. Several genes have been suggested by NCCN guideline (v7.2017) to test for NSCLC patients, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS. The aim of this study is to profile the landscape of actionable mutations in Chinese NSCLC patients. Methods: From 2015 to 2017 621 treatment naïve NSCLC patients enrolled in the affiliated cancer hospital of Zhengzhou University were included in this analysis. DNA was extracted from the FFPE biopsies of these patients and processed for target capture sequencing covering the exons and flanking splicing regions of the 8 genes suggested by NCCN guideline, as well as introns of ROS, ALK and RET. Results: In total, 593 out of the 621 NSCLC patients harbor one or more mutations in these 8 genes, accounting for 95.5% of all the cases. EGFR, ALK and HER2 are the top 3 mutants, with a frequency of 52%, 32% and 26% respectively. Genetic aberrations in BRAF, MET, ROS1, KRAS and RET occur in 22%, 18%, 16% and 14% of the patients. The most common variation is missense; T &gt; G, C &gt; T and C &gt; A changes are more often observed than T &gt; C, T &gt; A and C &gt; G; the median number of variants per sample is 2, ranging from 1 to 13. There are 418 mutations detected on EGFR, of which 206 (49.28%) are clinically relevant. EGFR L858R, Exon19 deletion, Exon20 insertion, G719, A750P were observed in 123 (29.43%), 43 (10.29%), 8 (1.91%), 6 (1.44%) and 6 (1.44%) cases respectively. Gene fusions were identified in 78 cases, and the EML4- ALK is the most common one occurred in 54 patients, other fusion genes include KIF5B- ALK (11) ， CCDC6- RET (4), CD74- ROS1 (4), EZR- ROS1 (2), ERC1- RET (1), , SDC4- ROS1 (1) and TCOF1- ROS1 (1). Conclusions: Target sequencing of the 8 genes suggested by NCCN guideline for NSCLC patients reveals essential information for designing personalized therapeutic regimen. Chinese patients, maybe other Asian countries also, may benefit more from this molecular testing, because of the high occurrence of actionable mutations.
Screening of colorectal cancer (CRC) patients for lynch syndrome (LS) emphasizes the need for public insurance coverage of genetic testing: Results of a national program by the Hellenic Society of Medical Oncology (HeSMO).
Authors: Zacharenia Saridaki, Emmanouil S. Saloustros, Nikolaos Tsoukalas, Thomas Makatsoris, Georgios Lypas, Haralabos Kalofonos, Athina Christopoulou, Iliada Bompolaki, Ioannis Sougklakos, Evangelos Voulgaris, Athanasios Karampeazis, Christos Papandreou, Athanasios Anagnostopoulos, Eleni P. Galani, Konstantinos Ballasis, Flora Zagouri, Georgios Rizos, Athanasios Athanasiadis, Ioannis I. Varthalitis, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2019)

e13141 Background: Lynch Syndrome is associated with germline mutations in Mismatch Repair (MMR) genes ( MLH1, MSH2, MSH6, PMS2). CRC patients whose tumors exhibit high-level microsatellite instability (MSI-H) have an increased probability of LS. Although the diagnosis of LS has important implications for the patient and the family, germline genetic testing is not reimbursed by the Hellenic Public State Healthcare Services. To address this need HeSMO conducted a national program to screen and diagnose CRC patients with LS. Methods: All patients with CRC were eligible. Assessment for LS involved initially screening tumor tissue for the presence of MMR deficiency, either via molecular MSI testing or via immunohistochemistry (IHC) to detect the absence of one or more MMR proteins. Patients with an MMR-deficient tumor in the absence of a somatic cause (e.g. BRAF mutation or MLH1 promoter hypermethylation) underwent genetic counseling and germline testing to confirm a LS diagnosis. Results: From June 2017 to December 2018, 104 patients diagnosed with CRC were enrolled and tested. Median age of diagnosis was 58,5 years (range 32 - 89) and male-to-female ratio was 1.6:1. Fifty patients (48%) had tumors that exhibited the MSI-H phenotype. From the MSI-H tumors, 41 (82%) did not harbor the BRAF V600E mutation and 33 of them (80.5%) did not harbor an MLH1 promoter hypermethylation. Therefore, 33 patients were invited for genetic counseling and testing. Fifteen patients (45.45%) were diagnosed with LS: 6 ( 40 %) had a mutation in MLH1 (one of which had also a mutation in PMS2 gene), 4 (26.6%) in MSH6, 4 (26.6%) in MSH2 and 1 (6.6%) in PMS2. Conclusions: In our series, 30% of the CRC patients with MSI-H tumors were tested positive for LS. These results confirm the value of a universal screening program of CRC patients for LS. Hopefully, these results will convince the Hellenic Public State Healthcare Services to reimburse screening and germline genetic testing of CRC patients for LS.
Genome-wide copy number alteration (CNA) of circulating cell-free DNA (cfDNA) as a prognostic biomarker in esophageal squamous cell carcinoma (ESCC).
Authors: Hyeon-Su Im, Yeonghak Bang, Hyehyun Jeong, Jihoon Kang, Eunhae Cho, Ja-Hyun Jang, Junnam Lee, Sook Ryun Park
Journal: Journal of Clinical Oncology (2019)

e15582 Background: Although neoadjuvant chemoradiation (nCRT) plus surgery or definitive CRT (dCRT) are the standard treatment for locally advanced ESCC, there are no reliable clinical tools for predicting prognosis or monitoring treatment response for CRT in ESCC. We aimed to identify a biomarker for predicting outcomes using cfDNA in ESCC patients (pts) receiving CRT. Methods: This prospective biomarker study analyzed pretreatment plasma cfDNA from pts with nCRT plus surgery (n = 23) and pts with dCRT for locally advanced ESCC (n = 17) at Asan Medical Center in South Korea from Jul. 2017 to Jun. 2018. Low depth whole-genome sequencing of cfDNA was used to identify CNA and I-score was developed to express genomic instability. I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The pathologic complete response (pCR) was achieved in 7 pts (30.4%) in the nCRT group, and the clinical complete response (cCR) was achieved in 3 pts (17.6%) and clinical partial response (cPR) in 8 pts (47.1%) in the dCRT. The baseline cfDNA concentrations were no significant association with the clinical T stage (cT 1-2 vs. cT 3-4; 0.27 vs. 0.28 ng/μL; p = 0.752), pathologic response (pCR vs. non-pCR; 0.26 vs. 0.30 ng/μL; p = 0.270), ypT stage (ypT 0-2 vs. ypT 3-4; 0.28 vs. 0.36 ng/μL; p = 0.161) and ypTNM stage (ypTNM 1 vs. ypTNM 2-4; 0.26 vs. 0.36 ng/μL; p = 0.065). When analyzing cfDNA concentration before and after CRT, cfDNA concentration was significantly increased after CRT (0.31 vs. 0.55 ng/μL; p = 0.007). The baseline I-score was not associated with baseline clinical stage, but was significantly associated with ypT stage (ypT 1-2 vs. 3-4; 30.4 vs 839.1; p = 0.009), time to progression (median TTP; 11.8 mo in the I-score-low group vs. 6.1 mo in the I-score-high group; p = 0.036), and overall survival (median OS; not reached vs. 10.4 mo; p = 0.046) in the nCRT group. In the dCRT group, I-score was significantly associated with higher disease progression rate (33.3 vs. 58.8%; p = 0.024) with tendency of distant metastasis (33.5 vs. 57.1%; p = 0.490), and short response duration (median, 5.7 mo in the I-score-high group vs not reached in the I-score-low group). Conclusions: The cfDNA concentration is not a good biomarker for prognostication and monitoring the course of treatment in ESCC pts treated with CRT. But the I-score, an indicator of genomic instability in ctDNA, was a significant predictor of poor prognosis.