tbuckley/cabot-search huggingface dataset:
IKKα as a potential novel target for treatment of colorectal cancer.
Authors: Jean A. Quinn, Meera Patel, Kathryn AF Pennel, Dustin Flanagan, Paul G. Horgan, Donald C. McMillan, Simon MacKay, Owen Sansom, Joanne Edwards
Journal: Journal of Clinical Oncology (2020)

174 Background: Colorectal cancer (CRC) is a heterogeneous disease leading to different survival outcomes for patients with the same stage of disease. The non-canonical NF-κB pathway has been shown to have a key role in tumorigenesis, and the aim of this study was to investigate the role of IKKα, the main catalytic component of this pathway in CRC. Methods: A tissue microarray was retrospectively constructed from a patient cohort (1033) with stage I-III CRC who underwent surgery. IHC was utilised to examine cytoplasmic and punctate IKKα expression and determine any association with clincopathological features and cancer specific survival (CSS). To assess IKKα inhibition, organoids were prepared from wild type (WT) mouse colon, mouse models of CRC (Apc and Apc.KRAS.pT53.TGFbR2 (AKPT)) and patient derived human organoids. These were treated with an IKKα inhibitor, SU1433 and organoid size and cell viability assessed. Results: High cytoplasmic expression of IKKα was associated with increasing T stage (p = 0.012), poor tumour differentiation (p = 0.010), tumour necrosis (p = 0.013) and low proliferation status (p = 0.013) but was not associated with CSS. High punctate IKKα expression associated with tumour differentiation (p = 0.001), necrosis (p = 0.004), proliferation (p = 0.044) and MMR competence (p &lt; 0.001) and was also significantly associated with reduced CSS (HR1.20 95%CI 1.02-1.42, p &lt; 0.001). SU1433 did not significantly impact on WT (C57/B16) organoid viability up to a concentration of 1 uM, however organoid size and cell viability was significantly reduced in a dose dependent manner in organoids from both Apc and AKPT mouse models. A similar reduction was observed in patient derived human organoids. Conclusions: Punctate IKKα expression was associated with poor cancer specific survival in CRC patients, and inhibition with SU1433, impacted on CRC mouse and patient derived human organoid size and cell viability. These results suggest that, following further investigation and confirmation, IKKα may be employed as a novel therapeutic target in CRC.
Association of objective response by mRECIST with better overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) treated with systemic therapies: A systematic review and meta-analysis of randomized controlled trials.
Authors: Masatoshi Kudo, Yasutaka Chiba, Tim Meyer, Riccardo Lencioni, Josep M. Llovet
Journal: Journal of Clinical Oncology (2020)

586 Background: EASL guidelines for management of HCC recommends assessing tumor response according to mRECIST at all stages of the disease (EASL guidelines, J Hep 2018). Several studies have reported that objective response by mRECIST predicted overall survival (OS) but definitive data are still lacking. Methods: The PubMed database and ASCO meeting library were searched for full reports of randomized trials in patients with advanced HCC treated by systemic therapy up to August 31, 2018. We search strategy used the following terms: HCC, mRECIST, OS and objective response rate (ORR). We assess the association between ORR and OS in a meta-analysis of pooled data by using random effects model comparing patients achieving objective response (complete or partial response) versus non responders (stable disease, progressive disease) and displayed the results as per hazard ratio (HR, 95% CI). Results: Among 14 articles assessing response by mRECIST to systemic therapies in randomized studies in advanced HCC, 4 studies (5 trials) including 1,463 patients were considered eligible. Systemic therapies tested included lenvatinib, sorafenib, brivanib and nintedanib. Overall, ORR as per mRECIST ranged from 11.5% to 18.8%, being the median OS for responders of 18.5 to 27.2 mo (as opposed 8.9 to 11.4 for non-responders). As per random effects model, the HR for overall survival (responders versus non responders) was 0.47 (95% confidence interval 0.34–0.66, p&lt;0.001). Conclusions: Objective response by mRECIST to systemic therapies in patients with advanced HCC is significantly and strongly associated to OS. Patients achieving an objective response can expect a significantly longer OS.
Tumor treating fields (TTFields; 150 kHz) and FOLFOX combination treatment effects on gastric cancer <i>in vitro</i>.
Authors: Einav Zeevi, Karnit Gotlib, Rosa S Schneiderman, Mijal Munster, Yaara Porat, Tali Voloshin, Shiri Davidi, Anna Shteingauz, Noa Kaynan, Moshe Giladi, Eilon D. Kirson, Uri Weinberg, Adrian Kinzel, Yoram Palti
Journal: Journal of Clinical Oncology (2020)

406 Background: Gastric cancer is the third most common cause of cancer mortality worldwide, yet long-term survival in gastric cancer remains poor despite systemic therapeutic advances. FOLFOX (oxaliplatin, fluorouracil [5-FU], and leucovorin) is an approved chemotherapy regimen for gastric cancer treatment. Tumor Treating Fields (TTFields) are an antimitotic, loco-regional anticancer treatment delivered via non-invasive application of low intensity (1-3V/cm), intermediate frequency (100-500 kHz), alternating electrical fields. TTFields targets rapidly dividing cancer cells by disrupting microtubules leading to mitotic catastrophe, abnormal chromosome segregation, and apoptosis induction. We investigated the potential use of TTFields alone and in combination with FOLFOX for gastric carcinomas. Methods: Gastric cells (AGS and KATO III) were treated for 72 hours with TTFields (1.1 and 1.7 V/cm, respectively) at frequencies of 100-400 kHz using the inovitro system. Efficacy of TTFields and FOLFOX and its individual components was tested by applying TTFields at the optimal frequency in combination with various drug concentrations. Cell counts, apoptosis induction, clonogenic potential, and overall effect were determined. Results: The optimal TTFields frequency that led to the greatest cell count reduction (AGS, 55%; KATO III, 52%) was 150 kHz. The clonogenic potential was reduced by &gt; 70% in both cell lines. TTFields combined with each FOLFOX component (oxaliplatin, 5-FU, or leucovorin) led to a significant reduction in AGS and KATO III cell survival (2-way ANOVA, P &lt; 0.001 for each cell line) versus each treatment alone. In AGS, TTFields plus FOLFOX combination treatment led to a further reduction in the overall effect (cytotoxic and clonogenic; 79%) versus TTFields alone (65%) and FOLFOX alone (34%). Similar results were observed in KATO III cells. Conclusions: These results suggest that TTFields (150 kHz; optimal frequency) are an effective gastric cancer treatment; and combining TTFields with FOLFOX may further enhance efficacy. There is a strong rational to continue exploring the use of TTFields in combination with standard of care for gastric cancer treatment in the clinical settings.
Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis
Authors: Jue Jiang, Jingchao Wang, Ming Yue, Xiaolian Cai, Tianci Wang, Chao Wu, Hexiu Su, Yanwu Wang, Meng Han, Yingchi Zhang, Xiaofan Zhu, Peng Jiang, Peng Li, Yonghua Sun, Wuhan Xiao, Hui Feng, Guoliang Qing, Hudan Liu
Journal: Cancer Cell (2020)
Is preoperative screening colonoscopy useful in patients with gastric cancer?
Authors: Yusuke Koseki, Makoto Hikage, Ko Ikegame, Kouta Itamoto, Yujiro Isobe, Taisuke Yagi, Masato Nagata, Yuhei Waki, Kenichi Nakamura, Furukawa Kenichiro, Keiichi Fujiya, Satoshi Kamiya, Yutaka Tanizawa, Etsuro Bando, Masanori Terashima
Journal: Journal of Clinical Oncology (2020)

290 Background: In patients with gastric cancer (GC), the most common double cancer is colorectal cancer (CRC). However, the meaning of screening colonoscopy has not been established. The aim of this retrospective study was to evaluate the useful of screening colonoscopy in preoperative patients with GC. Methods: This study included 689 patients who received screening colonoscopy before gastric surgery between 2012 and 2016. Multivariate analysis using logistic regression model was conducted to elucidate independent risk factors of CRC. Then, we investigated the clinicopathological factors for CRC. Results: Colorectal adenomas and CRC were observed in 315 patients (46%) and 37 patients (5.4%), respectively. The clinical T classification of the CRC were as follows; Tis: 24 patients (65%), T1: 8 patients (21%), T2: 2 patients (6%), and T3: 3 patients (8%). In multivariate analysis, male (OR 5.04, 95% C.I. 1.29-19.6, p = 0.020) was revealed as risk factor for affecting CRC. The treatments for CRC were as follows; EMR was performed in 27 patients, simultaneous resection with GC was performed in 9 patients, resection after gastrectomy was performed in 1 patient, respectively. Pathological stage of CRC was as follows; Stage 0: 24 patients, Stage I: 10 patients, and Stage IIA: 3 patients, respectively. As for the patients who underwent surgery for CRC, all of them received radical colectomy. No patient died for CRC who received colonoscopy before gastric surgery. Conclusions: Screening colonoscopy is useful for GC patients. Because most of the synchronous CRC were found early stage and curatively treated.
Molecular characterization of appendiceal goblet cell carcinoid.
Authors: Hiroyuki Arai, Yasmine Baca, Curtis Johnston, Richard M. Goldberg, Philip Agop Philip, Andreas Seeber, Francesca Battaglin, Joanne Xiu, Jingyuan Wang, Shivani Soni, Wu Zhang, Jimmy J. Hwang, Anthony Frank Shields, John Marshall, W. Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

231 Background: Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. There are a few reports focusing on the molecular differences between GCC and other appendiceal tumors such as adenocarcinoma and neuroendocrine tumor (NET). Methods: A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas and 14 NETs) were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) / mismatch repair (MMR) status was tested with a combination of NGS, IHC and fragment analysis. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 were tested by IHC (SP142). Molecular characteristics of GCCs are compared with those of adenocarcinomas and NETs, using Chi-square test. Results: The top five genes with most frequent mutation rate in GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), KRAS (7.5%) and CHEK2 (4.0%). Compared to adenocarcinomas, GCCs showed significantly lower mutation rates in KRAS (7.5% vs 60.4%), GNAS (3.8% vs 34.4%), APC (1.9% vs 11.7%), while significantly higher mutation rates in CDH1 (3.8% vs 0.7%), CHEK2 (4.0% vs 0.3%), CDC73 (2.0% vs 0.0%), ERCC2 (2.0% vs 0.0%) and FGFR2 (1.9% vs 0.0%). Compared to NETs, GCCs showed significantly lower mutation rate in KRAS (7.5% vs 28.6%), APC (1.9% vs 28.6%), BRCA2 (0.0% vs 7.1%) and FANCA (0.0% vs 7.1%), with all p &lt; 0.05. In GCCs, MSI-H/dMMR, TML-high (&gt; 17mut/Mb) and PD-L1 expression were seen in 0.0%, 0.0% and 2.0%, respectively. No significant difference was observed in these immune-related markers’ frequency, compared to adenocarcinomas and NETs. Conclusions: GCCs had considerably distinct mutational profile compared to appendiceal adenocarcinomas and NETs. Understanding these molecular characteristics may be critical for a development of effective treatment strategy in GCC.
Scoring model with serum albumin and CA19-9 in advanced pancreatic cancer in second-line treatment: Results from the NAPOLEON study.
Authors: Azusa Komori, Satoshi Otsu, Mototsugu Shimokawa, Taiga Otsuka, Futa Koga, Yujiro Ueda, Junichi Nakazawa, Shiho Arima, Masaru Fukahori, Yoshinobu Okabe, Akitaka Makiyama, Hiroki Taguchi, Takuya Honda, Taro Shibuki, Kenta Nio, Yasushi Ide, Norio Ureshino, Tsuyoshi Shirakawa, Kenji Mitsugi
Journal: Journal of Clinical Oncology (2020)

649 Background: Patients with metastatic pancreatic cancer refractory to first-line chemotherapy (CTx) have limited treatment options. Moreover, it is unclear what kind of patients could be brought about survival benefit by 2nd-line CTx after refractory to gemcitabine+ nab-PTX (GnP) or FOLFIRINOX. Methods: This analysis was performed as part of a multicenter retrospective study of GnP or FOLFIRINOX in patients with unresectable pancreatic cancer (NAPOLEON study) conducted by 14 centers in Japan. From December 2013 to March 2017, 255 patients with advanced or recurrent pancreatic cancer received GnP or FOLFIRINOX as 1st-line CTx. Excluding censored cases in first-line treatment, 156 and 77 patientsreceived 2nd-line CTx and best supportive care (BSC), respectively. Variables at the refractory or intolerant to the 1st-line treatment were used to investigate correlation with prognosis by Cox regression model. Then, we made scoring system using the prognostic factors to reveal the benefit of 2nd-line CTx. Results: Median post-progression survivals (PPSs) were 5.2 months in 2nd-line CTx group and 2.7 months in BSC group, respectively (hazard ratio [HR]; 0.42, 95% confidence interval [CI]; 0.31-0.57, p&lt;0.01). According to the Cox regression model, serum Alb level of less than 3.5 g/dL (HR; 1.98, 95% CI; 1.33–2.96, p&lt;0.01) and CA19-9 level of greater than 1,000 U/mL (HR; 1.87, 95% CI; 1.25–2.80, p&lt;0.01) were independent predictive factors. The scoring system for PPS was designed using these factors, which was obtained by summing up serum Alb (≥ and &lt; 3.5 g/dL allocated to scores 0 and 1) and CA19-9 (&lt; and ≥ 1,000 U/mL allocated to scores 0 and 1) at disease progression in patients with 2nd-line CTx group. Patients with score 0 and 1 displayed significantly favorable PPSs in comparison with BSC group; however, there was no significant difference in PPS between patients with score 2 and BSC group (Table). Conclusions: Survival benefit of 2nd-line CTx was observed in patients with the score 0 and 1, but not in the score 2. [Table: see text]
When bugs and drugs conspire: driving acneiform skin toxicity
Authors: Allison C. Billi, Mrinal K. Sarkar, Johann E. Gudjonsson
Journal: Journal of Clinical Investigation (2020)

Therapy with antineoplastic agents that inhibit EGFR and MEK is frequently limited by cutaneous adverse reactions, most commonly acne-like eruptions. In this issue of the JCI, Satoh et al. define a mechanism for acneiform skin toxicity wherein EGFR/MEK inhibitors cooperate with the skin commensal Cutibacterium acnes to induce IL-36γ in keratinocytes via the combined actions of Krüppel-like factor 4 and NF-κB transcription factors at the IL-36γ promoter, resulting in neutrophil recruitment. In addition to elucidating why EGFR/MEK inhibitor-induced rashes are often pustular and folliculocentric, this mechanism provides justification for the long-standing practice of management with antibiotic therapy.
Incidental venous thromboembolism, detected by chance, but still venous thromboembolism
Authors: Guy Meyer, Benjamin Planquette
Journal: European Respiratory Journal (2020)

Incidental venous thromboembolism (VTE) refers to deep venous thrombosis or pulmonary embolism (PE) diagnosed on an imaging test, usually computed tomography, performed for another reason than the clinical suspicion of VTE. Incidental VTE is particularly frequent in patients with cancer who have an increased risk of VTE and who underwent frequent imaging tests for staging purposes and assessment of anticancer treatment. Incidental venous thromboembolism and clinically suspected venous thromboembolism should receive the same anticoagulant treatment <http://bit.ly/2NQ4l8U>
Billing Quality Is Medical Quality
Authors: Simon C. Mathews, Martin A. Makary
Journal: JAMA (2020)

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Stereotactic radiotherapy in oligometastatic (OM) gastrointestinal (GI) tumors: A single institution retrospective analysis.
Authors: Renata Reis Figueiredo, Daniel Moore Freitas Palhares, Gustavo Dos Santos Fernandes, Allan Andresson Lima Pereira, Katia Regina Marchetti, Brenda Pires Gumz, Luiza Dib Faria, Marcela Alves Teixeira, Rafael Gadia
Journal: Journal of Clinical Oncology (2020)

825 Background: Metastatic GI cancers are mainly treated with systemic treatment (ST), in selected patients (pts), surgery is considered depending on pts characteristics and institutional preferences. Stereotactic Radiotherapy (SRT) is a growing treatment option in such landscape aiming to improve local disease control and maximize ST results for oligometastatic pts. Methods: This is a single center retrospective study. Data were collected from sequential pts with GI tumors who underwent SRT for OM-GI cancers from May 2014 to July 2019. Information was collected on pts characteristics, primary site, clinical staging at diagnosis, sites undergoing SRT, whether there was progression after the first SRT, time between the first SRT and progression and the last follow-up date. Results: 381 pts underwent SRT in our center, of these, 75 pts had OM-GI tumors and underwent 120 courses of SRT. 50,7% were women, the median age at diagnosis was 60 years and the median follow-up was 36 months. 76% had colorectal cancer (CRC) being 26% from the right, 26% from the left colon and 30% were from the rectum, in 18% of the patients we could not determine sidedness. 35% already had metastatic disease at diagnosis. The lung was the site with largest number of lesions treated with SRT (50), followed by central nervous system (CNS) (42), bones (32), liver (29) and lymph nodes (16). After a median follow up of 15.3 months, 11% of patients were progression-free and only 24% had progressed on treated lesions. The median progression free survival following SRT was 4.5 months (0.6-45.8 range) for distant metastasis and was not achieved for treated sites. Conclusions: This retrospective study adds to the previous body of evidence supporting the use of SRT to improve GI cancer management. Detailed information on pts characteristics, pathology, toxicity and previous treatments will be presented.
A multicenter clinical randomized phase II study of investigating duration of adjuvant chemotherapy with S-1 (six versus 12 months) for patients with resected pancreatic cancer: PACS-1 study.
Authors: Yo-ichi Yamashita, Shinji Itoh, Mototsugu Shimokawa, Hiroshi Takamori, Kengo Fukuzawa, Mizuki Ninomiya, Kenichiro Araki, Kiyoshi Kajiyama, Keishi Sugimachi, Hideaki Uchiyama, Yuji Morine, Tohru Utsunomiya, Tadashi Uwagawa, Takashi Maeda, Eisuke Adachi, Yasuharu Ikeda, Tomoharu Yoshizumi, Hideo Baba, Masaki Mori
Journal: Journal of Clinical Oncology (2020)

669 Background: Although adjuvant chemotherapy with S-1 has improved overall survival and progression-free survival (PFS) in patients with resected pancreatic cancer, the duration evaluation of adjuvant chemotherapy with S-1 have not established yet. Methods: We did a randomized, multicenter, phase 2 trial undertaken at 15 hospitals in Japan. Patients who were Eastern Cooperative Oncology Group performance states of 0 or 1 and aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive S-1 [40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles (6 months)] or up to eight cycles (12 months). The primary end point was overall survival rate. Secondary endpoints included PFS and safety. Results: The population consisted of 82 patients in the S-1 for 6 months group and 82 patients in the S-1 for 12 months group. The 2-year overall survival rate was 71.4% in the S-1 for 6 months group and 65.4% in the S-1 for 12 months, and the median overall survival was 31.0 months in the S-1 for 6 months group and 26.3 months in the S-1 for 12 months group [hazard ratio (HR) 1.23, 95% confidence interval (CI) 0.76-1.99, p = 0.377]. The PFS at 2 years was 56.8% in the S-1 for 6 months group, and 51.2% in the S-1 for 12 months. The HR for recurrence of S-1 for 6 months, compared with S-1 for 12 months, was 1.23 (95%CI 0.76-1.99, p = 0.392). Twenty-nine (35.3%) patients in the S-1 for 6 months group and 46 (56.0%) in the S-1 for 12 months group discontinued treatment before completion. In regard to patients completed treatment, the S-1 for 12 months group showed tendency to favorable prognosis on PFS compared with the S-1 for 6 months group (log-rank test; p = 0.175). Conclusions: In patients with resected pancreatic cancer, adjuvant chemotherapy with S-1 for 12 months is not superior to that for 6 months in terms of median overall survival and PFS. For patients who can tolerate adjuvant chemotherapy with S-1 for 6 months well, continuing treatment for up to 12 months may improve the prognosis.
Targeted measles and rubella vaccination campaign aims to stop global surge in cases
Authors: Elisabeth Mahase
Journal: BMJ (2020)

A new vaccination campaign will aim to vaccinate 45 million children in seven developing countries over the next six months, in an attempt to halt a recent surge in global measles cases.

Governments will carry out the campaign with funding from Gavi, the Vaccine Alliance, and support from the Measles & Rubella Initiative’s partners, including the World Health Organization and Unicef.

It will target children under 5 years old—the group most vulnerable …