bluuebunny/crossref_metadata_2025 huggingface dataset:
Proinflammatory T cell polarization is already present in patients with early knee osteoarthritis
Authors: Rosshirt Nils , Trauth Richard , Platzer Hadrian , Tripel Elena , Nees Timo A. , Lorenz Hanns-Martin , Tretter Theresa , Moradi Babak
Published: January 2021

Background

Investigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells.

Methods

A quantitative analysis of CD4+T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4+T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles.

Results

SF and SM showed a distinct infiltration of CD4+T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4+T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF.

Conclusions

Early OA joints show already significant inflammation through CD4+T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.
The serum levels of circulating matrix metalloproteinase MMP-9, MMP-2/TIMP-2 complex and TIMP-1 do not change significantly during normal pregnancy: a pilot study
Authors: Nissi Ritva , Santala Markku , Talvensaari-Mattila Anne
Published: January 2021

Objective

Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. They exhibit proteolytic activity implicating the efficiency of trophoblast invasion to the uterine wall involving marked hemodynamic and uterine changes. In this pilot study sera of 13 women with normal pregnancy was analyzed to evaluate the usage of MMPs as diagnostic tool. The concentrations of circulating MMP-9, MMP-2/TIMP-2 complex and TIMP-1 in different time points during normal pregnancy has not been studied. The serum levels of MMP-9, TIMP-1, TIMP-2 and MMP-2/TIMP-2 complex were determined by enzyme-linked immunosorbent assay (ELISA). Using the same method, we have shown that serum MMPs are elevated in spontaneous early pregnancy failure as compared to normal pregnancy.

Results

The serum levels of MMP-9 and TIMP-1 were stable throughout pregnancy. The level of MMP-2/TIMP-2 complex was slightly increased after week 15 without statistical significance. For our best knowledge, this is a first study of the serum levels of MMP-9, MMP-2/TIMP-2 and TIMP-1 on different time points during normal pregnancy. Further measurements with the correlation to the outcome of the pregnancy are needed.
A pilot trial of human amniotic fluid for the treatment of COVID-19
Authors: Selzman Craig H. , Tonna Joseph E. , Pierce Jan , Vargas Camila , Skidmore Chloe , Lewis Giavonni , Hatton Nathan D. , Phillips John D.
Published: January 2021

Objective

Vertical transmission from SARS CoV-2-infected women is uncommon and coronavirus has not been detected in amniotic fluid. Human amniotic products have a broad immune-mediating profile. Observing that many COVID-19 patients have a profound inflammatory response to the virus, we sought to determine the influence of human amniotic fluid (hAF) on hospitalized patients with COVID-19.

Results

A 10-patient case series was IRB-approved to study the impact of hAF on hospitalized patients with documented COVID-19. Nine of the 10 patients survived to discharge, with one patient succumbing to the disease when enrolled on maximal ventilatory support and severe hypoxia. The study design was altered by the IRB such that the last 6 patients received higher dose of intravenous hAF. In this latter group, patients that had observed reductions in C-reactive protein were associated with improved clinical outcomes. No hAF-related adverse events were noted. Acknowledging some of the inherent limitations of this case series, these results inform and catalyze a larger scaled randomized prospective trial to further investigate hAF as a therapy for COVID-19.

Trial Registration ClinicalTrials.gov: NCT04319731; March 23, 2020
Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids
Authors: Adhya Dwaipayan , Chennell George , Crowe James A. , Valencia-Alarcón Eva P. , Seyforth James , Hosny Neveen A. , Yasvoina Marina V. , Forster Robert , Baron-Cohen Simon , Vernon Anthony C. , Srivastava Deepak P.
Published: January 2021

Background

The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points.

Results

Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified, in vitro tissues, in both speed and resolution when compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes.

Conclusion

We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and cleared in vitro human brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. This process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes in vitro.
Resolvin E1 accelerates pulp repair by regulating inflammation and stimulating dentin regeneration in dental pulp stem cells
Authors: Chen Jie , Xu Huaxing , Xia Kun , Cheng Shuhua , Zhang Qi
Published: January 2021

Background

Unresolved inflammation and tissue destruction are considered to underlie the failure of dental pulp repair. As key mediators of the injury response, dental pulp stem cells (DPSCs) play a critical role in pulp tissue repair and regeneration. Resolvin E1 (RvE1), a major dietary omega-3 polyunsaturated fatty-acid metabolite, is effective in resolving inflammation and activating wound healing. However, whether RvE1 facilitates injured pulp-tissue repair and regeneration through timely resolution of inflammation and rapid mobilization of DPSCs is unknown. Therefore, we established a pulp injury model and investigated the effects of RvE1 on DPSC-mediated inflammation resolution and injured pulp repair.

Methods

A pulp injury model was established using 8-week-old Sprague-Dawley rats. Animals were sacrificed on days 1, 3, 7, 14, 21, and 28 after pulp capping with a collagen sponge immersed in PBS with RvE1 or PBS. Hematoxylin-eosin and Masson’s trichrome staining, immunohistochemistry, and immunohistofluorescence were used to evaluate the prohealing properties of RvE1. hDPSCs were incubated with lipopolysaccharide (LPS) to induce an inflammatory response, and the expression of inflammatory factors after RvE1 application was measured. Effects of RvE1 on hDPSC proliferation, chemotaxis, and odontogenic differentiation were evaluated by CCK-8 assay, transwell assay, alkaline phosphatase (ALP) staining, alizarin red staining, and quantitative PCR, and possible signaling pathways were explored using western blotting.

Results

In vivo, RvE1 reduced the necrosis rate of damaged pulp and preserved more vital pulps, and promoted injured pulp repair and reparative dentin formation. Further, it enhanced dentin matrix protein 1 and dentin sialoprotein expression and accelerated pulp inflammation resolution by suppressing TNF-α and IL-1β expression. RvE1 enhanced the recruitment of CD146+ and CD105+ DPSCs to the damaged molar pulp mesenchyme. Isolated primary cells exhibited the mesenchymal stem cell immunophenotype and differentiation. RvE1 promoted hDPSC proliferation and chemotaxis. RvE1 significantly attenuated pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and enhanced ALP activity, nodule mineralization, and especially, expression of the odontogenesis-related genes DMP1, DSPP, and BSP in LPS-stimulated DPSCs. RvE1 regulated AKT, ERK, and rS6 phosphorylation in LPS-stimulated DPSCs.

Conclusions

RvE1 promotes pulp inflammation resolution and dentin regeneration and positively influences the proliferation, chemotaxis, and differentiation of LPS-stimulated hDPSCs. This response is, at least partially, dependent on AKT, ERK, and rS6-associated signaling in the inflammatory microenvironment. RvE1 has promising application potential in regenerative endodontics.
Probiotics mixture reinforces barrier function to ameliorate necrotizing enterocolitis by regulating PXR-JNK pathway
Authors: Zhao Xiuhao , Zhou Jin , Liang Wenhua , Sheng Qingfeng , Lu Li , Chen Tong , Chen Jianglong , Tan Kezhe , Lv Zhibao
Published: January 2021

Background

Intestinal dysbiosis is believed to be one of the factors inducing neonatal necrotizing enterocolitis (NEC). Probiotics have been employed to treat NEC in a number of animal experiments and clinical trials, and some significant benefits of utilizing probiotics for the prevention or alleviation of NEC have been confirmed. However, the mechanism underlying the efficacy of probiotics in treating NEC has not been elucidated.

Results

Impairment of the intestinal barrier, which was characterized by the decreased expression of tight junction components, was observed in the pathogenesis of NEC. The probiotic mixture alleviated this intestinal damage by enhancing the function of the barrier. Meanwhile, the probiotics remodeled the composition of the intestinal microbiota in NEC mice. Furthermore, increased expression of the pregnane X receptor (PXR) was observed after treatment with the probiotic mixture, and PXR overexpression in Caco-2 cells protected the barrier from lipopolysaccharide (LPS) damage. Further research showed that PXR could inhibit the phosphorylation of c-Jun N-terminal kinase (JNK) and could increase the expression of tight junction components.

Conclusions

Our study confirmed that probiotics could ameliorate intestinal lesions by enhancing the function of the mucosal barrier. Specifically, probiotics may target PXR, which may subsequently enhance the expression of tight junction components by inhibiting the phosphorylation of JNK and enhance the function of the barrier.
Coincidence best proximity point theorems for proximal Berinde g-cyclic contractions in metric spaces
Authors: Klanarong Chalongchai , Chaiya Inthira
Published: January 2021

In this paper, we introduce the notions of proximal Berinde g-cyclic contractions of two non-self-mappings and proximal Berinde g-contractions, called proximal Berinde g-cyclic contraction of the first and second kind. Coincidence best proximity point theorems for these types of mappings in a metric space are presented. Some examples illustrating our main results are also given. Our main results extend and generalize many existing results in the literature.
Comparison of the antimicrobial efficacy of povidone-iodine-alcohol versus chlorhexidine-alcohol for surgical skin preparation on the aerobic and anaerobic skin flora of the shoulder region
Authors: Dörfel Dorothea , Maiwald Matthias , Daeschlein Georg , Müller Gerald , Hudek Robert , Assadian Ojan , Kampf Günter , Kohlmann Thomas , Harnoss Julian Camill , Kramer Axel
Published: January 2021

Background

Cutibacterium acnes is part of the anaerobic skin microbiome and resides in deeper skin layers. The organism is an agent of surgical site infections (SSI) in shoulder surgery. We hypothesized that prolonged skin preparation with an agent that penetrates deeply into the skin would be beneficial. Thus, we compared two classes of antiseptics, each combined with alcohol, each applied with two different contact times.

Methods

Using a cross-over arrangement, shoulders of 16 healthy volunteers were treated for 2.5 min (standard) or 30 min (prolonged) with alcohol-based chlorhexidine (CHG-ALC) or alcohol-based povidone-iodine (PVP-I-ALC). Skin sites were sampled before, immediately after, and 3 h after treatment, using a standardized cup-scrub technique.

Results

Aerobic skin flora was reduced more effectively by PVP-I-ALC than by CHG-ALC after 2.5 min application and immediate sampling (reduction factor [RF] 2.55 ± 0.75 vs. 1.94 ± 0.91, p = 0.04), but not after prolonged contact times and 3-h sampling. Coagulase-negative staphylococci were completely eliminated after PVP-I-ALC application, but still recovered from 4 of 32 samples after CHG-ALC application. Anaerobic flora was reduced more effectively by PVP-I-ALC than CHG-ALC after standard (RF 3.96 ± 1.46 vs. 1.74 ± 1.24, p < 0.01) and prolonged (RF 3.14 ± 1.20 vs. 1.38 ± 1.16, p < 0.01) contact times and immediate sampling, but not after 3-h sampling. No adverse events were reported.

Conclusions

PVP-I-ALC showed marginal benefits concerning the aerobic flora, but more substantial benefits over CHG-ALC concerning the anaerobic flora of the shoulder. Standard and prolonged contact times showed superiority for PVP-I-ALC for anaerobic flora at all immediate sampling points, but missed significance at 3-h sampling. The results underscore the need for protection against C. acnes and coagulase-negative staphylococci in orthopaedic surgery. The clinical relevance of these findings, however, should be studied with SSI as an endpoint.
Development and validation of bexarote by bioanalytical methods using liquid chromatography-tandem mass spectroscopy (LC-MS/MS)
Authors: Nagaraju K. , Chowdary Y. A. , Rao M. V. Basaveswara
Published: January 2021

Background

The aim of this study was to develop and validate accurate and precise UPLC method with tandem mass spectrometry (Waters) for the determination of bexarotene in human plasma using bexarotene D4 as internal standard (IS).

Results

The retention time of bexarotene was 2.75 ± 0.30 min. The method was validated with respect to system suitability, linearity, accuracy, precision, matrix effect, auto sampler carryover test, and recovery. Linearity was found to be 1.04 to 351.93 μg/mL. LOQQC, LQC, INTQC, MQC, and HQC were found to be 1.0550, 2.7800, 25.2700, 131.61, and 263.23 respectively. The mean percentage recovery was found to be 95.72%

Conclusion

The bioanalytical method, a selective and sensitive liquid chromatography-mass spectrometry method to quantitate bexarotene in K2EDTA human plasma over the concentration range 1.0440 to 351.9320 ng/mL, was successfully validated. This method is suitable for sample analysis to support bioequivalence/bioavailability and/or pharmacokinetic studies involving formulations of bexarotene.
Prognostic value of tumor deposits in stage III colon cancer patients, a post-hoc analysis of CALGB/SWOG 80702 phase III study.
Authors: Cohen Romain , Shi Qian , Meyers Jeffrey P. , Jin Zhaohui , Svrcek Magali , Fuchs Charles S. , Couture Felix , Kuebler J. Phillip , Bendell Johanna C. , De Jesus-Acosta Ana , Kumar Pankaj , Lewis DeQuincy Andrew , Tan Benjamin R. , Bertagnolli Monica M. , Hochster Howard S. , Blanke Charles David , O'Reilly Eileen Mary , Shields Anthony Frank , Meyerhardt Jeffrey A.
Published: January 2021

10

Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.
The effects of neoadjuvant chemoradiation on exosomal markers (CD63 and CD9) expression in patients with locally advanced rectal adenocarcinoma.
Authors: Khushman Moh'd M. , Prodduturvar Pranitha , Akbar Shalla , Mneimneh Wadad , Dal Zotto Valeria , Grimm Leander , Rider Paul , Hunter John , Patel Girijesh Kumar , Singh Ajay Pratap
Published: January 2021

101

Background: Exosomes mediate intercellular communications and have pivotal roles in cancer development. CD63 and CD9 are widely accepted exosomal markers. The effect of concurrent chemoradiation on the expression of exosomal markers is unknown. Here we explored the effect of neoadjuvant concurrent chemoradiation (NCCR) on exosomal markers (CD63 and CD9) expression in patients with locally advanced rectal cancer (LARC). Methods: Between 2015 and 2018, 33 patients had LARC treated with NCCR and had pre NCCR biopsy and post NCCR resected rectum examined for exosomal markers expression using immunohistochemistry. Two pathologists independently scored CD63 and CD9 staining in the tumor. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Un-Paired t test was used for statistical analysis. Results: In our cohort, median age was 59 years. Males represented 79% of the patients. Caucasians, African American and other ethnic groups represented 70%, 27% and 3% respectively.The mean tumor CD63 score in pre NCCR biopsy vs post NCCR resected rectum was 106 vs 165 (p = 0.0022). The mean tumor CD9 score in pre NCCR biopsy vs post NCCR resected rectum was 136 vs 215 (p < 0.0001). The exosomal markers expression in the adjacent normal mucosa (ANM) from pre NCCR biopsy and post NCCR resected rectum was only performed in16 out of 33 patients (due to ANM tissue availability). The mean ANM CD63 score in pre NCCR biopsy vs post NCCR resected rectum was 166 vs 183 (p = 0.37). The mean ANM CD9 score in pre NCCR biopsy vs post NCCR resected rectum was 104 vs 145 (p = 0.0897). Conclusions: In patients with LARC, the expression of exosomal markers (CD63 and CD9) increased after treatment with NCCR. Our results show that the expression of CD63 and CD9 is relatively higher in rectal cancer specimens treated with NCCR and thus suggest a possible role of these exosomes in adaptive response to NCCR. Further follow-up and laboratory studies are required to precisely understand the underlying mechanism(s).
Does non-TME surgery of rectal cancer compromise the chance of cure? Preliminary surgical salvage data from OPERA phase III randomized trial.
Authors: Myint Arthur Sun , Thamphya Brice , Gerard Jean-Pierre
Published: January 2021

12

Background: Non-operative modality (NOM) treatment of rectal cancer is gaining popularity as it avoids extirpative TME surgery and a stoma. OPERA trial was set up to evaluate the role of dose escalation using Contact X-ray brachytherapy [CXB] in improving the chance of organ preservation compared to the standard of care (EBCRT and TME surgery). We report on the preliminary surgical salvage data for treatment failures in the OPERA trial (NCT02505750). Methods: OPERA is a European phase 3 randomised trial between (Arm A- standard arm) EBCRT 45Gy/25/5weeks with oral capecitabine 825mg/m2 and EBRT boost of 9Gy/5/5 days randomised against (Arm B- experimental arm) EBCRT followed by CXB boost (90 Gy/3/4 weeks). Patients were assessed at 14, 20 and 24 weeks. Watch & wait policy was adopted for patients with cCR at 24 weeks after randomisation and surgery (TME or local excision) was offered for residual disease and also for local regrowth (recurrence) at a later date. Results: From July 2015 –June 2020, 148 patients were randomised of which 144 were evaluable (table). There were 71 patients in Arm A (standard) and 73 patients in Arm B (experimental). Median follow-up was 19 months (range 2-36 m). Overall clinical complete response (cCR) was observed in 103 out of 127 evaluable patients (81%) at 24 week in both arms (blinded). Surgery was carried out in 36/ 127 (28%) patients with suspected residual tumour. Further 13 patients had salvage surgery at a later date for local regrowth. At 19 months, 49/144 (34%) patients in total cohort had surgery. Local excision was carried out in 24 /49(49%) of which 3 proceeded to TME surgery due to R (1) or ypT2 adverse histology. TME surgery was carried out in 28/49 of which 8/28 (28.6%) had APER and 20/28(71.4%) had AR. In total, organ preservation (blinded) was achieved in 116/144 (80.5%) for the whole cohort. Kaplan Meier estimate of TME free survival is 76% at 19 months. Conclusions: Non-TME surgical treatment for cT2-cT3a-b rectal cancer is feasible in those who are fit and wish to avoid surgery (Watch & Wait). Those who needed surgery can be offered salvage surgery immediately for local residual disease or for local regrowth at a later date. Organ preservation of 80.5% (blinded) can be achieved without compromising their chance of cure. Clinical trial information: NCT02505750. [Table: see text]
CD8+ tumor-infiltrating lymphocyte infiltration prediction with radiomic signature in locally advanced rectal cancer.
Authors: Chie Eui Kyu , Jeon Seung Hyuck , Lim Yu Jin , Koh Jaemoon , Kim Sehui , Kim Kyubo
Published: January 2021

123

Background: Despite increasing use of cancer immunotherapies, no biomarker relevant to anti-tumor immunity has been developed in rectal cancer. The present study aims to develop a radiomic signature to predict the infiltration of CD8+ tumor-infiltrating lymphocytes (TILs). Methods: In total, 131 patients undergoing neoadjuvant chemoradiotherapy (CRT) from 2005 to 2012 were analyzed. The study included pre-CRT dataset A ( n = 113; n = 75 and 38 for training and validation) and post-CRT datasets B ( n = 32; predominance of tumor) and C ( n = 20; pure fibrosis). To build the radiomic signature, 38 features selected from pre-CRT T2-weighted MRI scans were incorporated into the least absolute shrinkage and selection operator method. Results: Higher CD8+ TIL infiltration was associated with better overall and progression-free survival ( P = 0.01 and 0.03, respectively). In pre-CRT dataset A, the area under the receiver operating characteristic curve values of radiomic score for predicting CD8+ TILs were 0.760 and 0.729 for training and validation subsets, respectively. A significant correlation was observed between the radiomic signature and CD8+ TIL density in the post-CRT dataset B (Pearson’s R = ‒0.372, P = 0.036), whereas no association was found within the dataset C accounting for pure fibrosis after CRT (Pearson’s R = ‒0.069, P = 0.77). Conclusions: We established the MRI-derived radiomic signature for predicting CD8+ TIL infiltration in the contemporary treatment era of rectal cancer. The noninvasive characterization of tumor immune status would provide insights into the role of radiomic-pathology modeling to predict the local immune phenotypes.
Effect of treatment disparities on survival in disadvantaged black and white patients with stage IV colorectal cancer (CRC).
Authors: Swords Douglas S , Tran Cao Hop Sanderson , Bednarski Brian K. , Vauthey Jean-Nicolas , Chang George J. , You Y. Nancy
Published: January 2021

13

Background: Non-Hispanic Black patients (NHBs) and low socioeconomic status (SES) non-Hispanic White patients (NHWs) have worse cancer outcomes. In most cancers, the relative importance of treatment disparities vs. other pathways are undefined. We estimated the proportion of overall survival (OS) disparities mediated by treatment disparities in NHBs and NHWs with stage IV CRC. Methods: We queried the National Cancer Database for NHBs and NHBs (aged 18-80) diagnosed with stage IV CRC in 2010-16. Zip code SES was defined as low (quartile 1 income and education), high (quartile 4 income and education), and middle. Exclusions were missing SES, chemotherapy contraindications/refusal, unknown treatment, and < 60 days follow-up. From available variables, we examined 3 plausible treatment mediators of OS: chemotherapy, metastatectomy, and treatment at > 1 CoC facility. Primary tumor resection was not analyzed to avoid immortal time bias. We used inverse odds ratio weighting (IORW) to estimate the proportion mediated ( PM) while adjusting for sex, age, cancer history, comorbidities, year, tumor location, grade, LVI, CEA, and KRAS status. Results: Among 70,773 patients, the rate of low SES was 3.6-fold higher among NHBs than NHWs. There were graded associations between higher SES and rates of each mediator (Cuzick trend tests, all p ⩽ 0.01). Furthermore, low and middle SES NHB and NHWs all had significantly lower rates of each mediator than high SES NHWs (Table, part A). 5-yr OS ranged from 14.5% in low SES NHBs to 21.9% in high SES NHWs. Low and middle SES NHWs and all NHBs had shorter adjusted OS than high SES NHWs (Table, part B). PMs were higher for low and middle SES NHBs vs. NHWs (27-28% vs. 19-22%). PMs were largest for metastasectomy (9.9-16.1%) and smallest for chemotherapy (5.0-7.9%). Conclusions: Treatment disparities mediate at least 20-30% of OS disparities in NHBs and NHWs with stage IV CRC. These estimates may represent the lower bound of true PMs since many aspects of treatment quality were unmeasured. These findings imply that policies addressing treatment disparities are projected to partially close survival gaps. [Table: see text]
Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.
Authors: Karki Sophiya , Madan Rashna , Schmitt Sarah , Pessetto Ziyan Y. , Godwin Andrew K. , Sun Weijing , Kasi Anup
Published: January 2021

132

Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]
Microsatellite instability in colorectal cancer: An analysis of the National Cancer Database.
Authors: Abushalha Kamelah , Abulaimoun Sawsan , Aurit Sarah J , Jenkins Erin , Silberstein Peter T.
Published: January 2021

134

Background: High-frequency microsatellite instability (MSI-H) accounts for roughly 15% of all cases of colorectal cancer (CRC). Studies suggest a significant non-adherence to routine MSI testing in patients diagnosed with CRC despite universal guidelines. Methods: We used the NCDB to identify adults with MSI-H status CRC from 2010-2015 with the following histologic subtypes: mucinous and not otherwise specified adenocarcinoma, and medullary carcinoma. The primary site was localized to the right colon, left colon, and rectum; demographic factors, clinicopathologic features, and treatments were identified. Patients were stratified by site and discrete and continuous variable comparisons were made using the chi-square and Mann-Whitney test, respectively. Survival was examined with the Kaplan-Meier method and a Cox proportional hazards regression model. A logistic regression model was used to examine MSI status. All analyses were conducted with SAS version 9.4. Results: A total of 5364 patients were identified and stratified by site into 3 groups: right colon (n = 4004, 74.6%), left colon (n = 890, 16.59%) and rectum (n = 470, 8.76%). Compared to the left colon and rectum, right colon patients were more likely to be older females with larger tumors and less likely to receive chemoradiation. After adjusting for all else, we found statistical evidence that female vs. male gender (OR = 1.47; 95% CI: 1.24 to 1.73), Black vs. White race (OR = 0.61; 0.45 to 0.83), left vs. right colon (OR = 0.33, 0.27 to 0.41), rectum vs. right colon (OR = 0.08, 0.05 to 0.13), mucinous adenocarcinoma vs. adenocarcinoma (OR = 2.37, 1.92 to 2.93), medullary carcinoma vs. adenocarcinoma (OR = 8.86, 4.56 to 17.22), positive vs. negative k-RAS mutation (OR = 0.49, 0.41 to 0.59), and positive vs. negative CEA status (OR = 0.79, 0.66 to 0.94) were factors associated with MSI-H status. Improved survival was associated were Hispanic white race, stage 1, and free surgical margins within a multivariable context. Factors associated with poor survival: increased Charlson/Deyo score, advanced stage, lymphovascular invasion, and positive CEA status. Conclusions: In settings where resources are scarce and universal testing is not possible, there is a benefit from MSI testing in female patients, those with right-sided colon cancer, mucinous adenocarcinoma, and medullary carcinoma.
Inoperable stage IV colorectal cancer with intact primary tumor in patients receiving palliative chemotherapy: Does the response to chemotherapy correlate between primary and metastatic sites? An Irish cancer center experience.
Authors: Hamed Ruba , McLaughlin Ronan Andrew , Ibrahim Hatim , Korpanty Greg , Osman Nemer
Published: January 2021

136

Background: Colorectal cancer (CRC) is the 3rd most common malignancy in Ireland with over 2700 cases annually. Approximately 20% are diagnosed with stage IV disease. The aim of this study is to evaluate the response to chemotherapy at primary and metastatic sites and review the frequency of intervention required to palliate the intact primary tumour in patients with stage 4 inoperable CRC in an Irish tertiary referral centre. Methods: A retrospective review of medical records was completed, identifying stage 4 CRC patients with primary tumour in situ diagnosed between January 2014 and December 2019, treated with chemotherapy (oxaliplatin or irinotecan based +/- bevacizumab or EGFR monoclonal antibody). Data and survival analysis were obtained using Kaplan-Meier methods. Results: 50 eligible patients were identified; 60% male, 40% female with a median age of 62 years. 2% had a transverse colonic primary, 32% right and 44% left sided and 22% had a rectal primary. 36% presented with liver metastasis only, 4% lung metastasis alone and 20% both. 48% were KRAS, 4% NRAS and 4% BRAF mutation positive while 1 patient was identified as having microsatellite instability. All patient received first-line chemotherapy either oxaliplatin or irinotecan based, 18% with the addition of Bevacizumab and 24% with EGFR monoclonal antibody. Overall response to first-line chemotherapy at the primary site and metastatic sites was assessed radiologically; 42% displaying a partial response, 36% had stable disease while 18% had progression at primary site. At the metastatic sites 50% responded, 10% stable disease and 40% progressed. Complication at primary tumour site included: obstruction 12%, with perforation in 6%, bleeding 10%, pain at tumour site in 6%, and one patient developed an abscess. Overall, after chemotherapy 76% of all patients did not require further intervention to manage primary site. 6% underwent curative surgery with resection of primary and metastatic lesions. Of those who had palliative intervention; 10% underwent palliative colostomy/ileostomy, 12% palliative radiotherapy, and 2% both. Overall survival was 14 months. At time of analysis 14% were alive, 10% receiving treatment and 4% on radiological surveillance. Conclusions: This retrospective study confirms that palliative chemotherapy +/- targeted therapy is effective in controlling the primary tumour in stage 4 inoperable CRC. In addition, it reveals a nearly 80% partial response or stable disease radiologically at the primary site after first-line chemotherapy. Furthermore, progression was significantly lower at primary site compared to distant metastasis (18% vs 40%). Almost 75% did not require palliative intervention for their primary tumour. Overall survival in our centre is higher compared to internationally observed data.
Continuing education curriculums and outcomes on progressive metastatic colorectal cancer treatment.
Authors: Parikh Kinjal , Cameron Davecia Ragoonath , Chen Pan , Cain Brittany , Carothers Ann
Published: January 2021

137

Background: The treatment armamentarium for patients with metastatic colorectal cancer (mCRC) has expanded significantly and treatment options for progressive disease remain limited. As data from clinical trials or subgroup analyses become available, landmark trials are published, and guideline recommendations or clinical utility of these therapies change, continuing medical education (CME) for oncologists is necessary to ensure that eligible patients continue to receive effective therapies. Methods: A series of 7 activities launched from 2016-2020 to reach a global oncology audience in the care of patients with mCRC. The educational activities included multi-modality approaches with didactics, cases, simulations, and panel discussions. Educational effectiveness was assessed with repeated paired pre/post assessment where learners served as their own controls to measure changes in knowledge, competence, confidence, and performance. Oncologists who completed both the pre- and post-CME questions or who made relevant clinical decisions in the simulation activity were included in analysis and McNemar’s tests were conducted to assess statistical significance of the results with p < .05 being considered significant. The first activity launched on 6/8/2016 and the data reported were collected through 7/20/20. Results: As of 7/20/2020, 59,595 learners participated in the activities, including 18,634 total physician learners with 5,862 oncologists. Significant improvements in knowledge, competence, and confidence among oncologists, measured as relative % changes in correct responses or confidence from pre- to post-CME, were seen (n=60-214) [% pre, % post, p value]: 11%: knowledge regarding therapies for progressive disease in mCRC (83; 92; p < .05); 17%: knowledge of clinical trials assessing impact of patient/disease specific aspects on treatment selection (63; 74; p < .001); 11%: competence selecting therapy (55; 61; p < .05); 41%: confidence selecting therapy (34; 48; p < .001); 24%: confidence addressing communication barriers in mCRC (50; 62; p < .01). Significant improvement in performance of oncologists, measured as absolute % changes in pre- to post-CME correct responses were seen (n = 46) [% pre, % post, p value]: 28%: starting preferred treatment options (24; 52; p < .01); 18%: prescribing regorafenib (24; 43; p < .01); 9%: prescribing trifluridine + tipiracil (0; 9; p < .05). Conclusions: This series of online, expert-led, CME-certified educational activities resulted in significant improvement in knowledge, competence, confidence, and performance among learners regarding the management of patients with progressive metastatic colorectal cancer over time. These results demonstrate the effectiveness of on-demand education as new data emerge and indications expand to reinforce existing knowledge, close persistent gaps, and increase confidence in managing these patients.
Factors associated with long-term survival in patients with early-onset and standard-onset colorectal cancer.
Authors: Patel Riya Jayesh , Lyudmer Michael , Chergui Adel , Tolu Seda Serra , Rao Devika , Kaubisch Andreas , Chuy Jennifer W. , Elrafei Tarek N. , Acuna-Villaorduna Ana , Goel Sanjay
Published: January 2021

141

Background: Differences in incidence, clinical features, and survival between early-onset (EO) and standard-onset (SO) colorectal cancer (CRC) are well-established. Factors associated with longer survival have not been reported. We aim to determine clinical and treatment factors associated with longer survival in patients (pts) with metastatic EO and SO CRC. Methods: Pts with metastatic CRC diagnosed between 2010-2019 at two NYC hospitals were identified by tumor registry and classified as EO (diagnosis at < 50 years) or SO (diagnosis at ≥ 50 years). Median overall survival (OS) was calculated for each group using Kaplan Meier curves. Long-term survival was defined as OS > 2 years (EO-CTC median OS). Data was collected by chart review and compared between short vs long-term survivors in EO and SO CRC pts independently. Stata v15 was used for statistical analysis. Results: Of 646 pts, 144 (22.3%) had EO and 502 (77.7%) had SO. High grade tumors were more likely in EO (33.3% vs 24%, OR: 1.59, p = 0.04) than SO; whereas no differences were seen in gender, sidedness, KRAS mutation or chemotherapy. Biologics were used more frequently in EO than SO (OR = 1.7; p = 0.008]. Median OS was 2.1 and 1.9 years in EO and SO. There were 53 (36.8%) and 175 (35.1%) long-term survivors in EO and SO groups. In pts with SO, metastasectomy, irinotecan-based chemotherapy and use of biologics were significantly associated with long-term survival, whereas metastasectomy was the only associated factor in pts with EO. Conclusions: Metastatectomy was the only factor associated with longer survival in both EO and SO groups. Other clinical/pathological and treatment-related factors associated with long-term survival among SO-CRC were not associated with long-term survival among EO-CRC patients. [Table: see text]
Confirmed three-year RFS and OS of the randomized trial of adjuvant S-1 versus S-1 plus docetaxel after curative resection of pStage III gastric cancer (JACCRO GC-07).
Authors: Yoshida Kazuhiro , Kodera Yasuhiro , Kochi Mitsugu , Sano Takeshi , Kakeji Yoshihiro , Ichikawa Wataru , Kurahashi Shintaro , Yamaguchi Hironori , Toyokawa Takahiro , Nakamura Masato , Fujitani Kazumasa , Mochizuki Yoshinari , Ota Mitsuhiko , Hihara Jun , Makari Yoichi , Takeno Atsushi , Takeuchi Masahiro , Fujii Masashi
Published: January 2021

159

Background: JACCRO GC-07 is a randomized controlled trial to explore postoperative S-1/docetaxel compared to S-1 alone after D2 gastrectomy for pStage III gastric cancer (GC) patients. The second interim analysis demonstrated that the significant improvement of RFS was obtained by S-1/docetaxel compared to S-1 alone. The study was terminated by the recommendation of independent data and safety monitoring committee and the results were reported at ASCO 2018 and published in the Journal of Clinical Oncology (Yoshida K et al. 2019; 37:1296-1304). As 3 years have passed after completion of the enrollment, preplanned analysis was performed with the updated information of the patients. Methods: Patients with pStage III GC were randomly assigned to receive either S-1/docetaxel (S-1 80-120mg/body on days 1-14 with a 7-day rest followed by docetaxel 40mg/m2 on day 1 and S-1 80-120mg/body on days 1-14 every 21 days for 6 cycles followed by S-1 80-120mg/body on days 1-28 every 42 days for 4 cycles) or S-1 (80-120mg/body on days 1-28 every 42 days for 8 cycles) after D2 gastrectomy. Block randomization was performed by a central interactive computerized system stratified by the stage (IIIA, IIIB, IIIC) and histological type (differentiated or undifferentiated). The sample size of 1,100 was necessary to detect a 7% increase in the 3-year RFS. The primary endpoint was 3y RFS and the secondary endpoints were OS, TTF and safety. Results: In the present analysis, 400 recurrences and 324 deaths were confirmed among 912 patients during the median follow-up period of 42.5 months (0.3-85.16). The 3y RFS of 67.7% in the S-1/docetaxel group was significantly superior to 57.4% in the S-1 group (HR 0.715, 95% CI: 0.587-0.871, p = 0.0008) and the 3y OS was 77.7% in the S-1/docetaxel group and that of S-1 group was 71.2%, respectively (HR 0.742, 95% CI: 0.596-0.925, p = 0.0076), confirming the significant improving effect on the survival of the patient. Conclusions: Adjuvant S-1 plus docetaxel is recommended for patients with pStage III gastric cancer who underwent D2 gastrectomy without neoadjuvant chemotherapy. Clinical trial information: UMIN 000010337.