bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting patient response to cancer immunotherapy using quantitative computed tomography based texture analysis.
Authors: Gordon Joshua Ian , Gordon Michael S. , Korn Ronald Lee
Published: September 2018

e14536

Background: Immuno-Oncology (I-O) therapies such as PD-L1/PD-1 antibodies disrupt a protective mechanism for tumor cells to evade the host immune system. To minimize toxicity and cost of care, we aim to determine if quantitative texture analysis (QTA) can be used as a predictive biomarker for response to these new drugs. Methods: A pilot study consisting of 20 cancer patients with metastatic disease who received PD-L1/PD-1 antibodies was performed. The subject pool consisted of 10 subjects (NSCLC 3, Urothelial CA 3, TNBC 1, RCC 3) who achieved objective responses to I-O therapy compared to 10 subjects (NSCLC 5, Urothelial CA 2, Ovarian 1, Pancreatic 1, Cervical 1) with primary progression as their best response. Pre-treatment diagnostic CT scans of the chest, abdomen, and pelvis were analyzed using QTA. A minimum of 1 objectively measurable lesion ( > 10 mm in diameter) per study was identified to undergo QTA. Histogram readouts of tumor texture based upon tissue densities per pixel were obtained. Output values from the QTA provided an estimate of tumor signal properties as expressed as the mean pixel density, standard deviation, entropy, kurtosis, skewness, and mean positive pixel value. Results: There was no identifiable signature when examining all of the lesions together. There was statistically significant correlation noted between QTA and RECIST response for lung lesions (n = 14) based on the mean pixel density. A mean pixel density cutoff of 11.91 at a spatial scale factor of 3 predicted response with a sensitivity of 75% and a specificity of 100%. This achieved a Mann-Whitney Z statistic of 2.6 (p = 0.0092). Conclusions: Despite the small number of patients in this pilot study, there were promising findings when examining the mean pixel density of lung lesions, suggesting that quantitative textural analysis can be used to predict response to PD-L1/PD-1 antibodies. Further investigation is warranted in a larger population that can be differentiated by tumor type to validate these results.
A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.
Authors: Wang Yuzi , Sun Lue , Li Xiaokang , Tsuboi Koji
Published: September 2018

e14541

Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.
Incidence of thyroid function test abnormalities in patients receiving immune checkpoint inhibitor therapy for cancer: A single institution retrospective review.
Authors: Patel Nisha Subhash , Oury Anais , Bazhenova Lyudmila , Daniels Gregory A. , Patel Sandip Pravin
Published: September 2018

e14569

Background: With the advent of immune-checkpoint inhibitor (ICI) therapy, thyroid function test abnormalities (TFTA) are common with reported incidence range of 2-15%. Our aim was to describe the incidence of TFTAs retrospectively in patients (pts) on ICI therapy. Methods: 285 pts reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had thyroidectomy (excluded). Pts received at least one dose of ipilimumab (I) and/or nivolumab (N) or pembrolizumab (P). Post-treatment TFTA was classified according to definitions of thyroid abnormalities when possible. Results: A total of 35% (76/218) pts had new onset TFTAs on ICI. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI. Median time to new onset or exacerbated baseline TFTA were 46 & 33 days respectively. Of note, 65% (20/31) of pts on both I+N had new onset TFTA, compared to 31.3% (15/48) with I, 31.5% (28/89) N, 26% (13/50) P. Conclusions: Incidence of TFTAs with ICI was higher than expected in our pts. Pts with baseline TFTA and/or I+N combination therapy had higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more frequent evaluation of TFT in the first two months, especially in those with baseline TFTA. [Table: see text]
Assay performance of the PD-L1 IHC 28-8 pharmDx assay in squamous cell carcinoma of the head and neck (SCCHN).
Authors: Alvarez Sara , Hanks Debra Ann , William Josette , Chan Joel A. , Felten Christopher L. , Northrup Adam , Jaiswal Dipeshkumar , Jansson Malinka , Phillips Therese , Segal Andrew , Satnick Ilana , McDonald Hendrick , Little Hunter , Pierce Coree , Wynne Bethany , Carnahan Josette , Reddy Swarnalatha Y. , Inzunza H. David , Novotny James , Oroudjev Emin
Published: September 2018

e14588

Background: The PD-L1 IHC 28-8 pharmDx assay has been developed for use in detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-squamous NSCLC and melanoma tissues for associated treatment effect with nivolumab. Validation of the assay for measuring PD-L1 expression level in human squamous cell carcinoma of the head and neck (SCCHN) FFPE sections has been conducted and results are described. Methods: Visualization of the PD-L1 IHC 28-8 pharmDx assay is based on the EnVision FLEX IHC technology. As described in the Instructions For Use, antigen retrieval was performed using the Dako PT Link, and the automated staining was conducted with Autostainer Link 48. The assay performance was validated on commercially procured FFPE SCCHN specimens. Results: Assessment of assay sensitivity to PD-L1 expression was measured on 236 unique specimens originating from squamous cell carcinoma of the tongue, tonsil, nasopharynx, oropharynx, hypopharynx, and larynx. The study demonstrated PD-L1 positive staining across a range of 0-95% positive tumor cells and 0 to 3+ staining intensity. Among these tested specimens, 44% of specimens had PD-L1 expression levels ≥1%. Assay robustness was validated by assessing critical parameters such as target retrieval solution pH, target retrieval solution temperature, target retrieval time, and cut section thickness. Assay reproducibility was evaluated in a study at three external sites. Reproducibility of intra-site, inter-day, and inter-site agreement was assessed in addition to inter- and intra-observer agreement. Assay robustness and reproducibility demonstrated agreement estimates above 85% with values for lower bound 95% confidence intervals calculated above 85%. Conclusions: These studies demonstrate that the PD-L1 IHC 28-8 pharmDx assay is reproducible and robust when used for automated detection of PD-L1 protein in FFPE human SCCHN specimens using Autostainer Link 48.
Clinical and biochemical parameters as predictors of response to checkpoint inhibitors (CPI): A single institution experience.
Authors: Gandhi Shipra , Pandey Manu , Ammannagari Nischala , Wang Katy , Vona Karen L , Nestico Jill , Hamad Lamya , Dy Grace K. , Ernstoff Marc S.
Published: September 2018

e14590

Background: The benefit of CPI is limited to a subgroup of patients. Significant toxicity and financial burden make it imperative to identify biomarkers predictive of clinical benefit. We aimed to analyze if immune related adverse events (irAE), laboratory parameters (besides PD-L1 status), prior chemotherapy and concomitant medication use could predict response to CPI. Methods: 216 consecutive patients treated at RPCI with single/multiple CPI from 2011 to 2016 were identified. Demographics, irAE (CTCAE v4.03), concomitant medication use, response (RECIST v1.1) and laboratory parameters were recorded. Progression free (PFS) and overall survival (OS) were calculated. Clinical benefit (responder) was defined as objective response or stable disease with PFS ≥ 6 months. Statistical analysis was performed using SAS v9.4. Results: 185/216 patients (86%) had clinical outcomes with first CPI available (55.7% melanoma, 28.1% lung, 10.8% kidney, 3.8% bladder, 1.6% others), 14% died before disease assessment. Median age was 61 years; 64% were males. 31% were responders (R); 69% non-responders (NR). Median PFS and OS for R were not reached and for NR were 4.7/7 months (p < 0.001). 26% R developed rash vs. 12% NR (p = 0.02). irAE diarrhea was associated with better OS (p = 0.03); rash with better PFS (p = 0.007) and OS (p = 0.05). Concomitant beta-blocker/NSAID use was noted in 35%/28% R vs 20%/12% NR (p = 0.04; p = 0.01). Higher median absolute eosinophil (AEC) and absolute lymphocyte count (ALC) were noted in R (400 and 2000/µl in R vs. 300 and 1600/µl in NR; p = 0.008 and 0.024). NR were noted to have a higher median lactate dehydrogenase (LDH) of 565 vs. 503 (p < 0.001). AEC > 100/µl and ALC > 1000/ µl were associated with better OS (P = 0.03; P = 0.001). Absolute neutrophil count (ANC) > 7500/µl and leucocyte count > 8750/ µl were associated with inferior PFS (p = 0.005; P = 0.02) and OS (p = 0.002; p = 0.03). Pre-CPI chemotherapy did not correlate with response to CPI. Conclusions: Among irAE, diarrhea and rash predicted improved outcomes. Eosinophilia, lymphocytosis, neutrophilia, leukocytosis and LDH could serve as potential prognostic biomarkers to CPI. Prospective studies are warranted to validate these findings.
Evaluation of tolerability and reactions of immune checkpoint inhibitors.
Authors: Sever Ozlem Nuray , Sonmez Ozlem , Demir Osman Gokhan
Published: September 2018

e14605

Background: Immunotherapies have revolutionized the treatment of cancer, especially in recent years. Today, there are anti-CTLA-4 antibodies and PD-L1 monoclonal antibodies which are active in use as checkpoint inhibitors. Side effects of these agents have a different spectrum in the form of immuno-related side effects. Methods: In this study, we aimed to evaluate the side effect and tolerability in patients treated with immune checkpoint inhibitors in our clinic. Results: 32 patients who were treated with PD-L1 monoclonal antibodies between August 2015 and January 2017 were screened retrospectively in our clinic. Six of the cases had immuno-related side effects (18.75%). 2 patients had a elevated liver function test. Both patients were diagnosed with NSCLC. In both of them, elevation was detected in the second course of nivolumab treatment, and the USG and hepatitis markers of the patients were normal. Enzymes returned to normal after treatment interruption. In a patient diagnosed with malignant melanoma that receiving pembrolizumab colitis was developed after 3th cycles of the therapy. The treatment of the patient who recovered after steroid administration and treatment interruption continued until the 8th cure. In the third cure of the patient with NSCLC, when nivolumab was used pneumonitis was diagnosed. Steroid treatment was applied for 2 weeks. Our patient continued to use nivolumab for up to 22 cycles. In our patient with malign melanoma that treated with pembrolizumab autoimmune thyroiditis developed. We started prednisolone treatment. After recovery our patient's treatment continued. In one of our patient who was diagnosed with malign melanoma, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. Control ejection fractions normalized. Conclusions: İmmuno-related side effects were regarded as manageable side effects and no treatment change was needed. Immune Checkpoint inhibitors, which have been shown to be useful for survival every day, are proceeding to take a favorable position in the treatment of cancer with ease of use and lack of side effects.
Safety and efficacy of concurrent administration of influenza vaccine in patients undergoing anti-PD-1 immunotherapy.
Authors: Kanaloupitis Dimitra Konstantinos , Chandran Anjana , Ralph Alyssa , Thompson Ryan , Richards Jon M. , Hallmeyer Sigrun
Published: September 2018

e14607

Background: Concerns have been raised over administration of influenza vaccination concurrent with immune checkpoint inhibitor therapy, specifically, implication in induction of Guillain-Barre syndrome. The aim of this study is to assess the safety and efficacy of influenza vaccination in patients undergoing anti-PD1 therapy. Methods: This is a prospective observational study evaluating the safety and efficacy of Afluria (Seqirus) in patients receiving anti-PD1 therapy. Antibody titers against common influenza A and B antigens were measured by a semi-quantitative ELISA on days 0, 45 and 90+ post vaccine administration to confirm anti-PD1 therapy did not interfere with anti-influenza humoral responses. Influenza infection, confirmed by rapid antigen testing, and influenza-related hospitalizations were reported among vaccinated patients. Safety was assessed using the FDA toxicity grading scale for clinical trials. Results: The acute humoral responses and subsequent IgG responses of the 28 patients included in this study are as follows in the table. IgM responses at 45 days to both influenza A and B common antigens were statistically significant (all P<0.05*). IgG response to common influenza B antigens was increased at day 45 ( P=0.001*). One of 28 patients contracted influenza B infection, confirmed by rapid antigen testing. There were no influenza-related hospitalizations. One patient had a grade 2 local adverse event (AE). A second patient had both a grade 2 local and a grade 2 systemic AE (myalgia). No grade 3/4 local or systemic AEs were reported. Conclusions: Administration of influenza vaccination concurrent with anti-PD1 therapy appeared safe in our study. No grade 3/4 local or systemic AEs were noted. Anti-PD1 therapy did not adversely affect anti-influenza humoral responses. Our data demonstrate that the increase in IgM reactivity to common influenza A and B antigens appears to be an immediate reaction to revaccination. Seroprotection can be inferred by documented infection in only one patient and absence of influenza related-hospitalizations. [Table: see text]
Specific adaptive immune pattern induced by NBTXR3 exposed to radiation therapy in soft tissue sarcoma (STS) patients.
Authors: Galon Jerome , Laé Marick , Papai Zsuzsanna , Rochaix Philippe , Mangel Laszlo Csaba , Mlecnik Bernhard , Hermitte Fabienne , Sapi Zoltan , Delannes Martine , Tornoczky Tamas , Vincent-Salomon Anne , Bonvalot Sylvie
Published: September 2018

e14615

Background: NBTXR3 are functionalized hafnium oxide nanoparticles, undergoing seven clinical trials for enhancing radiation therapy (RT). The high electron density of the nanoparticles, when exposed to radiotherapy (NBTXR3 + RT), allow absorption/deposition of a high radiation dose within the cancer cells to physically kill the cells, and possibly improve outcome. Besides, NBTXR3 + RT has shown subsequent ability to enhance immunogenic cell death and immune response in preclinics. We hypothesized that NBTXR3 + RT could trigger an enhanced immune response when compared to RT in patients with STS. Methods: Tumor tissues pre- (biopsy) and/or post-treatment (resection) were collected from patients (pts) with locally advanced STS, who received either NBTXR3 as intratumor injection and RT (14 pts) or RT (12 pts), as preoperative treatment (NCT02379845). Immunohistochemistry and Digital Pathology for immune biomarkers and for Immunoscore (CD3/CD8) were analyzed. Gene expression profiling and pre-optimized immune-gene signatures called Immunosign were also used. Results: A significant increase of T cells (CD3+, CD8+) and a marked increase of CD103+ immune cell infiltration post- vs pre-treatment were observed for NBTXR3 + RT ( P< 0.01), while no differences were seen for RT. Post-treatment, an increased Immunoscore (CD3 + CD8 cell densities) was observed for NBTXR3 + RT compared to RT (P < 0.07). Consistently, the up-regulation of pan immune genes expression and specifically expression of adaptive immunity genes between pre- and post-treatment, was pronounced for NBTXR3 + RT when compared to RT. Functional analysis of genes up-regulated in NBTXR3 + RT showed an enrichment of cytokine activity (IL7, IFNA, IL16, IL11, IFNG), adaptive immunity (RAG1, GZMA, TAP1, TAP2, TBX21, STAT4, IFNG, LCK, LTK, CD37, CD22) and T cell receptor signaling pathway (CD28, CTLA4, CD274, BTLA, TIGIT, CD40LG, CD5, CD3E, ZAP70). Conclusions: NBTXR3 + RT induces a specific adaptive immune pattern. As such, it may contribute to convert “cold” tumor into “hot” tumor and be effectively combined with immunotherapeutic agents across oncology. These data warrant more tissue samples evaluation to reinforce these findings.
5 x 5 Gy and consolidation chemotherapy vs long-course preoperative chemoradiation for locally advanced rectal cancer: An interim analysis of a randomized phase III study.
Authors: Jin Jing , Liu Shixin , Zhu Yuan , Wang Wenling , Wang Xin , Wang Jun , Li Gaofeng , Fan Lin , Zhang Kuan , Shi Mei , Tang Yuan , Zhang Haizeng , Chi Yihebali , Zhou Ai-Ping , Huang Jing , Zhang Hongmei , Jiang Liming , Jiang Jun , Zou Shuangmei , Li Ye-Xiong
Published: September 2018

e15006

Background: To present an interim analysis of a phase III trial comparing short-course radiotherapy followed by chemotherapy with long-course chemoradiotherapy in locally advanced rectal cancer. Methods: Patients with distal or middle third, MRI diagnosed cT3-T4 or N+ rectal adenocarcinomas were randomized to either 5 x 5 Gy and 4 courses of CAPOX (experimental group) or 50 Gy delivered in 25 fractions given concurrently with capecitabine (control group). Total mesorectal excision (TME) in both groups was performed 6-8 weeks after neoadjuvant treatment. This is an interim analysis of acute toxicities for the first 127 patients who finished neoadjuvant therapy, as well as the pCR and surgical complications for the first 100 patients who received surgery. Results: From 08/30/2015 to 12/11/2016, 63 patients in experimental group and 64 in control group from 10 Chinese hospitals were analyzed. During preoperative treatment, any acute toxicities were 100% in both groups and grade III-IV 19.0% vs. 6.3% ( p= 0.03) in experimental group and control group, respectively. Full-dose completion rates of planned neoadjuvant treatment were 88.9% and 93.7% in each group ( p= 0.33), respectively. After median duration of 7 weeks and 9 weeks in experimental group and control group, TME was performed. Among the 100 patients who have finished surgery, 94.1% and 89.8% in experimental and control group had R0 resection ( p= 0.426), while 21.6% and 6.1% of them achieved pCR ( p= 0.026), respectively. There were 8 patients in experimental group diagnosed as clinical CR and refused to further radical surgery, while, none in control group ( p= 0.003). The incidences of surgical complications were similar between two groups (experimental 29.1% vs. control 26.5%; p= 0.748), with perineal healing delay as the main reason. Conclusions: The acute toxicity and surgical complication were acceptable and comparable in both groups, however, the people in experimental group showed a significantly clinical and pathological response. The short-course irradiation and consolidation chemotherapy maybe an alternative standard of care, though the final result is in prospect. Clinical trial information: NCT02533271.
Adoptive transfer of NK cells in combination with chemotherapy to improve outcomes of patients with locally advanced colon carcinoma.
Authors: Li Lingyu , Cui Jiuwei , Wang Chang , Wang Yizhuo , Niu Chao , Yao Cheng , Tian Huimin , Jin Haofan
Published: September 2018

e15038

Background: The prognosis of advanced colon cancer (CC) patients remains disappointing, partly due to their greater proportion of CC-initiating cells (CICs), which is responsible for cancer drug-resistance and immune escape. Immunotherapies by harnessing the immune system to eliminate tumors have attracted broad attention. This study was to detect whether chemotherapy could enhance cytotoxicity of natural killer (NK) cells to CC cells (CCs), especially for CICs in vitro, and further evaluate the efficacy and safety of NK-cell therapy combined with chemotherapy in patients with local advanced CC. Methods: We observed that cytotoxicity of NK cells to CCs and CICs pretreated with 5-Fu or oxaliplatin. Then, an open-label pilot cohort study was conducted with local advanced CC patients who had received surgical excision. 60 patients elected to receive either NK-cell therapy combined with chemotherapy (NK-cell group, 27 patients) or pure chemotherapy (control group, 33 patients). Progression-free survival (PFS), overall survival (OS) and adverse effects were investigated. Results: Chemotherapy sensitized CCs and CICs to NK cell lysis through upregulation of their NK cell activating ligands and reducing inhibitory ligands. Poorly differentiated CCs were more susceptible to NK-cell than well-differentiated CCs, and CICs were more easily to be killed by NK cell than their differentiated CCs. In the cohort study, the 5-year PFS and OS rates in the NK-cell group were significantly higher than those in the control group (51.1% vs. 34.9%, p= 0.043; 73% vs. 51.3%, p= 0.038, respectively).Among patients with poorly differentiated carcinomas or low expression of HLA-1, median PFS in the NK-cell group vs. the control group was 23.5 vs. 11.5 months ( p= 0.047), and median OS was 30 vs. 15 months ( p= 0.043), respectively. No significant adverse reaction was found during NK-cell therapy. Conclusions: NK-cell therapy in combination with chemotherapy in locally advanced CC prevented recurrence and prolonged survival with acceptable adverse effects, especially for poorly differentiated carcinomas.
A phase II study of capecitabine, oxaliplatin and irinotecan (XELOXIRI) as salvage therapy in patients with refractory metastatic colorectal cancer.
Authors: Kwok Gin Wai , Leung Roland Ching-Yu , Chiu Joanne , Tang Vikki , Yau Thomas Cheung
Published: September 2018

e15049

Background: Advanced colorectal cancer (CRC) refractory to oxaliplatin, irinotecan, and fluoropyrimidines is associated with poor prognosis. The triplet combination of 5-fluorouracil, oxaliplatin, and irinotecan has shown efficacy and tolerability in treatment-naive disease. We investigated the efficacy and tolerability of salvage capecitabine, oxaliplatin and irinotecan (Xeloxiri) in patients who progressed on standard chemotherapy. Methods: This prospective phase 2 study with a primary endpoint of overall response rate (ORR) recruited patients with advanced CRC that have progressed on standard chemotherapy containing fluoropyrimidines, oxaliplatin, and irinotecan either as monotherapy or doublets. Prior use of anti-VEGF, and anti-EGFR agents were allowed. Patients received capecitabine 1250mg/m2 twice daily on day 1-7, oxaliplatin 85mg/m2 and irinotecan 165mg/m2 on day 1 every 2 weeks until disease progression or intolerable toxicity. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: Between July 2011 and May 2016, we recruited 32 patients. Median age was 57 and the median number of treatment cycles was 6. 16 patients (50%) were K-RAS wild-type (WT), of which 6 were also N-RAS WT. The ORR was 25% and the clinical benefit rate was 56%. 87.5% of patient received targeted therapy prior to study entry. 34% of patients had > 3 previous lines of therapy. Median PFS and OS were 5.0 months (95% CI 3.2 - 7.1) and 10.4 months (95% CI 7.2 - 11.4) respectively. K-RAS mutation status, number of lines of previous therapy, and site of primary tumour were not predictive of ORR, PFS or OS on univariate testing. Treatment-related adverse events (AEs) occurred in all patients, with the majority being hematological. Dose reductions occurred in 87.5% of patients. 59% required dose delays, and 56% received granulocyte-colony stimulating factor. Grade 3/4 AEs included neutropenia (34%), anemia (16%), thrombocytopenia (12.5%), febrile neutropenia (9%), diarrhea (6%), and anorexia (3%). Conclusions: Xeloxiri is efficacious and safe in patients with chemo-refractory CRC and is a promising treatment strategy as salvage. Clinical trial information: in progress.
Association of microsatellite instability with distinct clinical and molecular characteristics in resected colon cancer: Analysis of a platform trial of the AIO colorectal study group—Colopredict Plus.
Authors: Reinacher-Schick Anke C. , Juette Hendrik , Noepel-Duennebacke Stefanie , Arnold Dirk , Basara Nadezda , Boehner Hinrich , Dahm Thorsten , Feder Inke Sabine , Hansen Olaf , Hiller Wolfgang , Leins Alexander , Müller Lothar , Ueberrueck Torsten , Teschendorf Christian , Trenn Guido , Verdoodt Berlinda , Zwingmann Nadine , Uhl Waldemar , Tannapfel Andrea
Published: September 2018

e15086

Background: High microsatellite instability (MSI-H) is a prognostic marker in resected colon cancer (CC) identified in post-hoc analysis of multiple trials. However, validation in real-life cohorts and its association with clinical and molecular markers is lacking. Methods: In Sep 2013 we started a platform trial in 49 German cancer centers recruiting patients with UICC stage II and III CC diagnosed between 2008 to 2016. MSI was tested by immunohistochemistry (IHC) of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. In case of any loss of protein expression (IHC neg), fragment length analysis (FLA) was performed, defining MSI high tumors (MSI-H) and MS stable tumors (MSS). Besides, mutations in known prognostic factors for CC such as RAS, BRAF, PI3K and others were determined by next generation sequencing (NGS). Results: By end of 2016, 1249 patients have been recruited into the trial: median age 73yrs., stage II/III: 686/563 pts. So far, tissue was analysed in 512 pts. Of these, 182 pts. were IHC neg with 116 pts. tested MSI-H upon FLA (22.7%). Median age was 73yrs., female/male: 260/252 pts., stageII/III: 292/220 pts. Association of MS status with clinical factors is shown in Table 1. Upon NGS analysis we found 16.3% BRAF mutations, 39% KRAS mutations, 2.8% NRAS mutations and 22.6% PI3K mutations. MSI-H status was significantly associated with BRAF mutation and wildtype status of RAS. Conclusions: We found a higher percentage of MSI-H cancers in our registry compared to reported data from randomised trials, possibly related to a higher median age in this real-life cohort. MSI-H was associated with female sex, primary tumor site, and distinct molecular markers and should therefore be considered a heterogeneous subgroup of CC. Updated analysis including NGS data and survival will be presented at the meeting. Clinical trial information: AIO- KRK-0413, DKRS:00004305. [Table: see text]
Genomic overview of right-sided and left-sided colorectal cancer using comprehensive genomic sequencing.
Authors: Shimada Yoshifumi , Kameyama Hitoshi , Nagahashi Masayuki , Ichikawa Hiroshi , Yagi Ryoma , Tajima Yosuke , Yuza Kizuki , Nakano Masato , Nakajima Masato , Ishikawa Takashi , Sakata Jun , Kobayashi Takashi , Nogami Hitoshi , Maruyama Satoshi , Takii Yasumasa , Ring Jennifer E. , Lyle Stephen , Okuda Shujiro , Takabe Kazuaki , Wakai Toshifumi
Published: September 2018

e15101

Background: Although the difference in right vs. left sidedness of colorectal cancer (CRC) in response to targeted therapy has been reported, we hypothesized that right-sided colorectal cancer (RCC) is more likely to have genetic alterations associated with resistance of anti-EGFR therapy. We tested this hypothesis using comprehensive genomic sequencing (CGS) on a set of samples from well-characterized CRC patients. Methods: Two-hundred-one primary colon cancer patients with either RCC or left-sided colorectal cancer (LCC) were analyzed. We investigated gene alterations using 415 gene panel, which includes the gene alterations associated with resistance of anti-EGFR therapy: TK receptors ( ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway ( KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway ( PTEN and PIK3CA). We defined the patients who had no alterations in any of the genes as “all wild-type”, who are theoretically considered as responders of anti-EGFR therapy. Other patients with genetic alterations in resistance pathways were defined as “mutant-type”. Results: Fifty-six patients (28%) and 145 patients (72%) had RCC and LCC, respectively. Mutation of PIK3CA, BRAF, ACVR2A, MSH6, and CTNNB1 were significantly associated with RCC. Conversely, mutation of APC and TP53 were significantly associated with LCC. Regarding the gene alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) of RCC were “all wild-type”; in contrast to 41 of 145 patients (28%) of LCC that were “all wild-type” ( P = 0.009). In 45 Stage IV patients treated with anti-EGFR therapy, RCC showed significantly worse progression-free survival (PFS) than LCC ( P = 0.019), and “mutant-type” RCC showed worse PFS compared to the others ( P = 0.018). Conclusions: RCC is more likely to have the genetic alterations associated with resistance of anti-EGFR therapy compared to LCC. Primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes in CRC.
The relationship between Pim-3 expression and chemoradiotherapy resistance in locally advanced rectal cancer patients.
Authors: Zhang Rong-xin , Zhou Zhongguo , Lu Shi-xun , LU Zhen-hai , Wan Desen , Pan Zhi-zhong , Wu Xiao Jun , Chen Gong
Published: September 2018

e15112

Background: It is difficult for clinical oncologists to predict which types of rectal cancer patient would respond to neoadjuvant chemoradiotherapy. About 30% of rectal cancer patients who could not benefit from chemoradiotherapy, and about 10% of patients even suffered from disease progression. It is of considerable importance to identify a bio-marker to identify patients who would benefit from neoadjuvant treatment. Methods: This study enrolled 175 rectal cancer patients who underwent neoadjuvant treatment. Tissue samples from all the patients were deposited in the tissue bank of Sun Yat-sen University Cancer Center prior to neoadjuvant treatment. We compared the expression of Pim-3 in rectal tumors and investigated correlations with the response to chemoradiotherapy and with survival. Results: The Pim-3-negative patients were more likely to achieve a pathological complete response to chemoradiotherapy (P = 0.001, RR = 5.132, 95% CI: 2.442–10.787). Cox multivariate analysis in 137 patients with at least 24 months follow-up showed that the expression of Pim-3 (P = 0.041, RR = 1.209, 95% CI = 1.007–1.452) and cycles of neoadjuvant chemotherapy cycles (P = 0.006, RR = 0.557, 95% CI = 0.367–0.845) were significant factors affecting the survival status of patients. Cox multivariate analysis of disease-free survival showed that Pim-3 expression (P = 0.012, RR = 1.180, 95% CI: 1.037–1.344) and adjuvant chemotherapy cycles (P = 0.003, RR = 0.745, 95% CI: 0.615–0.902) were statistically significant factors. Conclusions: Pim-3 could be a potential predictive bio-marker of the response to chemoradiotherapy.
Mucinous colorectal carcinoma: A single center experience.
Authors: Oksuzoglu Berna , Zengin Guliz , Turker Ibrahim , Demirci Umut
Published: September 2018

e15116

Background: The aim of this study was to evaluate the clinical features and treatment outcomes of mucinous colorectal adenocarcinoma (MCA) followed in a single institution. Methods: Seventy-nine patients diagnosed with MCA admitted to our center between January 2003 and August 2016 included in this study. Demographic and clinico-pathologic characterictics of patients were analysed using patient medical records retrospectively. Results: Median age of the patients was 57 (24-83) with a male to female ratio of 1/3. Common symptoms were abdominal pain, rectal bleeding, abdominal distention, tenesmus and constipation in 44 (55.7%), 17 (21.5%), 7 (8.9%), 6 (7.6%), 5 (6.3%) of patients respectively. At the time of the diagnosis ECOG performance score was 0 or 1 in 74 (93.7%) of the patients. One (1.3%), 26 (32.9%), 37 (46.8%) and 15 (19%) of the patients had stage 1,2,3 and 4 disease respectively. Neoadjuvant chemo-radiotherapy with 5 FU and leucovorin (FUFA) was the treatment of choice in 11 (13.9%) of rectal MUC patients. The type of surgery was curative, palliative and emergent in 60 (76%), 9 (12.4%) and 9 (12.4%) respectively. Localisation of the primary tumor was right colon, left colon and rectum in 31 (39.2%), 30 (38%) and 18 (24.8) patients respectively. In the adjuvant setting, 59 (74.7%) of patients were received adjuvant chemotherapy. Only 6 patients had MSI, 26 patients had k-RAS, n-RAS and b-RAF mutation results. Metastatic sites were mostly visceral organ, intra-abdominal and local recurrence in 13 (16.5%), 12 (15.2%) and 6 (7.6%) of patients respectively. The median disease free survival, progression free survival and overall survival (OS), were 15.5 months, 17.5 months and 44.1 months, respectively. Conclusions: Survival rates were higher than literature in this study. This may be partly explained by better ECOG performance score of our patient group. We also found that better ECOG score, left sided tumor, younger age, were associated with better OS.
Association of LAG-3 expression in tumor infiltrating immune cells with prognosis in patients with microsatellite instability high colon cancer.
Authors: Lee Soo Jung , Kim Jong Gwang , Chae Yee Soo , Kang Byung Woog , Lee In Hee , Yoon Ghil Suk , Jun Sun-Young
Published: September 2018

e15126

Background: Recent findings demonstrated that microsatellite instability high (MSI-H) colon cancer contains high T-cell infiltration and upregulated expression of multiple immune checkpoints. The aim of this study was to reveal the prognostic impact of MSI-H colon cancer showing immune checkpoint protein expressions, which are good candidates for immunotherapy. Methods: From January 2011 to April 2015, we included 98 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Medical Center. Inhibitory receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1) and indolamine 2’3’-dioxygenase (IDO) expression status were retrospectively analyzed using immunohistochemistry (IHC). Positivity in tumor cells (T) and immune cells (I) were separately evaluated. IHC values were determined to be positive when moderate or strong intensity of the membranous to cytoplasmic staining pattern were shown in more than 5% of the tumor cells or immune cells. Results: Among the 93 patients, 22 patients (23.9 %) and 63 (68.5%) were determined as PD-L1(T) positive and PD-L1 (I) positive, while 12 (13.2%) and 42 (45.7%) were determined as LAG-3(I) positive and PD-1 (I) positive. Twenty-seven patients (29.3%) and 66 (71.7%) were determined as CTLA-4 (T) positive and CTLA-4 (I) positive, while 66 (71.7%) and 26 (28.3%) were determined as IDO (T) and IDO (I) positive. During median follow-up duration of 39 months, 16 (17.4%) patients experienced recurrence. LAG-3 (I) positivity was significantly associated shorter relapse-free survival (p = 0.016). Moreover, LAG-3 expression was significantly correlated with PD-L1 (T) expression (p = 0.003). Co-expression of PD-L1 and LAG-3 showed worse prognosis for relapse-free survival (p < 0.001). Conclusions: In conclusion, LAG-3 positivity showed worse prognosis in patients with MSI-H colon cancer. Potential differential therapeutic implications LAG-3 should be further investigated.
Short course radiotherapy (SCRT) and delayed surgery by 8-10 weeks for MRI defined high-risk rectal cancer.
Authors: Al-Hajri Thuraiya Nasser , Wells Lucy , Samuel Leslie M.
Published: September 2018

e15145

Background: Pelvic MRI can identify rectal cancer patients at risk of an incomplete (R1) resection, allowing pre-operative treatment, usually with pelvic chemo-radiotherapy (CRT) over 5 weeks. Co-morbidities (eg IHD) may make CRT high risk, & SCRT with delayed surgery 8-10 weeks later may be an option, but with relatively little published data on efficacy. Methods: Between 2004 & 2016 our database identified 573 patients with MRI defined high risk rectal adenocarcinomas, and 55 (9.6%) had SCRT & delayed surgery. Results: Patient characteristics: m 35, F 20, mean age 75 years (55- 90). Main co-morbidities were active IHD & frailty. Major post-operative complications were an anastomic leak in 1 (1.8%) patient & septicaemia/shock in 1 (1.8%) patient, with the latter being the only 30 day post-operative death (1.8%). The R1 resection rate was 7 (12.7%), affecting the circumferential resection margin (CRM) in 6, with 2 subsequently developing local recurrence. 4 CRM +ve patients are dead, all of systemic relapse. Distal margin involved in 1 patient, alive with no recurrence on follow up. Local recurrence (with systemic relapse) occurred in 1 patent with a clear CRM, 4 years after SCRT/surgery. Overall local recurrence rate was 5.4%. Pathology response was minimal 4 (7.3%), partial 28 (51%), good partial 15 (27%), & complete (pCR) 8 (14.5%). The 5 year disease specific survival rates, accepting small numbers in each group, were 60% for minimal, 96% for partial, 93% for good partial & 100% for pCR patients respectively. Systemic relapse occurred in 12 (22%) patients, with liver surgery & liver ablation in 2 patients respectively. 18 (33%) patients have died, 10 of infection, 2 of IHD, 2 of progressive disease, 2 of separate cancers, & 2 unknown. Conclusions: In a MRI defined high risk rectal cancer population & co-morbidities, the outcomes from SCRT with delayed surgery 8-10 weeks later are similar to CRT, & a reasonable option to consider.
Poor prognosis in patients with resectable KRAS-MUT colorectal liver metastases is improved by adjuvant hepatic arterial infusion chemotherapy.
Authors: Gholami Sepideh , Boucher Taryn Mary , Kemeny Nancy E. , Gonen Mithat , Cercek Andrea , Kingham T. Peter , Balachandran Vinod P. , Allen Peter J. , DeMatteo Ronald P. , Jarnagin William R. , D'Angelica Michael Ian
Published: September 2018

e15161

Background: Patients with KRAS-mutated colorectal cancer liver metastases (CRLM) have worse outcomes after resection. Adjuvant hepatic artery pump chemotherapy (HAIC) improves overall survival. We investigated the impact of HAIC in relation to KRAS mutational status in patients with resected CRLM. Methods: Patients with resected CRLM treated with and without adjuvant HAIC and available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospective institutional database. Correlations between KRAS status, adjuvant HAIC, clinical factors, and overall survival (OS) were analyzed. Cox proportional hazard model was used to adjust for confounders. Results: Between 1993-2012, 675 patients (419 KRAS-WT, 256 KRAS-MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAIC. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAIC group, however, there were more patients with extrahepatic metastases in the no-HAIC group. Adjuvant HAIC was associated with improved OS in both KRAS-WT (5-yr OS 76% vs 57%, HR 0.51, p<0.01) and KRAS-MUT (5-yr OS 59% vs 40%, HR 0.56, p<0.01) patients. On multivariate analysis, HAIC remained associated with improved OS (HR 0.6, p<0.001) independent of KRAS status and other clinico-pathologic factors. Conclusions: Adjuvant HAIC after resection of CRLM is independently associated with improved OS regardless of KRAS status and may abrogate the poor prognosis in resectable KRAS-MUT CRLM. [Table: see text]
Peri/post-operative chemotherapy of oxaliplatin combined with S-1 (SOX) versus post-operative oxaliplatin with capecitabine (XELOX) in locally advanced gastric cancer: RESOLVE Trial.
Authors: Ji Jiafu , Liang Han , Xue Yingwei , Shen Lin , Wang Yanong , Zhou Zhiwei , Yu Jiren , Du Yian , Li Guoli , Chen Lin , Xiao Gan , Wu Dan , Dang Chengxue , Zhou Yanbing , He Yulong , Zhang Zhongtao , Li Yong , Li Ziyu , Zhang Xiaotian
Published: September 2018

e15519

Background: Peri-operative treatment of locally advanced gastric cancer (LAGC) has always been argued. We aim to compare the survival benefit and safety for SOX as peri-opertative therapy versus SOX or XELOX as postoperative therapy after D2 dissection. Methods: RESOLVE is a phase III trial investigating effects of post-operative SOX and XELOX, and peri-operative SOX on LAGC. RESOLVE is the first RCT investigating different therapeutic timeframes in gastric cancer patients with stratification by Lauren classification. Clinical trials JCOG 0501 and RESOLVE exploring optimal chemotherapy modalities are compared in the table below. Results: The study enrolled the first patient in Aug 2012. By Dec 31, 2016, a total of 1061 patients were recruited. Currently 136 patients have died (arm A: 54; arm B: 44; arm C: 37) and 187 patients are under treatment (arm A: 60; arm B: 61; arm C: 66). Conclusions: The patient recruitment has completed and events of DFS will be achieved in 2 years. Clinical trial information: NCT01534546. [Table: see text]
RNA sequencing to highlight the heterogeneity in circulating exosomes from patients with esophageal squamous cell carcinoma.
Authors: Yang Lin , Zheng Wenjing , Wang Zheng , Ding Peikun , Ling Lijuan , Chen Bin , Zhai Rihong
Published: September 2018

e15546

Background: Dissecting tumor heterogeneity is crucial for understanding tumor prognosis, response to therapy, and metastasis. But current tissue biopsy-based strategies for characterizing molecular heterogeneity are invasive and may be confounded by intra-tumor heterogeneity. Here we explore whether exosomes that contain bioactive molecules from the cell of origin can provide new noninvasive means to delineate the heterogeneity of human cancers. Methods: We used RNA-sequencing (RNA-seq) to perform unbiased profiling of mRNAs and long noncoding RNAs (lncRNAs) in plasma exosomes isolated from patients with esophageal squamous cell carcinoma (ESCC, n = 6), patients with esophagitis (n = 6), and healthy controls (n = 6). Results: The number of expressed genes detected in our data set is 63355, including 29615 lncRNAs. We found that exosomes from ESCC have dramatically distinct transcriptome and lncRNA landscapes from that of esophagitis and healthy controls, with 2278 genes and 584 lncRNAs showing differential expression between ESCC and controls; and 854 genes and 126 lncRNAs displaying differential expression between ESCC and esophagitis. We also observed variable expression of diverse transcriptional patterns related to immune response, signal transduction, cell mobility, and transmembrane protein binding, as well as differentially expressed 953 lncRNAs between Stage I and Stage II ESCC samples. Finally, we discovered that both gene and lncRNA expression profiles are variably across exosomal samples from different ESCC patients. Conclusions: Our data reveals that exosomes from ESCC contain distinct transcriptional and lncRNA profiles that separate ESCC from benign esophagitis and healthy controls. Our analysis also identifies unappreciated molecular heterogeneity in exosomes of ESCC, which may pave the way for using exosomal RNA-seq to decode molecular heterogeneity in cancers.
Escape of gastric cancer cell from metabolic stress via DLC3/MACC1 axis.
Authors: Lin Li , Pan Changqie , Li Xiaoyin , Liu Yantan , Wang Chunlin , Zhao Yang , Shi Min , Liao Wangjun
Published: September 2018

e15550

Background: Metabolic stress usually occurs in rapidly proliferating cells when energy demand exceeds supply. Interestingly, cancer cells can somehow sustain the stress and get rid of it. The mechanisms remain unclear. Previously we discovered that MACC1 is an oncogene promoting gastric cancer (GC) growth and metastasis. Besides, it is upregulated by metabolic stress and promotes glycolysis [2014 ASCO annual meeting abstract e15054 & Oncogene 2015;34(21)]. In current study, we aim to further discover how it helps GC cell metabolize and metastasis. Methods: MACC1 and its correlated gene expression were analyzed via immunohistochemistry staining in GC patients. The mRNA and protein expressions were evaluated under glucose deprivation-induced metabolic stress in human GC cell lines. Cell metabolism, motility, invasiveness and viability were analyzed in GC cells. Promoter luciferase assay and Electrophoretic mobility shift assay (EMSA) were performed to confirm the transcriptional regulatory signals. Results: MACC1 expression is found to be negatively correlated with DLC3 in GC patients and DLC3 low expression indicates an adverse prognosis. Silencing DLC3 significantly promotes MACC1 expression, while silencing MACC1 showed no influence on DLC3, indicating that DLC3 is an upstream regulator of MACC1. Intriguingly, DLC3 is found significantly downregulated under metabolic stress in GC. Silencing DLC3 promotes GC migration and invasion via epithelial to mesenchymal transition (EMT), whereas overexpressing DLC3 demonstrates opposite functions. Moreover, DLC3 suppresses GC cell glycolysis but increases reactive oxygen species production and the mitochondrial membrane potential, which lead to more apoptosis. These DLC3 suppressive effects on GC are reversed by MACC1. Promoter luciferase assay and EMSA show that DLC3 inhibits MACC1 expression in a transcriptional manner, which is regulated via RhoA/JNK/c-JUN signaling. Conclusions: Metabolic stress transcriptionally upregulates MACC1 expression by suppressing DLC3, which facilitates GC glycolysis and metastasis. DLC3/MACC1 axis is one of the mechanisms that help GC cell escape from metabolic stress.