Double Cancer Research Articles

Is preoperative screening colonoscopy useful in patients with gastric cancer?

290 Background: In patients with gastric cancer (GC), the most common double cancer is colorectal cancer (CRC). However, the meaning of screening colonoscopy has not been established. The aim of this retrospective study was to evaluate the useful of screening colonoscopy in preoperative patients with GC. Methods: This study included 689 patients who received screening colonoscopy before gastric surgery between 2012 and 2016. Multivariate analysis using logistic regression model was conducted to elucidate independent risk factors of CRC. Then, we investigated the clinicopathological factors for CRC. Results: Colorectal adenomas and CRC were observed in 315 patients (46%) and 37 patients (5.4%), respectively. The clinical T classification of the CRC were as follows; Tis: 24 patients (65%), T1: 8 patients (21%), T2: 2 patients (6%), and T3: 3 patients (8%). In multivariate analysis, male (OR 5.04, 95% C.I. 1.29-19.6, p = 0.020) was revealed as risk factor for affecting CRC. The treatments for CRC were as follows; EMR was performed in 27 patients, simultaneous resection with GC was performed in 9 patients, resection after gastrectomy was performed in 1 patient, respectively. Pathological stage of CRC was as follows; Stage 0: 24 patients, Stage I: 10 patients, and Stage IIA: 3 patients, respectively. As for the patients who underwent surgery for CRC, all of them received radical colectomy. No patient died for CRC who received colonoscopy before gastric surgery. Conclusions: Screening colonoscopy is useful for GC patients. Because most of the synchronous CRC were found early stage and curatively treated.

A case of double bile duct cancer that developed 49 years after cystoduodenostomy for congenital biliary dilatation

A case of double bile duct cancer that developed 49 years after cystoduodenostomy for congenital biliary dilatation

Double Cancers of Gallbladder and Distal Bile Duct Associated with Pancreaticobiliary Maljunction

Double Cancers of Gallbladder and Distal Bile Duct Associated with Pancreaticobiliary Maljunction

A Case of Resected Double Cancer Involving a Retroperitoneal Undifferentiated Pleomorphic Sarcoma and an Ascending Colon Cancer

A Case of Resected Double Cancer Involving a Retroperitoneal Undifferentiated Pleomorphic Sarcoma and an Ascending Colon Cancer

超音波気管支鏡ガイド下針生検（EBUS-TBNA）により診断した肺腺癌と甲状腺乳頭癌の同時性重複癌の1例

超音波気管支鏡ガイド下針生検（EBUS-TBNA）により診断した肺腺癌と甲状腺乳頭癌の同時性重複癌の1例

S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis

BackgroundPIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations.MethodsA Pik3caH1047R;Trp53R270H;MMTV-Cre double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis.ResultsWe found Pik3caH1047R and Trp53R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified S100a4 as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial–mesenchymal transition (EMT)-signature positive and S100a4-expressing cells. CRISPR/CAS9-mediated knockout of S100a4 in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for S100a4 in metastasis.ConclusionsPik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

Abstract NT-109: VAL-083 (DIANHYDROGALACTITOL) SYNERGIZES WITH PARP INHIBITORS IN BRCA-PROFICIENT AND BRCA-DEFICIENT OVARIAN CANCER MODELS

Abstract BACKGROUND: Ovarian cancer is normally treated with platinum (Pt)-based chemotherapy, but patients frequently develop Pt-resistance. Dysfunctional p53 is implicated in Pt-resistance, comprising a therapeutic challenge in high grade serous ovarian carcinoma (HGSC), where p53 is universally mutated (96%). Attempts to overcome Pt-resistance in HGSC include agents blocking the DNA repair pathways, most notably the PARP inhibitors (PARPi), leading to the accumulation of DNA double strand breaks (DSBs) and cancer cell death. Sensitivity to PARPi is correlated with deficiencies in the homologous recombination (HR) DNA repair system, which is in charge of accurately repairing DSBs. BRCA1 and BRCA2 are key proteins in HR, and mutated BRCA1/2 (present in 20% of HGSC) are well-established biomarkers for PARPi sensitivity. PARPi treatment of Pt-sensitive gynecologic malignancies have improved progression free survival (PFS); however, improvements in overall survival have not been achieved and a 5-year survival rate of only 40% remains in ovarian cancer. Additionally, resistance to PARPi in the clinical setting is emerging as a significant medical challenge. VAL-083 is a first-in-class bifunctional DNA damaging agent with demonstrated clinical activity against a range of cancers, including ovarian. VAL-083 rapidly induces interstrand cross-links at guanine-N7 leading to DSBs, activation of the HR repair pathway and cancer cell death. Notably, VAL-083 induces cell death through two parallel pathways - one p53-independent and one p53-dependent. We have shown that VAL-083 is able to overcome cisplatin-resistance in a panel of ovarian cancer in vitro models, independent of p53 status. We have also shown that VAL-083 maintains activity independent of prominent DNA repair mechanisms such as O6-methylguanine DNA methyltransferase (MGMT), non-homologous end-joining (NHEJ) and mismatch repair (MMR) implicated in resistance to numerous chemotherapeutics, including cisplatin and PARPi. Cancer cells thus rely heavily on functional HR pathway for repair of VAL-083-induced DSBs. This suggests combination therapy with agents further inducing DSBs or blocking their repair, including PARPi. Taken together, these data propose VAL-083's potential for targeting Pt-resistant HGSC and for combination treatment with PARPi. METHODS: In this study, we examined the cytotoxicity of VAL-083 in combination with PARPi (olaparib, niraparib, rucaparib, veliparib or talazoparib) against HR-proficient and HR-impaired ovarian cancer cells. VAL-083 cytotoxicity alone and in combination with PARPi was investigated using the 5-day MTT assay in HR-proficient (control siRNA) and HR-impaired (BRCA1 siRNA knockdown) A2780 ovarian cancer cells. RESULTS: We report increased VAL-083 cytotoxicity against HR-impaired A2780 cancer cells. We further report synergy between VAL-083 and PARPi olaparib, talazoparib and niraparib in both HR-proficient and HR-deficient settings. VAL-083 combination with rucaparib produced synergistic cytotoxicity in the HR-deficient setting, while VAL-083 combination with veliparib was no more than additive. These data demonstrate that VAL-083 can synergize with some PARP inhibitors in both a HR-proficient and HR-deficient setting. CONCLUSION: Our results demonstrate a distinct DNA damaging mechanism for VAL-083, resulting in the ability to overcome cisplatin-resistance, target HR-impaired tumors and overcome MGMT, MMR and NHEJ-related chemoresistance. In addition, VAL-083 synergized with several PARPi, particularly olaparib, rucaparib and talazoparib, in both HR-proficient and HR-deficient ovarian tumor cells. Citation Format: Anne Steino, Guangan He, Jeffrey Bacha, Dennis M. Brown and Zahid H. Siddik. VAL-083 (DIANHYDROGALACTITOL) SYNERGIZES WITH PARP INHIBITORS IN BRCA-PROFICIENT AND BRCA-DEFICIENT OVARIAN CANCER MODELS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-109.

Aberrant Bone Marrow Microenvironment in Therapy Related Myeloid Neoplasm (t-MN)

Introduction: Therapy-related myeloid neoplasm (t-MN) is a lethal second hematological malignancy following chemotherapy (CT) and radiotherapy (RT) for primary cancers. It accounts for 15-20% of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). AML and MDS are considered to be hematopoietic stem cell (HSC)-autonomous disorders, in which initiation and progression are mainly driven by HSC-intrinsic genetic events. However, emerging data suggest that bone marrow (BM) microenvironment plays critical role in initiation and evolution of MDS and AML (Raaijmakers et al., 2010). Malignant clones can also shape the BM-microenvironment conducive for its survival and proliferation (Medyouf et al., Cell Stem Cell 2014). Although CT/RT can damage BM-microenvironment, very limited studies assessed role of BM-microenvironment in t-MN pathogenesis. Aim: To assess BM-microenvironment changes induced by malignant HSC and changes induced by previous genotoxic stress on BM-microenvironment, we compared BM-mesenchymal stromal cells (MSC) from t-MN patients, with BM-MSC from 1) patients with two unrelated cancers, one of the cancer being MDS/AML, without prior exposure to CT/RT (Double cancers, DC), 2) primary MDS patients (pMDS) and 3) age matched healthy controls (HC). Methods: We characterized BM-MSC from t-MN (n=10), DC (n=8), pMDS (n=6) and age-matched healthy controls (n=10). Morphology (Fei et al., 2014), clonogenic potential (Geyh et al., 2013), proliferation (Prata et al., 2010) and cellular senescence was assessed using previously described methodology. Differentiation potential was assessed by the respective lineage cytochemical staining and quantification of positive cells (mineral quantification for osteogenic cells, and Nile red for adipocytes). DNA damage response was determined by assessing H2AX phosphorylation in the MSC. Results: Only 70% of BM-MSC from t-MN cohort could be expanded to passage 6 compared to 100% of MSC cultures from pMDS, DC and HC. Proliferation rate, assessed by population doubling time, and clonogenic potential was significantly reduced in t-MN patients compared to p-MDS, DC and HC (Fig 1Ai-ii). This was further substantiated by higher senescence rates, assessed by β-galactosidase positive cells at passage 3 (HC 7%±1.9%; pMDS 39%±6%; DC 27%±1%; t-MN 68%±4%) (Fig 1B). Together, it demonstrates that MSC from t-MN have significantly impaired proliferation capacity and higher senescence rate compared to HC, pMDS and DC patients. Interestingly, proliferation capacity and senescence rate was not significantly different between MSC from DC and pMDS patients. We also compared DNA damage repair, following sub-lethal dose of RT, in MSC from t-MN, pMDS and HC. DNA damage repair in t-MN MSC was significantly impaired compared to pMDS and HC (Fig. 1F). Impaired DNA repair could be due to pathogenic germline mutation in DNA repair pathways in some t-MN patients (Singhal et al., ASH 2018). Although MSC from pMDS and DC appeared disorganized, they maintain fibroblast-like morphology similar to HC-MSC. Whereas, most of the MSCs from t-MN cases lost spindle shape morphology and were significantly larger than DC, pMDS and HC (p<0.0001; Fig 1C). Further characterization of the MSC's phenotype revealed that ability to form a mineralized matrix was significantly increased in t-MN MSC compared to HC, pMDS and DC (p=0.04; Fig 1Di-ii). In contrast, quantification of lipid-laden Nile-red-stained adipocytes in t-MN MSCs showed a 5-fold decrease in adipocytes formation compared to HC and ~2-fold compare to pMDS and DC (Fig 1Ei-ii). Conclusions: Our data demonstrate that BM-MSCs from patients with myeloid malignancies are significantly abnormal as compared to age-matched healthy controls. BM-MSCs from T-MN patients have significantly reduced proliferative, clonogenic and DNA repair capacity and have higher senescence rate as compared to BM-MSCs from patients with double cancers. The critical difference between t-MN and DC is previous exposure to CT/RT, providing evidence that prior CT/RT leads to long-term damage to BM-microenvironment, which could be contributing t-MN pathogenesis. Disclosures No relevant conflicts of interest to declare.

P2.03-58 Double Primary Lung Cancer and Breast Cancer Is a Distinct Disease Entity

P2.03-58 Double Primary Lung Cancer and Breast Cancer Is a Distinct Disease Entity

P2.09-08 Correlation Between Hormone Receptor Expression and EGFR Gene Mutation in Lung Cancer Patients with Simultaneous Primary Breast Cancer

Double primary breast cancer (BC) and lung cancer (LC) is not uncommon but research is limited. To decipher the inner pathogenesis, relationship between hormone receptor (HR) protein expression and EGFR gene mutation was explored in the present study. Clinicopathological characteristics of 400 female patients with double primary BC and LC were analyzed, while another 114 patients with single LC were compared correspondingly. Tissue samples were obtained from enrolled subjects to detect EGFR mutation status by gene sequencing analysis, and estrogen receptor (ER) and progesterone receptor (PR) expression was determined by immunohistochemistry. Among 169 patients, synchronous and metachronous double primary BC-LC cases accounted for 39.1% and 61.0%, respectively. For most female LC patients with simultaneous primary BC, adenocarcinoma was the dominant subtype (95.1%). The positivity rates were 13% for ER and 13% for PR in lung tumor tissues of 200 double BC-LC patients, slightly higher than those in single LC patients. Among BC-LC patients with mutant EGFR, 48.2% were either ER-positive (30.6%) or PR-positive (30.6%). But for those without EGFR mutation, both ER and PR could not be detected in lung tumor tissue samples. χ2 testfurther confirmed a significantly positive correlation between ER, PR expression and EGFR mutation in lung tumor tissues in double primary patients (P < 0.05). However, such relationship could not be similarly observed in single LC cases. Besides, the presence of family tumor history was associated with the onset time of the two primary cancers. Double primary BC-LC patients have distinctive clinicopathological features. Expression of HRs (both ER and PR) significantly correlated with EGFR mutation status in their lung tumor tissues.

Paraneoplastic Syndrome in Double Cancer (Renal Cell Carcinoma and Colon Cancer) Presenting with Polymyalgia Rheumatic: A Case Report

68歳男性．腎癌術後フォロー中に腰痛・股関節痛にて整形外科入院．抗菌剤投与に反応せず炎症反応高値と臨床症状の間に乖離を認め，強直性脊椎炎の疑いでステロイド投与され症状軽減し退院．免疫アレルギー内科でリウマチ性多発筋痛症と診断される．腹腔内リンパ節及び皮下の転移に対し摘出術施行．術後疼痛改善したことで腫瘍随伴症候群と診断された．4ヶ月後重複大腸癌に対し手術施行された後にリハビリテーション介入．経過中に関節炎の再燃を疑わせる股関節痛が出現，疼痛対応に苦慮しながら自宅退院することができた．急性期病院では疾患の治療成績に関心が向きがちであるが，臨床経過中に骨関節の痛みを訴えるものの中にはPMRを含めた腫瘍随伴症候群があることに注意して対処すべきである．腎癌術後にPMR様症状が出現した重複大腸癌の報告は本例が初めてであり，リハビリテーションは総合診療を担う一翼であると再認識させてくれた症例である．

The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (−)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (−)-4i induced cell apoptosis and reduced phosphorylation of EGFR and AKT in a dose-dependent manner. Furthermore, (−)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t1/2 = 1.12 h) of (−)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (−)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (−)-4i warrants further investigation in Non-Small cell lung cancer (NSCLC) therapy.

Targeted sequencing identifies the mutational signature of double primary and metastatic malignancies: a case report

BackgroundThe accurate identification of the tissue of origin is critical for optimal management of cancer patients particularly those who develop multiple malignancies; however, conventional diagnostic methods at times may fail to provide conclusive diagnosis of the origin of the malignancy. Herein, we describe the use of targeted sequencing in distinguishing the primary and metastatic tumors in a patient with metachronous malignancies in the lung, colon and kidney.Case presentationIn December 2016, a 55-year-old Chinese male was diagnosed with stage IB lung adenosquamous carcinoma and treated with left lower lobectomy and 4 cycles of platinum-based chemotherapy. After being disease-free for 3.5 months, three colonic polyps were discovered and were diagnosed as invasive adenocarcinoma after polypectomy. Within 5.4 months from the polypectomy, squamous cell renal carcinoma was identified and was managed by radical nephrectomy. Immunohistochemistry results were inconclusive on the origin of the kidney tumor. Hence, the three archived surgical tissue samples were sequenced using a targeted panel with 520 cancer-related genes. Analysis revealed similar mutational signature between the lung and kidney tumors and a distinct mutational profile for the colon tumor, suggesting that the lung and colon malignancies were primary tumors, while the kidney tumor originated from the lung, revealing a diagnosis of metastatic double primary cancer – lung carcinoma with renal cell metastasis and second primary colon carcinoma.ConclusionMutational profiling using targeted sequencing is valuable not only for the detection of actionable mutations, but also in the identification of the origin of tumors. This diagnostic approach should be considered in similar scenarios.

Analysis of the Cardiovascular Complications after Definitive Chemoradiotherapy for Esophageal Cancer Using Biological Dose Volume Histogram

The purpose of this study was to evaluate the relation between the cardiovascular complications after definitive chemoradiotherapy (CRT) for esophageal cancer and dose volume histogram (DVH) of organs at risk (OAR) using biological equivalent dose (BED). We analyzed the data of patients with esophageal cancer treated by definitive CRT between January 2001 and December 2016. Selection criteria were that primary site was from middle thoracic to abdominal esophagus, observation period was at least two years or more, total irradiation dose was at least 50 Gy or more. Exclusion criteria were patients with history of thoracic irradiation or operation, patients with recurrence or metastasis or double cancer within two years from CRT. In this study, we analyzed pericardial effusion and pleural effusion as the cardiovascular complications. We contoured heart, pericardium, lung, pleura as OARs based on RTOG atlas. We created dose distribution of each plan converted of DVH to DVH using BED (bDVH). We prescribed that alpha / beta ratio of heart, pericardium, lung, pleura was 3 Gy. Toxicity was evaluated by CTCAE v4.0. We analyzed bDVH of each OAR from V5 to V100 and investigated a significant difference in the incidence of cardiovascular complications. We analyzed data of 83 patients. Median total irradiation dose was 60 Gy (50.4–71 Gy). Symptomatic pericardial effusion (≧ G3) was observed in 12 patients (14%). Symptomatic pleural effusion (≧ G2) was observed in 17 patients (20%). In the symptomatic pericardial effusion (≧ G3), there were significant differences in V5 – V100 of heart and pericardium. In the symptomatic pleural effusion (≧ G2), there were significant differences in V55 - 100 of lung and V50 – V100 of pleura respectively. Receiver Operating Characteristic (ROC) Curve analysis results were that the largest Area under the ROC curve (AUC) was observed in V75 of heart (0.9002), V80 of pericardium (0.9108), V90 of lung (0.7647) and V75 of pleura (0.7950) respectively. The cutoff of V75 of heart and V80 of pericardium were 33.79% and 27.38%, for which sensitivity and specificity were 75%, 75% and 86%, 90% respectively. The cutoff of V90 of lung and V75 of pleura were 1.58% and 7.75%, for which sensitivity and specificity were 76%, 71% and 71%, 70% respectively. We showed the relation of the irradiated dose of the OARs to the cardiovascular complication using bDVH. V75, V80 of heart and pericardium were most relevant about symptomatic pericardial effusion. In addition, V90, V75 of lung and pleura were most relevant about symptomatic pleural effusion.

Genetic epidemiology of colorectal cancer and associated cancers.

We review here data on familial risk in colorectal cancer (CRC) generated from the Swedish Family-Cancer Database, the largest resource of its kind in the world. Although the concordant familial risk for CRC (i.e. CRC risk in families of CRC patients) has been reasonably well established, the studies on discordant familial risks (i.e. CRC risk in families with any other cancers) are rare. Because different cancers could be caused by shared genetic susceptibility or shared environment, data of associations of discordant cancers may provide useful information for identifying common risk factors. In analyses between any of 33 discordant cancers relative risks (RRs) for discordant cancers were estimated in families with increasing numbers of probands with CRC; in the reverse analyses, RRs for CRC were estimated in families with increasing numbers of probands with discordant cancers. In separate analyses, hereditary non-polyposis colorectal cancer (HNPCC) families were excluded from the study, based on HNPCC related double primary cancers, to assess the residual familial RRs. We further reviewed familial risks of colon and rectal cancers separately in search for distinct discordant associations. The reviewed data suggested that colon cancer was associated with a higher familial risk for CRC compared to rectal cancer. The previous data had reported associations of CRC with melanoma, thyroid and eye cancers. Nervous system cancer was only associated with colon cancer, and lung cancer only associated with rectal cancer. The reviewed data on discordant association may provide guidance to gene identification and may help genetic counseling.

Monthly tegafur\u2013uracil maintenance for increasing relapse-free survival in ypStage III rectal cancer patients after preoperative radiotherapy, radical resection, and 12 postoperative chemotherapy cycles: a retrospective study

BackgroundCurrent advancements in neoadjuvant therapy and total mesorectal excision have engendered increased local control. However, the survival benefit of preoperative radiotherapy (RT; 5 × 5 Gy) in rectal cancer patients remains inadequate, primarily because of systemic recurrence. In this retrospective single-center study, the effects of monthly tegafur–uracil maintenance (≥6 cycles) after 12 fluorouracil-based adjuvant chemotherapy cycles on 3-year relapse-free survival (RFS) was estimated in ypStage III rectal cancer patients.MethodsOf ypStage III rectal cancer patients who received preoperative RT (5 × 5 Gy) in January 2006–December 2015, those who had ypStage III cancer after preoperative radiation, radical resection, and postoperative chemotherapy were enrolled; excluded patients had ypStage I and II rectal cancer, had double cancer, had synchronous distant metastasis, had local excision, received preoperative chemoradiation, and were lost to follow-up within 1 year after cancer treatment. Included patients received either maintenance therapy or observation after postoperative chemotherapy. The primary endpoint was the effect of maintenance therapy on 3-year RFS. We set the median follow-up duration to be 69.7 (range, 15.4–148.3) months.ResultsOf 259 ypStage III rectal cancer patients, 102 (59 men and 43 women) were enrolled based on the inclusion criteria. The maintenance and observation groups comprised 55 and 57 patients, respectively (mean age = 62.2 and 65.7 years, respectively; p = 0.185). The 3-year RFS observed in the maintenance group (85.1%) was longer than that observed in the observation group (67.5%; p = 0.039). Multivariate analysis proved the following to be independent prognostic factors for RFS: higher metastatic lymph node ratio (LNR ≥0.3), tegafur–uracil maintenance (≥6 cycles), and lower rectal cancer (< 6 cm from the anal verge). The higher the rectal cancer location (≥6 cm from the anal verge) was, the higher the tegafur–uracil maintenance survival benefit became (p = 0.041). Moreover, lower cancer location (< 6 cm from the anal verge) and LNR ≥0.3 were both associated with a trend of longer RFS after tegafur–uracil maintenance therapy (p = 0.164 and 0.113, respectively).ConclusionsAfter the execution of fluorouracil-based adjuvant chemotherapy, administering monthly tegafur–uracil (≥6 cycles) may improve the 3-year RFS of ypStage III rectal cancer patients.

Predictive Factors of Postendoscopic Submucosal Dissection Electrocoagulation Syndrome and the Utility of Computed Tomography Scan after Esophageal Endoscopic Submucosal Dissection

Background/Aims: Recently, postendoscopic submucosal dissection electrocoagulation syndrome (PEECS) has attracted attention. However, the criteria for computed tomography (CT) scanning following esophageal endoscopic submucosal dissection (ESD) are unclear. In this study, we aimed to identify the predictive factors of PEECS and the usefulness of CT scanning after esophageal ESD. Methods: A total of 245 lesions in 223 patients who underwent esophageal ESD between February 2008 and October 2018 were retrospectively analyzed. Patients with double cancers, those who experienced procedural accidents, such as aspiration pneumonitis or perforation, and those who were unable to undergo CT were excluded from the study. PEECS evaluation items included body temperature (≤37.7°C = 1 point, ≥37.8°C = 2 points), white blood cell count (<10,800/μL = 1 point, ≥10,800/μL = 2 points), and chest pain (numerical rating scale [NRS] ≤4 = 1 point, NRS ≥5 = 2 points). Scores of ≥5 points were categorized as the PEECS-positive group, and scores of ≤4 points were categorized as the PEECS-negative group. The degree of mediastinal emphysema on CT was stratified into 5 grades, in which grades 0 and 1 were considered as the “low-grade” group, and grades 2, 3, and 4 were considered as the “high-grade” group. We analyzed the prognostic factors of high-grade mediastinal emphysema, including the presence or absence of PEECS. Results: The PEECS-positive group comprised 18 out of the 163 patients (11.0%), and mediastinal emphysema was stratified into grades 0 (94), 1 (51), 2 (12), 3 (5), and 4 (1 patient). Three independent risk factors for the onset of PEECS were identified, as follows: resected area ≥750 mm² (OR 7.28, 95% CI 1.42–37.33, p = 0.017), treatment duration ≥75 min (OR 10.26, 95% CI 1.20–87.77, p = 0.034), and muscle layer exposure (OR 10.92, 95% CI 2.22–53.74, p = 0.003). Two independent predictive factors of high-grade mediastinal emphysema were identified, which were PEECS positivity (OR 4.31, 95% CI 1.29–14.41, p = 0.018), and muscle layer exposure (OR 4.08, 95% CI 1.18–14.06, p = 0.026). Conclusions: A large resected area, prolonged treatment duration, and muscle layer exposure are risk factors for the onset of PEECS. Mediastinal emphysema was observed in 43% of patients following ESD. When marked clinical symptoms of PEECS appear, high-grade mediastinal emphysema may be observed, and therefore CT should be performed in these cases.

Polydopamine coated hollow mesoporous silica nanoparticles as pH-sensitive nanocarriers for overcoming multidrug resistance

A nanocarrier system of methoxypolyethylene glycol amine (mPEG-NH2) functionalized polydopamine (PDA) coated hollow mesoporous silica nanoparticles (HMSNs-PDA-PEG) was developed with pH-responsive, which combined doxorubicin hydrochloride (DOX) and quercetin (QUR) to reverse multidrug resistance (MDR) and improved anticancer effects on taxol (TAX) and DOX double resistant human colorectal cancer cell line HCT-8 (HCT-8/TAX cells). Well-dispersed nanoparticles (HMSNs-PDA-PEG) were prepared with a dimension of around 170 nm. The surface morphology and chemical properties of HMSNs-PDA-PEG were also successfully characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) method, Fourier transform infrared spectroscopy (FT-IR) and dynamic light scattering (DLS). Drug release experiments results indicated that DOX and QUR (QD) loaded nanoparticles (HMSNs-PDA-PEG@QD) had similar release kinetic profiles of each drug, which all exhibited highly sensitive to pH value due to the surface PDA coating. Additionally, the HCT-8 cells or HCT-8/TAX cells were employed to assess the cellular uptake and cytotoxicity of various drug-free or drug-loaded HMSNs samples. Meanwhile, a series of biological evaluations demonstrated that the HMSNs-PDA-PEG@QD exhibited remarkable ability to overcome MDR compared with free DOX and HMSNs-PDA-PEG@DOX. Taken together, these results revealed that HMSNs-PDA-PEG@QD was suitable as a prospective and efficient drug delivery nanosystem for overcoming multidrug resistance.

3170 – ABERRANT BONE MARROW MICROENVIRONMENT IN THERAPY RELATED MYELOID NEOPLASM

Introduction Therapy related myeloid neoplasm (t-MN) is a lethal second hematological malignancy following chemotherapy (CT) and radiotherapy (RT) for primary cancers. It accounts for 15-20% of myelodysplastic syndromes (MDS) and acute myeloid leukemia. Prognosis of t-MN is poor with no effective therapies. Although CT/RT can damage the bone marrow microenvironment, very limited studies assessed it in t-MN. Aim To compare bone marrow microenvironment milieu and mesenchymal stromal cells (MSC) from primary MDS (pMDS), t-MN and double cancers (DC, primary cancer and MDS but without a history of CT/RT for primary cancer). Methods Bone Marrow plasma cytokines/chemokines (CCK) and bone marrow MSC proliferation, senescence, morphology and differentiation potential of pMDS, t-MN and DC was compared. Results Proliferation and clonogenic potential of MSC from t-MN were significantly lower than pMDS and DC (Fig.1A). MSC from t-MN could not be maintained in culture and had higher senescence rates, assessed by β-galactosidase positive cells, compared to pMDS and DC (p Conclusions Our data demonstrate that MSC from t-MN patients have significantly altered morphology, a lower proliferation rate, and higher senescence rate compared to pMDS and DC. Osteogenic differentiation of t-MN MSC was higher at the cost of reduced adipogenic differentiation. This data suggests that RT/CT leads to long term damages to bone marrow microenvironment which may play a role in t-MN pathogenesis.

Impact of solid tumor history on treatment response and survival of patients with diffuse large B-cell lymphoma

目的观察合并实体肿瘤病史是否会影响弥漫大B细胞淋巴瘤（DLBCL）患者的治疗效果以及生存情况。方法回顾性收集2013–2018年在上海交通大学医学院附属瑞金医院血液科治疗的DLBCL患者836例，其中34例有实体肿瘤病史的DLBCL患者归为双癌组，从802例无实体肿瘤病史的DLBCL患者中，应用倾向评分匹配方法，根据性别、年龄、分期、IPI评分等因素进行1∶2匹配，筛选出68例作为对照组。通过门诊、住院资料及电话随访，比较两组患者的治疗缓解率、3年总生存（OS）及无进展生存（PFS）期的差异。结果双癌组和对照组RCHOP（利妥昔单抗+环磷酰胺+长春新碱+阿霉素50 mg/m2或表阿霉素或脂质体阿霉素+泼尼松）治疗完全缓解率分别为79.4%及67.6%，差异无统计学意义（P=0.210）；3年OS率分别为（74.7±9.5）%及（63.5±6.1）%（χ2=2.791，P=0.095），差异无统计学意义；3年PFS率分别为（72.1±8.8）%及（54.3±6.4）%（χ2=1.400，P=0.237），差异亦无统计学意义。结论DLBCL合并实体瘤病史不影响患者近期生存及RCHOP方案疗效。