Identification of Molecular Subtypes and Potential Small-Molecule Drugs for Esophagus Cancer Treatment Based on m6A Regulators

Background. Esophagus cancer (ESCA) is the sixth most frequent cancer in males, with 5-year overall survival of 15%–25%. RNA modifications function critically in cancer progression, and m6A regulators are associated with ESCA prognosis. This study further revealed correlations between m6A and ESCA development. Methods. Univariate Cox regression analysis and consensus clustering were applied to determine molecular subtypes. Functional pathways and gene ontology terms were enriched by gene set enrichment analysis. Protein-protein interaction (PPI) analysis on differentially expressed genes (DEGs) was conducted for hub gene screening. Public drug databases were employed to study the interactions between hub genes and small molecules. Results. Three molecular subtypes related to ESCA prognosis were determined. Based on multiple analyses among molecular subtypes, 146 DEGs were screened, and a PPT network of 15 hub genes was visualized. Finally, 8 potential small-molecule drugs (BMS-754807, gefitinib, neratinib, zuclopenthixol, puromycin, sulfasalazine, and imatinib) were identified for treating ESCA. Conclusions. This study applied a new approach to analyzing the relation between m6A and ESCA prognosis, providing a reference for exploring potential targets and drugs for ESCA treatment.

Impacts of Inflammatory Microenvironment on the Development of Cancer Relapse after Combined Treatment

The purpose of the work was to study the impact of certain elements of the inflammatory microenvironment of the tumor on the development of cancer relapse of main localizations with the amplification of ERBB2 after combined treatment. Materials and methods. 80 patients, who had been treated for the period from 2016 to 2021 in National Cancer Institute, Kyiv, Ukraine. They were 42-78 (average 60) years old, ECOG 0-2, female. All patients histologically proved adenocarcinoma GIII-GIV. Everyone was studied for the level of chitinase-like proteins, cryoglobulins, tumor-associated macrophages in the preoperative (with the first identified disease for the first time, prior to the beginning of the neoadjuvant chemotherapy) and in the postoperative period. 1st block: with a confirmed mutation of HER-2/neu gene (amplification ERBB2 (3+)): a) inflammatory breast cancer (primary-edema form) – 10 people, b) diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophagus cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. 2nd block: without a confirmed mutation of HER-2/neu gene: a) inflammatory breast cancer (primary edema form) – 10 people; b) a diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophageal cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. Results and discussion. In patients with infiltrative breast cancer, diffuse-infiltrative stomach cancer, and diffuse-infiltrative esophagus cancer, and diffuse-infiltrative colorectal cancer there was a tendency to an increase in the expression of YKL-39 with the ERBB2 amplification during inflammatory tumor infiltration in the stroma. High expression of Stabilin-1 (2.1±0.70, n = 22) was found compared to patient tumors that did not reveal the amplification of ERBB2 (1.46±0.67, n = 13, p = 0.015). In most patients with amplification ERBB2, the cryoglobulin content was average (298.6±2.5 mg/l; 1.3±0.08%) – 20 (50%), which corresponds to cryoglobulinemia type II; with conditioned cryoglobulinemia (79.4±1.01 mg/l) in 10 (25%); high content (477.3±48 mg/l; 3.4±0.2%) was recorded in 10 (25%), which indicates the type III of cryoglobulinemia [the hazard ratio (HR) = 0.71, 95%, сonfidence interval (CI): 0.22-0.83, p = 0.005] Conclusion. Amplification of ERBB2 and macrophages surroundings markers CD68, M2 subpopulation RS1 (Stabilin-1), chitinase-like proteins YKL-39 and SI-CLP independently identified subgroups of patients with inflammatory breast cancer, diffuse stomach and diffuse esophageal, diffuse colorectal cancer with a bad forecast. In patients with the presence of the amplification of ERBB2 in the inflammatory tumor infiltrate, in the stroma, the higher expression of the chitinase-like protein YKL-39 and M2-polarization RS1 of the marker Stabilin-1, was detected compared to the patient's tumors without amplifying ERBB2. This study shows an important role of quantitative values associated with the tumor phenotype and macrophages in tumor progression, depending on the presence of ERBB2 gain. In patients with cryoglobulinemia with inflammatory cancer the secondary immunodeficiency is developed. This is determined by anomalies in the cell and humoral immune system, and leads to the development of postoperative inflammatory complications and relapses

A phase 2 study of liposomal irinotecan with 5-fluorouracil and leucovorin in squamous cell carcinoma of head and neck or esophagus after prior platinum-based chemotherapy or chemoradiotherapy.

6025 Background: Liposomal irinotecan (nal-IRI) + 5-FU/LV has been approved and used in treating patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study result. This phase 2 trial evaluated the activity of NAPOLI-1 regimen in patients with squamous cell carcinoma (SCC) of head and neck (H&N) or esophagus that progressed on or recur after platinum-based chemotherapy or concurrent chemoradiotherapy. Methods: Patients with histologically confirmed SCC of H&N or esophagus whose disease progressed while on or progressed/recurred within 6 months after platinum-based chemotherapy or chemoradiotherapy, and unsuitable for further surgical or radiation intervention were eligible. Prior anti-EGFR or anti-PD1/anti-PDL1 treatment was allowed. The regimen consisted of nal-IRI 70 mg/m2 (irinotecan free base) followed by LV 400 mg/m2 and 5-FU 2400 mg/m2, every 2 weeks. A Simon’s 2-stage design was used with planned 30 evaluable patients in the first stage and 52 evaluable patients in total. The primary endpoint is objective tumor response. Results: From December 2018 to April 2020, 59 subjects were enrolled, including 16 with esophagus cancer and 43 with H&N cancer. Thirty-seven (63%) patients had metastatic disease at enrollment. The mean of treatment cycles were 5 (range, 1-21). Among the total 59 enrolled subjects, 53 subjects (14 esophagus cancer, 39 H&N cancer) were evaluable for objective tumor response. The disease control rate in esophagus cancer was 50% (7 SD, intent-to-treat (ITT) population 43.8%). For H&N patients, 1 CR, 4 PR, and 23 SD resulted in the response rate 12.8% (11.6% in ITT population) and disease control rate 72% (65% in ITT population). The median progression free survival (N = 59) was 2.5 months (esophagus/H&N: 1.5/2.7 months) and the median overall survival was 5.9 months (esophagus/H&N: 4.2/7.3 months). Seventy-eight percent of patients had ≥grade 3 treatment-related adverse events. The most frequent ≥grade 3 toxicities were decreased lymphocyte count (50.8%), decreased neutrophil count (42.4%), and decreased white blood count (33.9%). Only 3 patients (5%) had grade 3 diarrhea during the treatment period. Conclusions: This study showed the modest efficacy and manageable toxicity profile of nal-IRI+5-FU/LV in platinum-refractory locally advanced or metastatic H&N or esophagus cancer patients. Clinical benefits including complete tumor response were noted in H&N patients. The role of this regimen in selective patients and the efficacy of combination with immunotherapeutic agents warrant further explorations. Clinical trial information: NCT03712397.

Natural Language Processing to Identify Cancer Treatments With Electronic Medical Records

PURPOSE Knowing the treatments administered to patients with cancer is important for treatment planning and correlating treatment patterns with outcomes for personalized medicine study. However, existing methods to identify treatments are often lacking. We develop a natural language processing approach with structured electronic medical records and unstructured clinical notes to identify the initial treatment administered to patients with cancer. METHODS We used a total number of 4,412 patients with 483,782 clinical notes from the Stanford Cancer Institute Research Database containing patients with nonmetastatic prostate, oropharynx, and esophagus cancer. We trained treatment identification models for each cancer type separately and compared performance of using only structured, only unstructured ( bag-of-words, doc2vec, fasttext), and combinations of both ( structured + bow, structured + doc2vec, structured + fasttext). We optimized the identification model among five machine learning methods (logistic regression, multilayer perceptrons, random forest, support vector machines, and stochastic gradient boosting). The treatment information recorded in the cancer registry is the gold standard and compares our methods to an identification baseline with billing codes. RESULTS For prostate cancer, we achieved an f1-score of 0.99 (95% CI, 0.97 to 1.00) for radiation and 1.00 (95% CI, 0.99 to 1.00) for surgery using structured + doc2vec. For oropharynx cancer, we achieved an f1-score of 0.78 (95% CI, 0.58 to 0.93) for chemoradiation and 0.83 (95% CI, 0.69 to 0.95) for surgery using doc2vec. For esophagus cancer, we achieved an f1-score of 1.0 (95% CI, 1.0 to 1.0) for both chemoradiation and surgery using all combinations of structured and unstructured data. We found that employing the free-text clinical notes outperforms using the billing codes or only structured data for all three cancer types. CONCLUSION Our results show that treatment identification using free-text clinical notes greatly improves upon the performance using billing codes and simple structured data. The approach can be used for treatment cohort identification and adapted for longitudinal cancer treatment identification.

Nutritional Status and Feeding Regimen of Patients with Esophagus Cancer—A Study from Vietnam

Background: Esophagus cancer patients are at high risk of malnutrition. This study was performed to assess the nutritional status and dietary intake of newly diagnosed esophageal cancer patients in Vietnam National Cancer Hospital (NCH). Methods: A cross-sectional study was conducted on 206 early esophageal cancer inpatients after gastrostomy from September 2017 to June 2018. The chi-squared test, Fisher exact test, and Mann–Whitney test were performed. The software of the Vietnam National Institute of Nutrition was used to evaluate the dietary intake of patients. Results: All the participants were male with a mean age of 57.1 ± 8.5 years. Overall, 87.4% of patients had dysphagia. Furthermore, 82.5% and 90.8% of patients reported weight loss one and six months pre-diagnosis, respectively. Moreover, 52.9% of patients suffered from mild/moderate malnutrition and 29.6% of patients had severe malnutrition according to the Patient-Generated Subjective Global Assessment (PG-SGA). The body mass index (BMI) and mid upper arm circumference (MUAC) measurement revealed 47.6% and 50% of undernourished patients, respectively. The proportions of patients having malnutrition were 10.7%, 55.8%, and 27.2% according to albumin, prealbumin, and total lymphocyte counts, respectively. The means of energy, protein, lipid, and carbohydrate in the patients’ 24 h preoperative diets were 973.6 ± 443.0 kcal/day, 42.4 ± 21.6 g/day, 31.0 ± 15.5 g/day, and 130.0 ± 64.5 g/day. The total energy, total protein, animal protein, total lipid, and plant lipid in the dietary intake of patients were strongly correlated with age, economic classification, and PG-SGA (each p < 0.05). The total energy intake increased day by day, with the average energy intake of 1343.9 ± 521.3 kcal on the seventh day. Energy and protein response rates increased day by day and were highest at 7 days post-operation at 18.0% and 19.4%. Conclusion: Malnutrition and insufficient intake are noteworthy in esophageal cancer patients. The PG-SGA is strongly correlated with the dietary intake of patients. The results from this study will help medical staff to prevent malnutrition and improve the nutritional status of esophageal cancer inpatients. Furthermore, public awareness should be raised on recognizing weight loss as an early symptom of esophageal cancer and the utilization of preoperative assessment tools for nutritional assessment and malnutrition management.