Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

Osimertinib and Bevacizumab Cotreatment for Untreated EGFR-Mutated NSCLC With Malignant Pleural or Pericardial Effusion (SPIRAL II): A Single-Arm, Open-Label, Phase 2 Clinical Trial.

Introduction: First-line treatment of EGFR-mutated NSCLC with erlotinib plus antiangiogenic inhibitor exhibits promising results. However, the efficacy of this combination has not been fully investigated. Therefore, we evaluated the efficacy and safety of osimertinib plus bevacizumab in patients with EGFR-mutated NSCLC complicated with malignant pleural or pericardial effusion (MPE) for whom combination therapy may be particularly effective. Methods: This single-arm, open-label, phase 2 study aimed to investigate the clinical benefits of the bevacizumab (15 mg/kg) and osimertinib (80 mg) combination in the first-line setting for advanced EGFR-mutated NSCLC with MPE. The primary end point of this study was 1-year progression-free survival (PFS). The secondary end points were objective response rate, PFS, overall survival, drainage-free survival without the need for thoracic or pericardial drainage, and safety. Results: Between January 2019 and August 2020, a total of 31 patients with EGFR-mutated NSCLC were enrolled from Japan in the study. The median PFS was 8.5 months (95% confidence interval [CI]: 5.3-11.3), the 1-year PFS was 32.1% (80% CI: 21.4-43.3), and the objective response rate was 74.2% (95% CI: 56.8-86.3). The median overall survival was not reached. The median drainage-free survival was 18.4 months (95% CI: 10.3-not estimable). Anorexia was the most common grade 3 or higher adverse event (four patients, 12.9%), followed by fatigue and dyspnea (three patients, 9.7%). No treatment-related deaths were recorded. Conclusions: Osimertinib and bevacizumab combination in patients with advanced EGFR-mutated NSCLC with MPE were safe but did not effectively increase PFS when compared with the inferred value from previous literature.

Multidisciplinary Lung Cancer Tumor Board Connecting Eight General Hospitals in Japan via a High-Security Communication Line.

PURPOSE: The complexity of lung cancer treatment is rapidly increasing, necessitating the use of multidisciplinary approaches for improving outcomes. Although it is common for institutions to have their own tumor boards, tumor boards connecting several general hospitals, and therefore allowing for more diverse opinions, are not prevalent. MATERIALS AND METHODS: A tumor board connecting eight hospitals was formed to discuss patients for whom formulating a treatment strategy was difficult. Physicians and hospital staff accessed a high-security communication line via LiveOn ( Japan Media Systems Corporation, Tokyo, Japan), which is completely isolated from the Internet and password protected, that enables each hospital to share the electronic medical records and images of relevant patients at other hospitals on desktop computers in real time. The lung cancer tumor board began in April 2017 and has since been held every Tuesday evening for 1 hour. Preparatory records containing the age, sex, histology, TNM classification, background, and discussion points for each patient are created before each tumor board meeting. After the tumor board discussion, all conclusions and related articles used in the board are added to the minutes, which are finalized as Microsoft Word files, consolidated, and archived. These files can be retrieved later using key words. RESULTS: From April 2017 to June 2018, 202 patients were discussed. Although TNM classification was not changed for any patient, diverse opinions led to a change in the proposed strategy for 49 of 202 patients. CONCLUSION: The multidisciplinary tumor board was useful in obtaining various opinions from the perspectives of different experts. This should be evaluated in a prospective study.

MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer.

We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (P<0.0001; P = 0.0021; P<0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, P = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, P = 0.001) and lymph node metastasis (r = 0.296, P = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, P = 0.032) and venous invasion (r = 0.377, P = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.

A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach.

BACKGROUND: Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily. METHODS: Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C). RESULTS: In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (≥5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, ≥75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2). CONCLUSIONS: The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.

Degradation of Aflatoxins by Food Additives.

Degradation of four aflatoxins (AFB1, AFB2, AFG1 and AFG2) by food additives was investigated. Pure aflatoxins were degraded by treatment with solutions of acidic food additives (hydrochloric acid:HCl and sulfuric acid:H2SO4), alkaline food additives (sodium bicarbonate:NaHCO3, sodium carbonate:Na2CO3, sodium hydroxide:NaOH, sodium sulfite:Na2SO3, and sodium hypochlorite:NaOCl) and neutral food additives (potassium metabisulfite:K2S2O5, sodium bisulfite:NaHSO3, sodium hydrosulfite:Na2S2O4, hydrogen peroxide:H2O2, sodium chlorite:NaClO2, and ammonium peroxodisulfate:(ÑH4)2S2O8). The aflatoxins were treated with these neutral food additives under several conditions, and the effects of treatment temperature, time, and concentration of food additives on aflatoxin degradation were studied. Potassium bromate (KBrO3), potassium nitrate (KNO3), and sodium nitrite (NaNO2) had no effect on aflatoxins. Of the aflatoxin added to corn, 20% AFB, remained after treatment with the solution of NaHSO3 (0.5%, 48 h), but all of the AFB1 was completely degraded by NaClO2 (0.25%, pH 4, 48 h) and (NH4)2S2O8 (0.25%, 48 h) at 60°C. Of the aflatoxins added to butter beans, less than 20 and 5% of AFB1 remained after boiling treatment with a 2 and 0.5% solution of Na2S2O4, respectively. These findings suggested that aflatoxins can be degraded or removed by treatment with food additives during food processing.