Acquired drug resistance conferred by a KRAS gene mutation following the administration of cetuximab: a case report

BACKGROUND: Although a number of studies have reported acquired drug resistance due to administration of epidermal growth factor receptor antibody inhibitors, the underlying causes of this phenomenon remain unclear. CASE PRESENTATION: Here we report a case of a 75-year-old man with liver metastasis at 3 years after a successful transverse colectomy to treat KRAS wild-type colorectal cancer. While initial administration of epidermal growth factor receptor inhibitors proved effective, continued use of the same treatment resulted in new peritoneal seeding. An acquired KRAS mutation was found in a resected tissue specimen from one such area. This mutation, possibly caused by administration of epidermal growth factor receptor inhibitors, appears to have conferred drug resistance. CONCLUSION: The present findings suggest that administration of epidermal growth factor receptor inhibitors results in an acquired KRAS mutation that confers drug resistance

Prolapse of Intussusception through the Anus as a Result of Sigmoid Colon Cancer

Adult intussusception is rare and most often associated with cancer. We report a case of intussuscepted sigmoid colon into the rectum protruding from the anus of a 47-year-old woman. The cause of the intussusception was sigmoid colon cancer. We removed the intussuscepted part of the sigmoid colon as well as the rectum and regional lymph nodes. The patient recovered uneventfully and there has been no evidence of recurrence of the cancer

Circulating Tumor DNA as a Novel Biomarker Optimizing Chemotherapy for Colorectal Cancer

Liquid biopsy is a minimally invasive method for detecting soluble factors, including circulating tumor DNA (ctDNA), in body fluids. ctDNA carrying tumor-specific genetic or epigenetic alterations is released into circulation from tumor cells. ctDNA in the plasma contains somatic mutations that have occurred in the tumor, and reflects tumor progression and therapeutic effects promptly and accurately. Furthermore, ctDNA is useful for early detection of recurrence and estimation of prognosis and may be utilized for diagnosis and personalized medicine for treatment selection. Thus, in the near future, it will be possible to select the most appropriate treatment based on real-time genetic information using ctDNA

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors

Abstract Background Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. Methods This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. Results Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). Conclusion Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients

A significant increase in the pepsinogen I/II ratio is a reliable biomarker for successful <i>Helicobacter pylori</i> eradication

<div><p>Background</p><p><i>Helicobacter pylori</i> (<i>H</i>. <i>pylori)</i> eradication is usually assessed using the ¹³C-urea breath test (UBT), anti-<i>H</i>. <i>pylori</i> antibody and the <i>H</i>. <i>pylori</i> stool antigen test. However, a few reports have used pepsinogen (PG), in particular, the percentage change in the PG I/II ratio. Here, we evaluated the usefulness of the percentage changes in serum PG I/II ratios for determining the success of eradication therapy for <i>H</i>. <i>pylori</i>.</p><p>Materials and methods</p><p>In total, 650 patients received eradication therapy from October 2008 to March 2013 in our Cancer Institute Hospital. We evaluated the relationship between <i>H</i>. <i>pylori</i> eradication and percentage changes in serum PG I/II ratios before and 3 months after treatment with CLEIA^® (FUJIREBIO Inc, Tokyo, Japan). The gold standard of <i>H</i>. <i>pylori</i> eradication was defined as negative by the UBT performed 3 months after completion of eradication treatment. Cut-off values for percentage changes in serum PG I/II ratios were set as +40, +25 and +10% when the serum PG I/II ratio before treatment was below 3.0, above 3.0 but below 5.0 and 5.0 or above, respectively.</p><p>Results</p><p>Serum PG I and PG II levels were measured in 562 patients with <i>H</i>. <i>pylori</i> infection before and after eradication therapy. Eradication of <i>H</i>. <i>pylori</i> was achieved in 433 patients studied (77.0%). The ratios of first, second, third-line and penicillin allergy eradication treatment were 73.8% (317/429), 88.3% (99/112), 75% (12/16) and 100% (5/5), respectively. An increasing percentage in the serum levels of the PG I/II ratios after treatment compared with the values before treatment clearly distinguished success from failure of eradication (108.2±57.2 vs. 6.8±30.7, <i>p</i><0.05). Using the above cut-off values, the sensitivity, specificity and validity for determination of <i>H</i>. <i>pylori</i> were 93.1, 93.8 and 93.2%, respectively.</p><p>Conclusion</p><p>In conclusion, the percentage changes in serum PG I/II ratios are useful as evaluation criteria for assessing the success of eradication therapy for <i>H</i>. <i>pylori</i>.</p></div

Correlation between the percentage change in the PG I/II ratio and the PG I/II ratio before treatment.

<p>Correlation between the percentage change in the PG I/II ratio and the PG I/II ratio before treatment.</p

Patient characteristics.

<p>Patient characteristics.</p

Evaluation of the RAS signaling network in response to MEK inhibition using organoids derived from a familial adenomatous polyposis patient

Abstract RAS signaling is a promising target for colorectal cancer (CRC) therapy, and a variety of selective inhibitors have been developed. However, their use has often failed to demonstrate a significant benefit in CRC patients. Here, we used patient-derived organoids (PDOs) derived from a familial adenomatous polyposis (FAP) patient to analyze the response to chemotherapeutic agents targeting EGFR, BRAF and MEK. We found that PDOs carrying KRAS mutations were resistant to MEK inhibition, while those harboring the BRAF class 3 mutation were hypersensitive. We used a systematic approach to examine the phosphorylation of RAS effectors using reverse-phase protein array (RPPA) and found increased phosphorylation of MEK induced by binimetinib. A high basal level of ERK phosphorylation and its rebound activation after MEK inhibition were detected in KRAS-mutant PDOs. Notably, the phosphorylation of EGFR and AKT was more closely correlated with that of MEK than that of ERK. Transcriptome analysis identified MYC-mediated transcription and IFN signaling as significantly correlated gene sets in MEK inhibition. Our experiments demonstrated that RPPA analysis of PDOs, in combination with the genome and transcriptome, is a useful preclinical research platform to understand RAS signaling and provides clues for the development of chemotherapeutic strategies