Hiroki Osumi

RAS mutation is a prognostic biomarker in colorectal cancer patients with metastasectomy.

Studies have demonstrated a relationship between clinical outcomes after curative resection for colorectal cancer (CRC) and gene mutations of the EGFR pathway; however, no studies have examined metastatic CRC (mCRC) patients with metastasectomy. The aim of this study was to evaluate the relationship between gene mutations of EGFR pathway and clinical outcomes after metastasectomy in mCRC patients. A total of 1,053 patients histopathologically confirmed CRC received a genotyping test for the EGFR pathway from February 2012 to October 2013. Detailed information was obtained through review of medical records. Gene mutations of EGFR pathway were analyzed by Luminex assay. Overall survival (OS) and recurrence free survival were estimated by the Kaplan‐Meier method and the log‐rank test was used to compare the survival outcomes by gene mutation status. A total of 132 patients received metastasectomy. The frequencies of KRAS exon 2, KRAS exon 3.4, NRAS, BRAF, and PIK3CA mutations were 38.6% (51/132), 3.6% (5/132), 5.1% (7/132), 5.1% (7/132), and 8.7% (12/132), respectively. With a median follow‐up of 84.1 months (57.2—NA) for a survivor, the 4‐year OS rate was 65.6% for mCRC with RAS mutation, and 81.3% for mCRC with wild‐type RAS (p < 0.05). We observed a statistically significant correlation for only the RAS mutation and OS. In multivariate analysis, RAS mutation and liver metastasis were independent factors for shorter OS. There were no significant differences between gene mutations of EGFR pathway and recurrence free survival. RAS mutation in mCRC metastasectomy patients was associated with shorter overall survival.

Advantages of magnifying narrow-band imaging for diagnosing colorectal cancer coexisting with sessile serrated adenoma/polyp.

In the present study, we investigated the advantages of narrow‐band imaging (NBI) for efficient diagnosis of sessile serrated adenoma/polyp (SSA/P). The main objective of this study was to analyze the characteristic features of cancer coexisting with serrated lesion by carrying out NBI.

Associations between deepness of response and clinical outcomes among Japanese patients with metastatic colorectal cancer treated with second-line FOLFIRI plus cetuximab.

Background In the FIRE-3 trial, overall survival (OS) was significantly longer in patients treated with FOLFIRI plus cetuximab (C-mab) than in those treated with FOLFIRI plus bevacizumab (Bev), but progression-free survival (PFS) was not significantly different. This may be associated with the deepness of response (DpR) in patients treated with FOLFIRI plus C-mab. We aimed to evaluate the relationship between clinical outcome and DpR in metastatic colorectal cancer (mCRC) patients treated with second-line FOLFIRI plus C-mab. Methods A total of 112 patients with histopathologically confirmed mCRC treated with second-line FOLFIRI in combination with C-mab (N=42) or Bev (N=70) were retrospectively enrolled between October 2008 and June 2013. The relationship between DpR and clinical outcome in patients treated with FOLFIRI plus C-mab or Bev was determined. Results Forty-two patients treated with FOLFIRI plus C-mab had a mean DpR of 6.1% (inter-quartile range: −13.7%, 20.8%) and a minimum DpR of −62.7%. On the other hand, 70 patients treated with FOLFIRI plus Bev had a mean DpR of 0% (interquartile range: −16%, 10%) and a minimum DpR of −111%. DpR ≥30% was associated with significantly longer OS and PFS when compared with DpR ≤30% in patients given FOLFIRI plus C-mab. DpR (≥30%) was independently associated with prolongation of OS and PFS. In patients treated with FOLFIRI plus C-mab, there was a moderate positive correlation between DpR and clinical outcomes (OS: r=0.51, P<0.001; PFS: r=0.54, P<0.001). Conclusion FOLFIRI plus C-mab yielded a stronger correlation between DpR and clinical outcomes. These results indicate the potential of DpR as a new measure of efficacy in mCRC patients treated with second-line chemotherapy plus C-mab.

Early hypertension is associated with better clinical outcomes in gastric cancer patients treated with ramucirumab plus paclitaxel

Anti-vascular endothelial growth factor (VEGF) therapeutics such as bevacizumab, which are widely used in cancer treatment, commonly leads to hypertension. Moreover, bevacizumab-induced hypertension is associated with improved clinical outcomes in several cancers. We retrospectively analyzed 89 patients with histologically confirmed advanced gastric cancer who received the human monoclonal anti-VEGF receptor-2 antibody ramucirumab plus paclitaxel at our hospital between June 2015 and October 2016 to evaluate the impact of treatment-associated hypertension occurring within the first two treatment cycles (“early hypertension”) on outcome. The objective response rate was 40%, median progression-free survival was 5.4 months, and overall survival was 10.4 months, which is similar to previous reports. Early hypertension in patients who received more than two cycles of ramucirumab + paclitaxel was associated with longer progression-free and overall survival. Objective response rates were also higher in patients with early hypertension. These data indicate that early hypertension may be predictive of better outcomes in gastric cancer patients who receive ramucirumab + paclitaxel treatment.

Advantages of magnifying narrow‐band imaging (NBI) for diagnosing the colorectal cancer coexisting with sessile serrated adenoma/polyp (SSA/P)

In the present study, we investigated the advantages of narrow‐band imaging (NBI) for efficient diagnosis of sessile serrated adenoma/polyp (SSA/P). The main objective of this study was to analyze the characteristic features of cancer coexisting with serrated lesion by carrying out NBI.

Severe ischemic colitis after treatment of bile-duct cancer using gemcitabine and cisplatin

A 71-year-old male who had a bile-duct cancer with liver metastases underwent systemic chemotherapy with cisplatin (25 mg/m) followed by gemcitabine (GC) (1000 mg/m). Two days after the first administration, he complained of ‘crampy’ abdominal pain. White blood cell count and levels of C-reactive protein and liver enzymes were elevated but those of creatine phosphokinase and lactate Figure 1. Japanese Journal of Clinical Oncology, 2015, 45(4) 402–403 doi: 10.1093/jjco/hyv038 Image of the Month

Endoscopic criteria to evaluate tumor response of rectal cancer to neoadjuvant chemoradiotherapy using magnifying chromoendoscopy

BACKGROUND AND AIMS Precise endoscopic assessment of complete response to neoadjuvant chemoradiotherapy before surgery is important for optimizing surgical and non-surgical treatment. We prospectively evaluated the accuracy of the newly proposed endoscopic criteria to identify complete response, using magnifying chromoendoscopy. METHODS New endoscopic criteria were created to define endoscopic complete response, near complete response and incomplete response, using magnifying chromoendoscopy. The criteria contained notable endoscopic findings, including shape of the scar, state of the ulcer, finding of white moss, presence of residual protruded nodules, regenerated pits of the scar, presence of neoplastic pit patterns, and extension of rectal wall. Seventy-nine patients with rectal cancer who received neoadjuvant chemoradiotherapy were prospectively evaluated 1-3 days before resection. Diagnostic accuracy to identify pathological complete response and interobserver agreement among a supervising colonoscopist and two trainees were investigated. RESULTS Pathological complete response was obtained in 17 patients (21.5%). The diagnostic accuracy of endoscopic complete response was 85%, with a sensitivity of 47%, specificity of 97%, positive predictive value of 80% and negative predictive value of 77%. The kappa-value for interobserver agreement across 3 doctors was 0.57 (standard error, 0.74; 95% confidence interval, 0.39-0.76). CONCLUSION The newly proposed endoscopic criteria using magnifying chromoendoscopy achieved excellent diagnostic accuracy to determine good responders to neoadjuvant chemoradiotherapy in rectal cancer, with fair interobserver agreement. The criteria could be clinically useful to select patients for non-surgical management.

Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third‐line treatment for pretreated metastatic colorectal cancer (mCRC) patients harboring wild‐type KRAS exon 2. Objective response rate (ORR) was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% CI, 0.105‐0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first‐ and second‐line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine, were enrolled. ORR and disease control rate were 25.0% (95% CI: 11.5‐38.4) and 72.5% (95% CI: 56.8‐86.4), respectively. Median progression‐free survival (PFS), overall survival (OS), and number of courses were 5.70 months (95% CI: 2.7‐7.9), 15.1 months (95% CI: 11.8‐19.0), and 10.5 (range: 3.0‐31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). Cmax mean was 723.2 μg/mL after first dose. High area under the curve (AUC)last variance was associated with t1/2 range of 131.2‐1209.6 hours (median, 174.4 hours). Early tumor shrinkage (ETS) and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS, BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and ETS are predictors for PFS, and whether performance status, synchronous metastasis, and ETS are predictors for OS. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in mCRC patients.

Giant duodenal Brunner’s gland hamartoma successfully treated via endoscopic mucosal resection

We describe a patient with a giant Brunners gland hamartoma in the duodenum who was safely treated by endoscopic mucosal resection (EMR). A 64-year-old woman visited our hospital for a workup of severe anaemia (haemoglobin level: 5 g/dL). Oesophagogastroduodenoscopy revealed a large pedunculated and elongated polypoid lesion measuring approximately 70 mm in longitudinal diameter, located at the anterior wall of the duodenal bulb. We diagnosed her as having gastrointestinal bleeding originating from this lesion. Although we considered surgical intervention initially, en bloc EMR, a less invasive treatment, was finally accomplished safely by placing endoclips before resection. The histological examination of the specimen revealed a hamartomatous lesion consisting of Brunners glands with cystic change and adipose tissue separated by the septa of smooth muscle fibers. Ultimately, we diagnosed her as having Brunners gland hamartoma. Notably, there were tiny foci of heterotopic pancreatic tissue containing islets and duct epithelium. Although this type of lesion is benign, a larger one may cause clinical symptoms such as obstruction or bleeding, and thus, local resection is preferable.

Change in clinical outcomes during the transition of adjuvant chemotherapy for stage III colorectal cancer

Background There are robust data supporting the contribution of oxaliplatin (L-OHP) regarding clinical outcomes for colorectal cancer (CRC) in an adjuvant setting in European and US trials; however, there is no Japanese clinical evidence although L-OHP has been approved since 2009. We examined the transition of adjuvant chemotherapy for stage III colorectal cancer in our institute. Methods A total of 642 patients with histopathologically confirmed stage III CRC underwent curative surgery from 2005 to 2010. We examined disease free survival (DFS), overall survival (OS) and prognostic factors for stage III CRC patients who underwent adjuvant chemotherapy. Results A total of 509 patients received adjuvant chemotherapy. 3-year DFS and 5-year OS rates were 74.5% and 87.5%, respectively. The frequency of inclusion of L-OHP as adjuvant chemotherapy was increased after 2008. A total of 189 patients received adjuvant chemotherapy from 2005 to 2007 increasing to 320 patients from 2008 to 2010; the 5-year OS rates were 82.4% and 91.5%, respectively, and the 3-year DFS rates were 69.2% and 76.6%, respectively (OS, P = 0.007; DFS, P = 0.023). In univariate analysis, adjuvant chemotherapy including L-OHP was no significant deference compared to FU monotherapy. (OS: HR 0.88, 95%CI 0.4–1.91, p = 0.75, DFS: HR 0.78, 95%CI 0.21–2.3, p = 0.29). In multivariate analysis, the OS was predicted by means of N stage (HR = 2; 95%CI, 1.1–3.8; P = 0.02) and pathology (HR = 0.28; 95%CI, 0.13–0.59; P = 0.0008). The DFS was predicted by means of N stage (HR = 2.67; 95%CI, 1.82–3.9; P < 0.05), T stage (HR = 1.61; 95%CI, 1.1–2.3; P = 0.01) pathology (HR = 0.47; 95%CI, 0.29–0.75; P < 0.05) and venous invasion (HR = 2.06; 95%CI, 1.12–3.77; P = 0.01). Conclusions Clinical outcomes of stage III CRC patients receiving adjuvant chemotherapy improved. The frequency of L-OHP usage was increasing annually, however it was no influence for clinical outcomes in this study. It will be necessary to reevaluate additional effect of L-OHP with more patients.