Kazuki Yamashita

XAGE-1 expression in non : Small cell lung cancer and antibody response in patients

Purpose:XAGE-1 was originally identified by the search for PAGE/GAGE-related genes using expressed sequence tag database and was shown to exhibit characteristics of cancer/testis-like antigens. Four transcript variants XAGE-1a, XAGE-1b, XAGE-1c, and XAGE-1d have been identified thus far. We recently identified XAGE-1b as a dominant antigen recognized by sera from lung adenocarcinoma patients. We here investigated the mRNA expression of four XAGE-1 variants and XAGE-1 protein expression in non–small cell lung cancer (NSCLC). Humoral immune response to XAGE-1b was also evaluated in patients. Experimental Design: Forty-nine NSCLC specimens were analyzed for the expression of four XAGE-1 transcript variants by conventional 30-cycle and real-time reverse transcription-PCR and XAGE-1 protein expression by immunohistochemistry. Sera from 74 patients were analyzed for XAGE-1b antibody production by ELISA and Western blot. Results:XAGE-1b and XAGE-1d mRNA were detected in 15 and 6 of 49 lung cancer specimens, respectively. No XAGE-1a or XAGE-1c mRNA expression was observed. XAGE-1b mRNA expression was observed in 14 of 31 (45%) adenocarcinoma and 1 of 18 (6%) lung cancer with other histologic types. Immunohistochemical analysis using a XAGE-1 monoclonal antibody showed that 14 of 15 XAGE-1b mRNA-positive and 3 of 34 XAGE-1b mRNA-negative specimens expressed XAGE-1 protein. Seropositivity was observed in 5 of 56 patients with adenocarcinoma, whereas none of 18 patients with other histologic types produced XAGE-1b antibody. Conclusion: XAGE-1b is highly and strongly expressed in lung adenocarcinoma and immunogenic in patients, suggesting that XAGE-1b is a promising antigen for immunotherapy against lung adenocarcinoma.

Gender differences in the dihydropyrimidine dehydrogenase expression of colorectal cancers

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD expression levels are believed to correlate with the 5-FU sensitivity of malignant tumors. In colorectal cancer (CRC), a few previous studies demonstrated that females could benefit more from adjuvant chemotherapy. However, it is still unknown why the effectiveness of postoperative chemotherapy is affected by gender. The objective of this study was to clarify the beneficial differences in 5-FU chemotherapy between genders in patients with the CRC based on DPD expression. Ninety-seven tumor specimens and 92 adjacent normal tissue specimens from 97 patients with the CRC and no prior therapy were obtained. The DPD expression in the tissues was quantified and analyzed based on clinicopathological factors. In the tumor tissue, the DPD expression in females was significantly lower than that in males. In the normal tissues, however, there were no significant differences in DPD expression between genders. In the treatment of CRC, cases who will benefit most because of 5-FU sensitivity; i.e. cases with lower DPD expression, must be given priority. Based on DPD expression, female gender seems to be a predictive factor for a better response to chemotherapy with 5-FU.

Lower esophageal sphincter- and vagus-preserving proximal partial gastrectomy for early cancer of the gastric cardia.

PurposeProximal gastrectomy and lymph node dissection are often performed for T1 cancer of the gastric cardia; however, direct esophagogastrostomy is frequently complicated by reflux esophagitis. We describe a simple technique for preventing esophageal reflux and discuss its results.MethodsThis technique is indicated for T1 cancer of the gastric cardia without lymphadenopathy. Partial resection, including the lesion, is performed, preserving the vagus nerve and lower esophageal sphincter (LES). Lymph node dissection is done around the left gastric, celiac, and splenic arteries. The esophagus is then anastomosed to the anterior wall in the center of the remnant stomach.ResultsWe evaluated the results of this procedure in eight patients. X-ray films showed no esophageal reflux in either the supine or the right decubitus position. None of the patients complained of reflux or other dyscrasic symptoms, and none had any feeling of microgastria. One patient had some localized erosion near the anastomosis.ConclusionsThis simple and safe technique does not result in post-gastrectomy syndrome or microgastria, and the risk of leaving cancer cells is minimal.

Laparoscopy-assisted spleen-preserving pancreatic resection for epidermoid cyst in an intrapancreatic accessory spleen.

A rare case of an epidermoid cyst originating in an intrapancreatic accessory spleen in a 50‐year‐old Japanese female is reported. A hypoechoic cystic tumor was detected incidentally by abdominal ultrasonography. It appeared to be a single cyst in the pancreatic tail with a contrasted mass lesion beside it. Laparoscopy‐assisted spleen‐preserving pancreatic tail resection was performed. Microscopic examination revealed that the cyst was surrounded by fibrous tissue and a thin layer of splenic tissue, adjacent to normal pancreatic parenchyma. The inner surface of the cyst was lined with non‐keratinizing squamous epithelium. The diagnosis of an epidermoid cyst occurring in an intrapancreatic accessory spleen was confirmed. Laparoscopy‐assisted spleen‐preserving pancreatic resection is a safe and effective procedure for benign or low‐grade malignant cystic diseases in the pancreas.

In vitro detection of cross-resistant and non-cross-resistant agents with fluorouracil for patients with colorectal cancer.

BackgroundFluorouracil-based chemotherapy, such as that with 5-fluorouracil (5-FU)/leucovorin, is standard as first-line chemotherapy for advanced colorectal cancer (CRC) in Japan. However, the best agent for second-line chemotherapy after fluorouracil failure is yet to be determined. This study was undertaken to find an appropriate agent for second-line chemotherapy.MethodsSeventy-five tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their chemosensitivity to five anticancer agents; i.e., 5-FU, mitomycin C (MMC), cisplatin, docetaxel, and an active metabolite of irinotecan (SN-38), was analyzed in an in vitro chemosensitivity test. In this method, the degree of chemosensitivity was expressed as the percent T/C ratio, where T was the total volume of the tumor colonies in the treated group and C was that of the control group. Pearsons correlation coefficients were used to assess the relationship between two agents.ResultsFifty-eight specimens (colon, 28; rectum, 30) were successfully analyzed. Positive correlations with 5-FU chemosensitivity were verified for the chemosensitivity of MMC, cisplatin, and docetaxel. No correlation with 5-FU chemosensitivity was verified for SN-38 chemosensitivity. Although the functional mechanism of each of the agents differs from that of 5-FU, with the exception of irinotecan, they all had a spectrum closely similar to the 5-FU spectrum.ConclusionOnly irinotecan exhibited a spectrum independent of that of 5-FU, thus indicating that it could be an appropriate agent for second-line chemotherapy after fluorouracil failure.

Cetuximab retreatment in patients with metastatic colorectal cancer who exhibited a clinical benefit in response to prior cetuximab: A retrospective study

Clinical benefits of cetuximab retreatment in patients with metastatic colorectal (mCRC) have been reported. In the present study, the effect of cetuximab retreatment on predictive markers was investigated by evaluating the clinical benefit of initial cetuximab treatment prior to cetuximab retreatment. Between November 2012 and March 2017, 14 patients with KRAS proto-oncogene GTPase exon 2 wild-type mCRC who exhibited a clinical benefit (confirmed stable disease for at least 6 months or a clinical response) to an initial cetuximab-based regimen, who received multiple lines of chemotherapy following disease progression and ultimately received a second cetuximab and irinotecan regimen, were retrospectively analyzed. For retreatment, patients received bi-weekly irinotecan (120–150 mg/m2) combined with cetuximab (400 mg/m2 as an initial dose, followed by 250 mg/m2, weekly). The median age of the 14 patients (11 males, 3 females) was 68 years (32–77). The median progression-free survival (PFS) following prior cetuximab-based therapy was 6.6 months (range, 4.1–18.4). Initial cetuximab treatment was administered as a first-line treatment in 11 patients, a second-line treatment in 1 patient and a third-line treatment in 2 patients. The median interval time between the last cycle of initial cetuximab-based therapy and the first cycle of cetuximab retreatment was 13.1 months (range, 6.0–37.1). The objective response rate of cetuximab retreatment was 21.4% and the median PFS was 4.4 months (95% confidence interval, 1.4–5.6). The Spearmans correlation coefficient for the PFS following retreatment and duration of initial cetuximab-based regimens demonstrated a more marked correlation compared with that between the PFS following retreatment and the interval time between the two regimens (r=0.45, P=0.11 vs. r=0.08, P=0.79). Cetuximab retreatment may provide clinical benefit to patients with mCRC who were good responders with longer periods of initial cetuximab-based therapy.

Determination of a second-line chemotherapy agent for patients with colorectal cancer (CRC) after fluorouracil failure

3638 Background: Fluorouracil-based chemotherapy, such as with 5-FU/leucovorin, is standard as first-line chemotherapy for advanced CRCs. However, the best agent for chemotherapy after fluorouracil failure is still unknown. The primary objective of this study was to determine the best agent for second-line chemotherapy. METHODS Seventy-eight tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their sensitivity against five anticancer drugs, 5-FU, Mitomycin C, Cisplatine, Decetaxel and CPT-11, in an in vitro chemosensitivity test using CD-DST methods was analyzed. The chemosensitivity was expressed as the percentage T/C ratio, where T was the total volume of the treated group and C was that of the control group. Pearsons correlation coefficients were used to assess the relationship. P<0.05; statistically significant. A statistically significant correlation between two drugs was defined as a correlation of cross-resistance between them. Conversely, non-positive correlation was defined a correlation of no cross-resistance between them, with each of them having an independent spectrum. RESULTS Fifty-four specimens (colon, 30; rectum, 24) were successfully analyzed. The mean T/C ratios of 5-FU, Mitomycin C, Cisplatine, Decetaxel and CPT-11 were 79.1%, 69.9%, 81.2%, 59.4% and 63.8%, respectively. Although each of the agents has a different functional mechanism from that of 5-FU, with the exception CPT-11, all of them had a closely positive correlation with 5-FU. CONCLUSIONS Only CPT-11 expressed an independent spectrum from 5-FU, thus indicating it to be the best agent for second-line chemotherapy after fluorouracil failure. [Figure: see text] No significant financial relationships to disclose.