Yuki Yamane

Expression of podoplanin, CD44, and p63 in squamous cell carcinoma of the lung

Recent molecular biological studies have identified podoplanin as a candidate cancer stem cell (CSC) marker in squamous cell carcinoma (SqCC). The purpose of this study was to examine the expression pattern of podoplanin, and the other stem cell markers CD44 and p63, and their relationship to clinico‐pathological features including survival in pulmonary SqCC. We examined histologically the expression of podoplanin, CD44, and p63 in 162 consecutive SqCC by immunostaining. Podoplanin expression was observed in 107 (66%) tumors, CD44 in 145 (89.5%), and p63 in 151 (93.2%), respectively. In 95.3% of the podoplanin‐positive tumors, tumor cells showing strong expression were localized in the periphery of the tumor nests. However, this peripheral localization was observed in only 55.9% of the CD44‐positive and 43% of p63‐positive tumors. In 88.8% of the podoplanin‐positive tumors, positive cells were localized more peripherally in the tumor nests than CD44‐ or p63‐positive cells and when CD44 and p63 expressions were compared in these podoplanin‐positive tumors, p63‐positive layers in the periphery of the tumor nests were broader compared to CD44‐positive layers. These findings suggest tumor cells are aligned in the “hierarchical distribution pattern” according to the expression of these three markers. Patients who had podoplanin‐positive tumors with the “hierarchical pattern” resulted in significantly better overall survival than those who had podoplanin‐negative tumors (P = 0.043). These results suggest that podoplanin expression would reflect the most immature status in the differentiation process of SqCC, and SqCC with hierarchical expression would be a well‐organized tumor group with lower biological aggressiveness based on the CSC concept. (Cancer Sci 2009)

Identification and Characterization of Cancer Mutations in Japanese Lung Adenocarcinoma without Sequencing of Normal Tissue Counterparts

We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.

A Novel Histopathological Evaluation Method Predicting the Outcome of Non-small Cell Lung Cancer Treated by Neoadjuvant Therapy The Prognostic Importance of the Area of Residual Tumor

Background: Histopathological evaluation method for predicting the outcome of non-small cell lung cancer (NSCLC) treated by neoadjuvant therapy has not been fully assessed. The purpose of this study was to assess a novel histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy. Methods: We reviewed the histopathology of the tumors of 53 NSCLC treated by neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy followed by complete resection and identified the histologic features produced by neoadjuvant therapy by comparing them with the histologic features of the tumors in 138 NSCLC cases treated by surgery without neoadjuvant therapy. We also measured the area of residual tumor (ART) on the maximum cut surface of the tumors and analyzed the relationships between the histologic features, ART, and the outcome. Results: The proportions of cases with the histologic features “cholesterin clefts,” “foreign body reactive giant cells,” “stromal hyalinosis,” and “bizarre nucleus in more than 50% of the cancer cells” were significantly higher in the neoadjuvant therapy group than in the surgery alone group. However, the presence of none of these features had any significant effect on survival. Although pathologic T factor and N factor had no significant effect on overall survival, smaller ART (≤400 mm2) and absence of pleural invasion (p [−]) were predictors of a outcome (p = 0.014 and p = 0.003, respectively). Conclusions: Smaller ART and p (−) predict a better outcome of NSCLC treated by neoadjuvant therapy. We concluded that ART is a novel histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy.

Area of residual tumor beyond the muscular layer is a useful predictor of outcome in rectal cancer patients who receive preoperative chemoradiotherapy.

The purpose of the present study was to determine whether the amount and the location of residual tumor are associated with outcome in surgically treated rectal cancer patients who receive preoperative chemoradiation therapy. Forty‐three rectal cancer patients who underwent sphincter‐saving operations after preoperative chemoradiation therapy were enrolled in the study. The total area of residual tumors was measured using morphometry software, and then the area of the residual tumors located within and beyond the muscular layer was also determined. Associations between clinicopathological features were evaluated. The results showed that the total area of residual tumor and area of residual tumor within the muscular layer were associated with TNM stage, tumor regression, and microscopy features, but not with patient disease‐free survival. The area of the residual tumor located beyond the muscular layer was significantly associated with pathological ypT, ypN stage, tumor downstaging, perineural invasion, and the depth of tumor invasion beyond the muscular layer (P < 0.05). Further, large residual tumor area beyond the muscular layer was associated with shorter disease‐free survival (P < 0.05). Morphometry of residual tumor area beyond the muscular layer is a new pathological prognostic factor for rectal cancer patients receiving preoperative chemoradiation therapy.

1519PORAL HYDRATION AS A POST-HYDRATION METHOD FOR CISPLATIN (CDDP) ADMINISTRATION IN PATIENTS WITH LUNG CANCER: A PROSPECTIVE MULTICENTER TRIAL

ABSTRACT Aim: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous (IV) hydration after CDDP administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years, and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant and dexamethasone. CDDP was administered after IV pre-hydration with MgSO4 (8 mEq) and KCL. Five hundred milliliters of commercially available oral hydration solution (OS-1®: Otsuka Pharmaceutical Factory, Inc., Japan) was used as a substitute for IV post-hydration and was administered orally within an hour after CDDP administration. OS-1® contains 50 mEq/L of NaCl, 20 mEq/L of K and 2 mEq/L of MgSO4. The primary endpoint was the proportion of patients without a grade (G) 2 or higher creatinine (Cr) elevation after the first cycle of chemotherapy. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 64 (33-74) years were enrolled from three institutions. Of these, 5 received adjuvant chemotherapy, 17 received definitive chemoradiotherapy, and 24 received chemotherapy for advanced diseases. All the patients were able to consume OS-1® within 1 hour without requiring IV post-hydration. The median (range) number of chemotherapy cycles was 4 (3-5). Seven patients received additional IV hydration on day 2 or later, with a median duration (range) of 2 (1-19) days, mainly because of chemotherapy-related anorexia. After the first cycle of CDDP administration, none of the patients experienced a Cr elevation of G 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%) completed the CDDP-based chemotherapy without G 2 or higher renal dysfunction. The only patient who experienced a G 2 elevation in Cr (maximum value, 1.97 mg/dL) experienced G 3 chemotherapy-induced diarrhea and exhibited a prompt improvement in the Cr level to 1.11 mg/dL after the resolution of the diarrhea. Conclusions: Oral hydration can be used as a safe and convenient substitute for IV post-hydration for CDDP administration at the standard dose. Disclosure: K. Kubota: Honoraria from TAIHO PHARMACEUTICAL CO., LTD.; All other authors have declared no conflicts of interest.

Oral rehydration solution (OS-1) as a substitute of intravenous hydration after cisplatin administration in patients with lung cancer: a prospective multicenter trial

Background The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33–74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1–5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number UMIN000010201.