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5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is a minimally invasive therapeutic modality used in the management of various cancers, but to a lesser extent for esophageal cancer (EC). The current study investigated the antitumor effects of ALA-PDT. Human EC cells were treated with ALA, after which ALA-induced fluorescence was examined under a fluorescence microscope. The cytotoxic effects of ALA-PDT were assessed using three types of LEDs (blue, green and red) in vitro and in vivo. Subcutaneous tumor model mice was constructed with KYSE150 cells. ALA-PDT was performed once a week for 4 weeks and tumor weights were measured. A popliteal lymph node (PLN) metastasis murine model was generated using KYSE150 cells. KYSE150 cells were inoculated into the left footpad of nude mice. ALA-PDT was performed on the footpad once a week for 4 weeks. PLNs were then removed 3 weeks after the last treatment. The lymph nodes were evaluated by hematoxylin and eosin staining. Red fluorescence of protoporphyrin IX (PpIX) was observed in all EC cell lines. ALA-PDT using LEDs exerted significant antitumor effects in vitro and in vivo. The antitumor effects of ALA-PDT with blue LED were the strongest, followed by green and red LEDs. The number of metastasized PLNs was significantly smaller in the ALA-PDT group (0%) than in the control group (37.5%). The present results indicated that ALA-PDT is effective for EC.

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BACKGROUND: 5-aminolevulinic acid (5-ALA) has been utilized for cancer diagnosis as a fluorescence probe. We have reported the feasibility of 5-ALA-induced protoporphyrin IX (PpIX) fluorescence for detecting lymph node (LN) metastasis in gastrointestinal malignancies. However, a major barrier to the fluorescence diagnosis has been that the evaluation has been highly dependent on the observers. In this study, we examined the validity of a developed device for automated detection without subjectivity. METHODS: Gastric cancer patients who received oral administration of 5-ALA (20 mg/kg) prior to surgery were enrolled. For a total of 323 LNs obtained from 64 patients, the diagnostic results of the device were compared to those of conventional histopathological examination based on hematoxylin-and-eosin-stained slides. The accuracy with the device was compared to that of stereoscopic detection with conventional fluorescence microscopy for 211 LNs from 42 patients. We used two types of image processing that we previously developed to eliminate autofluorescence of background tissues: differential and ratio methods. RESULTS: For detection of metastasis in 323 LNs, the areas under the receiver operating characteristic curves with the differential method and ratio method were 0.921 and 0.909, respectively. The sensitivity, specificity, and accuracy with the differential method were 78.0%, 96.8%, and 94.4%; while those with the ratio method were 78.0%, 96.1%, and 93.8%, respectively. In 211 LN analysis, the diagnostic accuracy with the device was comparable to that of stereoscopic examination. CONCLUSION: Our device for automated detection of LN metastasis using 5-ALA can be a useful tool for intraoperative diagnosis.

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Peritoneal metastasis is an important prognostic factor for pancreatic cancer. The present study evaluated the possibility of diagnosing peritoneal metastasis by a photodynamic diagnosis using 5-aminolevulinic acid (5-ALA-PDD). In vitro, protoporphyrin IX (PpIX) accumulation was examined in the AsPC-1-GFP cell line following 5-ALA hydrochloride administration. In vivo, AsPC-1-GFP cells were injected into the peritoneal cavities of mice. Three weeks later 5-ALA hydrochloride was intraperitoneally administered to the mice. The peritoneal nodules were observed under fluorescence excitation. A total of 34 patients were enrolled in the present study who were clinically diagnosed with pancreatic malignancy. 5-ALA hydrochloride was orally administered to the patients prior to surgery. During the operation the abdominal cavity was observed under white light and fluorescence. In vitro and in vivo, it was confirmed that PpIX-induced red fluorescence. In 9 patients peritoneal nodules suspected to be peritoneal metastasis were observed under white light. In 4 of the 9 patients nodules were detected on the basis of the fluorescence images. Fluorescent nodules were histopathologically diagnosed as metastatic. In the present study it was confirmed that 5-ALA-PDD holds promise for the rapid diagnosis of peritoneal metastasis in patients with pancreatic cancer.

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Protoporphyrin IX (PpIX), a biochemical converted from 5-aminolevulinc acid (5-ALA) in living cells, is useful for intraoperative fluorescent detection of cancer metastasis in lymph nodes (LNs). However, unknown is whether the fluorescence of PpIX can be detected in the LNs when they coexist with indigo carmine, a blue dye commonly used for identification of sentinel LNs during surgery. To address this issue, we sought to evaluate the diagnostic usefulness of PpIX fluorescence in the presence of indigo carmine in a mouse LN metastasis model of rectal cancer after administration of 5-ALA. Spectral analysis of pure chemicals revealed that the absorption spectrum of indigo carmine widely overlapped with the fluorescence spectrum of PpIX specifically at the peak of 632nm, a common emission wavelength for detecting PpIX, but not at the other peak of 700nm. Due to such spectral overlap, the PpIX fluorescence intensity was significantly attenuated by mixture with indigo carmine at 632nm, but not at 700nm. Accordingly, fluorescent measurements of the mouse metastatic LN revealed more intense presentation of PpIX at 700nm than at 632nm, indicating that the diagnostic usefulness is greater at 700nm than at 632nm for the indigo carmine-dyed LNs after administration of 5-ALA. From these observations, we propose that the fluorescence measurement is more efficient at 700nm than at 632nm for detection of PpIX in metastatic LNs stained with indigo carmine.

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5-aminolevulinic acid (5-ALA)-based fluorescence diagnosis is now clinically applied for accurate and ultrarapid diagnosis of malignant lesions such as lymph node metastasis during surgery. 5-ALA-based diagnosis evaluates fluorescence intensity of a fluorescent metabolite of 5-ALA, protoporphyrin IX (PPIX); however, the fluorescence of PPIX is often affected by autofluorescence of tissue chromophores, such as collagen and flavins. In this study, we demonstrated PPIX fluorescence estimation with autofluorescence elimination for 5-ALA-based fluorescence diagnosis of malignant lesions by simplified and optimized multispectral imaging. We computationally optimized observation wavelength regions for the estimation of PPIX fluorescence in terms of minimizing prediction error of PPIX fluorescence intensity in the presence of typical chromophores, collagen and flavins. By using the fluorescence intensities of the optimized wavelength regions, we verified quantitative detection of PPIX fluorescence by using chemical mixtures of PPIX, flavins, and collagen. Furthermore, we demonstrated detection capability by using metastatic and non-metastatic lymph nodes of colorectal cancer patients. These results suggest the potential and usefulness of the background-free estimation method of PPIX fluorescence for 5-ALA-based fluorescence diagnosis of malignant lesions, and we expect this method to be beneficial for intraoperative and rapid cancer diagnosis.

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A 37-year-old man visited a previous hospital because of left abdominal pain. A contrast-enhanced CT scan revealed a 7 cm solid tumor in the pancreas body, and the patient was referred to our hospital. EUS-FNA showed that the tumor cells were positive for b-catenin in the nuclei, as well as for CD10 and CD56. On the other hand, the cells were negative for chromogranin A and synaptophysin. This is the typical immunohistochemical pattern of a solid pseudopapillary neoplasm(SPN). Therefore, we diagnosed this case as SPN before surgery. As the tumor progressed rapidly in 2 months, we performed distal pancreatectomy, total gastrectomy, and partial liver resection of the left lateral segment because of suspicious invasion of the pancreatic tumor to the stomach and the liver. On histological examination of the resected specimen, tumor invasion to the stomach was apparent, but the tumor did not invade the liver. Immunohistochemical staining showed the same SPN pattern as the EUS-FNA results. We identified small and uniform tumor cells, although no pseudopapillary pattern was observed with HE staining. Finally, we diagnosed this case as an undifferentiated carcinoma. We need to consider the possibility of malignant transformation or undifferentiated carcinoma even when a tumor is diagnosed as SPN on EUS-FNA.

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OBJECTIVE: Although the efficacy of adjuvant chemotherapy with oxaliplatin for colorectal cancer patients has been established, the tolerability of this regimen is rarely reported in Japan. The aim of this study was to clarify the tolerability of adjuvant oxaliplatin-based regimen for Japanese patients with colorectal cancer. METHODS: This study included 158 advanced colorectal cancer patients who consecutively underwent a surgical procedure at our hospital and received adjuvant chemotherapy. Completion rate and adverse events were monitored in this study. RESULTS: Among the 158 patients, 44 received oxaliplatin-based chemotherapy and the remaining received chemotherapy without oxaliplatin. The use of oxaliplatin was significantly correlated with more cases of adverse events such as myelosuppression (p<0.001) and peripheral neurotoxicity (p=0.005), which lead to dose reduction (p<0.001) or drug withdrawal (p<0.001). However, the completion rate did not significantly differ between the 2 groups. The median relative dose intensity (RDI) was 85.7%, which means that the oxaliplatin-based regimen is feasible. As for recurrence-free survival, no significant differences were observed between the 2 groups. CONCLUSION: This study demonstrates that adjuvant chemotherapy with oxaliplatin is tolerable by colorectal cancer patients in Japan.

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In advanced gastric cancer patients, preoperative multi detector row computed tomography (MDCT) often reveals abnormal ascites, which can indicate the possibility of peritoneal metastasis. The aim of this study was to clarify the clinical significance of preoperative ascites revealed by MDCT in gastric cancer patients. The study included a total of 183 advanced gastric cancer patients who underwent consecutive surgical procedures from February 2008 to November 2011. The results indicate that the presence of ascites on MDCT is significantly correlated with peritoneal metastasis (p<.005), pathological T4 (p< 0.005), R1-R2 (p<.01), and a positive diagnosis of peritoneal washing cytology(p<.05). Multivariate analysis indicated that the presence of ascites on MDCT was an independent prognostic factor (hazard ratio[HR]2.6). In conclusion, the presence of ascites on preoperative MDCT is strongly associated with peritoneal metastasis, and might indicate the need for diagnostic laparoscopy to evaluate Stage IV factors and select the best treatment strategy.

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Case 1: A 58-year-old man who initially presented with diarrhea was diagnosed with rectal gastrointestinal stromal tumor (GIST). The patient initially received neoadjuvant therapy with imatinib mesylate. After imatinib therapy( 400 mg/day) for 23 weeks, the patient's abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a reduction of approximately 67% in tumor size. He underwent sphincter-preserving surgery with intersphincteric resection, and the tumor was resected radically and safely. Case 2: A 66-year-old man with a complaint of hematochezia was diagnosed with rectal GIST during treatment for infective endocarditis. Neoadjuvant imatinib therapy (400 mg/day) was started. However, the treatment was stopped after 11 weeks because of rhabdomyolysis, which was suspected to be an adverse effect of imatinib administration. Abdominal CT and MRI revealed a reduction of approximately 53% in tumor size. A radical operation was considered feasible and sphincter-preserving surgery with intersphincteric resection was performed. Currently, neoadjuvant imatinib mesylate therapy is performed in the setting of clinical trials, but the cases suggest that it can be a promising strategy for locally advanced rectal GIST, improving the complete resection rate and the safety of operations by reducing the size of the tumor.

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