Extended Total Mesorectal Excision Based on the Avascular Planes of the Retroperitoneum for Locally Advanced Rectal Cancer with Lateral Pelvic Sidewall Invasion.

INTRODUCTION: It has been considered difficult to achieve en bloc resection in cases of locally advanced rectal cancer with lateral pelvic sidewall invasion. The present study demonstrates a novel surgical procedure for these tumors. TECHNIQUE: There are 3 avascular planes of the retroperitoneum in the pelvic sidewall. Two visceral pelvic fasciae, namely the ureterohypogastric fascia and umbilical prevesical fascia, and the parietal pelvic fascia can be identified. In addition, the key structures of these fasciae, the ureter, umbilical artery, and external iliac vessels, can be identified transperitoneally before any dissection. Thus, these 3 avascular planes can be dissected without resorting to dissection of the retrorectal space. The key steps to this technique are: 1) after dissection from the side opposite to the site of tumor invasion to the dorsal side of the rectum, the avascular planes of the retroperitoneum among the 3 above-mentioned fasciae are dissected; and 2) the retrorectal space and pelvic sidewall space are connected by sharp dissection. RESULTS: Recognizing the 3 above-mentioned fasciae enables the dissection of the avascular planes of the pelvic sidewall, which helps to achieve en bloc dissection in cases of locally advanced rectal cancer with lateral pelvic sidewall invasion. CONCLUSION: The pelvic sidewall could be divided into 3 areas based on the visceral pelvic fasciae, which has helped to achieve en bloc dissection in cases of locally advanced rectal cancer with lateral pelvic sidewall invasion.

Sacrectomy for Recurrent Rectal Cancer Using the Transanal Total Mesorectum Excision Technique.

INTRODUCTION: In high sacrectomy, it is difficult to secure the lateral surgical margin and prevent severe postoperative complications. In this report, we present our unique surgical procedure using transanal total mesorectal excision for locally recurrent rectal cancer. TECHNIQUE: A 49-year-old woman was diagnosed with locally rerecurrent rectal cancer, which was located at the height of the S3 vertebra by preoperative imaging, and posterior pelvic exenteration concomitant with high sacrectomy below the S2 vertebra was planned. A multiaccess transperineal platform was placed to secure the lateral surgical margin using transperineal minimally invasive surgery during the perineal and sacral side procedure. Transperineal minimally invasive surgery has several clinical benefits over the conventional approach. For the perineal approach, a 2-team laparoscopic approach was performed. This surgical intervention with laparoscopic perineal assistance contributed to the completion of the dissection of the planned lateral surgical margin, such as the distal piriformis muscles and the sacrotuberous and sacrospinous ligaments, which are the most difficult areas to access in the lithotomy position. Regarding the sacral approach, it facilitated the dissection of the dorsal space of the sacrum; therefore, only a 7-cm transverse skin incision was required during sacrectomy. Small skin incisions and minimal dissection may reduce surgical site infections. RESULTS: The operative time was 933 minutes, with 80 mL of blood loss. There were no major complications, and pathologically confirmed curative resection was achieved. CONCLUSIONS: Our new technique utilizing transanal total mesorectum excision is feasible to secure the lateral surgical margin with minimal skin incision and dissection and may prevent severe postoperative complications.

Long-term clinical outcomes and follow-up status in Japanese patients with familial adenomatous polyposis after radical surgery: a descriptive, retrospective cohort study from a single institute.

PURPOSE: Data on long-term outcomes of familial adenomatous polyposis (FAP) are unclear in Japan because a nationwide registry system is lacking. We assessed overall survival, incidence of neoplasms, fecal incontinence, and postoperative follow-up status of patients with FAP treated surgically in our hospital. METHODS: In total, 154 patients with FAP who underwent radical surgery from 1981 to 2017 in our department were available for the questionnaire. Sixty-five patients, 36 of whom were followed at our hospital, were assessed using clinical records and the questionnaire. RESULTS: The median follow-up time was 187 months (interquartile range, 93.5-296 months). The median age at surgery was 36 years (range, 12-69 years). The 5-, 10-, 15-, and 20-year overall survival rate was 100%, 98%, 95%, and 89%, respectively. All five deaths were caused by diseases other than colorectal cancer. FAP-related neoplasms comprised 23 colorectal cancers, five duodenal cancers, three gastric cancers, five thyroid cancers, two ileal pouch cancers, and nine desmoid tumors. The incidence of desmoid tumors was significantly associated with the operation date. The duration from radical surgery to neoplasm onset significantly differed by neoplasm type. Forty-five of 54 patients (excluding those who died or underwent ileostomy) developed fecal incontinence (median Wexner score of 8). Surgical procedures involving hand-sewn sutures with rectal mucosal stripping were significantly associated with fecal incontinence and the Wexner score. Fifty-eight of the 60 surviving patients underwent follow-up examinations. CONCLUSION: Overall survival was favorable. Fecal incontinence depended on the surgical procedures. Most patients continued to receive follow-up examinations. TRIAL REGISTRATION: No. 3112 by Institutional Review Board of Hyogo College of Medicine.

UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan.

The purpose of the present study was to assess the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan against locally advanced lower rectal cancer according to UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms. Between 2009 and 2016, 46 patients with resectable rectal cancer (T3-T4, N0-N2, M0) received preoperative chemoradiotherapy consisting of 80 mg/m2 per day tegafur/gimeracil/oteracil (S-1; days 1-5, 8-12, 22-26, and 29-33), 60 mg/m2 per day irinotecan (days 1, 8, 22, and 29), and 45 Gy radiation (1.8 Gy/day, 5 days per week for 5 weeks). Six to eight weeks after completing chemoradiotherapy, total mesorectal excision was carried out. Patients with UGT1A1 polymorphisms were divided into WT (n = 26), heterozygous (n = 15), and homozygous (n = 5) groups, the latter including double heterozygosities. We evaluated associations between clinical characteristics, including UGT1A1 polymorphisms, and chemoradiotherapy efficacy and toxicity. Incidence rates of grade 3+ neutropenia and diarrhea were 17.0% and 30.4%, respectively. Relative dose intensity was 89.3%. Pathological complete response rate (grade 3) was 26.1%, and the good response (grade 2/3) rate was 84.8%. UGT1A1 polymorphisms were significantly associated with neutropenia and pathological good responses, but not with diarrhea. UGT1A1 polymorphism was the only predictive factor for pathological good responses. Our results indicate that UGT1A1 polymorphism is a predictive factor to determine the clinical efficacy of preoperative chemoradiotherapy and hematological toxicity induced by chemoradiotherapy using irinotecan in locally advanced rectal cancer patients.

[Two Cases of CT-Guided Radiofrequency Ablation Therapy for Pelvic Recurrence from Rectal Cancer].

We experienced 2 cases of pelvic recurrence from rectal cancer. These patients received radiofrequency ablation(RFA) therapy. Case 1 was a 76-year-old man who underwent intersphincteric resection for lower rectal cancer in October 2013. In May 2015, the patient received systemic chemotherapy for multiple lung metastases and pelvic local recurrence. In January 2017, RFA was performed to reduce the pain of the pelvic recurrence. Immediately after RFA, the pain markedly reduced, and 2 months after treatment, the patient discontinued his pain therapy. Case 2 was a 48-year-old man who underwent Hartmann 's procedure for ulcerative colitis with rectal cancer in November 2011. In July 2012, we performed abdominoperineal resection for rectal cancer that developed in the remnant rectum. In November 2012, he received systemic chemotherapy for multiple lung metastases and pelvic recurrence. In addition, we performed stereotactic radiotherapy(SRT)for the pelvic recurrence. In May 2016, because he developed bilateral hydronephrosis and painful pelvic recurrence, we performed bilateral nephrostomy and RFA for the painful pelvic recurrence. After RFA, pain reduced, but he developed a pelvic abscess that was treated by CT-guided drainage. He underwent complete ablation for the recurrent pelvic mass 2 years after RFA but died of exacerbation of multiple lung metastases. CT-guided RFA for painful pelvic recurrence from rectal cancer can be considered a feasible and effective treatment to reduce pain.

Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan.

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are major sources of hereditary colorectal cancer (CRC) and are associated with other malignancies. There is some heterogeneity in management strategies in Japan. We undertook a survey of management of hereditary CRC in hospitals that are members of the Japan Society of Colorectal Cancer Research. One hundred and ninety departments responded, of which 127 were from designated cancer care hospitals (DCCHs) according to the Japanese government. There were 25 488 operations for CRC in these departments in 2015. The DCCHs performed better with regard to usage of Japan Society of Colorectal Cancer Research guidelines, referring new CRC patients for LS screening, and having in-house genetic counselors and knowledge of treatment for LS. There were 174 patients diagnosed with LS and 602 undergoing follow-up in 2011-2015, which is fewer than the number expected from CRC operations in 2015. These numbers were not affected by whether the institution was a DCCH. Universal screening for LS was carried out in 8% of the departments. In contrast, 541 patients were diagnosed with FAP and 273 received preventive proctocolectomy/colectomy in 2011-2015. The DCCH departments undertook more surgery than non-DCCH departments, although most of the management, including surgical procedures and use of non-steroidal anti-inflammatory drugs, was similar. Management of desmoid tumor in the abdominal cavity differed according to the number of patients treated. In conclusion, there was heterogeneity in management of LS but not FAP. Most patients with LS may be overlooked and universal screening for LS is not common in Japan.

[A Case of Cecal Cancer with Para-Aortic Lymph Node Metastasis and Peritoneum Dissemination Treated with Curative Resection after mFOLFOX6 plus Panitumumab Chemotherapy].

A 67-year-old woman was diagnosed with cecal cancer, para-aortic lymph node metastasis, peritoneum dissemination, and left breast cancer. We administered mFOLFOX6 plus panitumumab for cecal cancer and an aromatase inhibitor for her breast cancer. She received 7 courses of systemic chemotherapy and showed a partial response. She additionally received 5 courses of mFOLFOX6 plus panitumumab. We performed ileocecal resection, sigmoidectomy, right oophorectomy, dissection of the para-aortic lymph nodes, and peritoneal dissemination. The histopathological findings revealed adenocarcinoma, ypT3, ypN0, ycM0, ypStage II (therapeutic effect Grade 2). One month later, she underwent an enforced left breast segmental resection and sentinel lymph node biopsy(0/2). The results of the pathological examination indicated no residual cancers (therapeutic effect Grade 3). The patient is now in good health and was administered S-1 as an outpatient.

[Two Cases of Achieving a Pathological Complete Response via Hepatic Arterial Infusion Chemotherapy for Liver-Limited and Unresectable Liver Metastases from Colorectal Cancer with RAS Mutations].

We had 2 cases of liver-limited and unresectable liver metastases from colorectal cancer with RAS mutations. These patients received hepatic arterial infusion chemotherapy(HAI), finally achieving pCR. Case 1 was a 76-year-old female with rectosigmoid cancer and multiple liver metastases. We underwent anterior resection for primary lesion. After surgery, the patient had received first-line and second-line systemic chemotherapy for the multiple liver metastases. The patient achieved SD and had Grade 3 neutropenia. We then performed HAI as third-line chemotherapy and we therefore underwent hepatectomy. The results of the pathological examination after hepatectomy pCR and is currently alive without cancer recurrence for 61 months. Case 2 was a 53-year-old male with sigmoid colon cancer and multiple liver metastases. We underwent sigmoidectomy with laparoscopic assistance. Three months after surgery, we underwent resection of the lateral segment of the liver under laparoscopy. This patient had cancer recurrence in the remnant liver at 6 months after surgery and had received first-line systemic chemotherapy. The patient had Grade 3 neutropenia after 1 course of chemotherapy and showed no improvement. We then performed HAI as second-line chemotherapy, and we therefore underwent hepatectomy. The results of the pathological examination after hepatectomy were pCR and he is currently alive without cancer recurrence for 30 months.

[Radiofrequency Ablation Pulmonary Metastasis of Colorectal Cancer - Two Cases of Report].

Case 1: 63-year-old woman received abdominoperineal resection with lateral lymph node dissection for rectal cancer in 2008. After adjuvant chemotherapy, she suffered from lung metastasis and received partial pneumonectomy in 2012. However, chemotherapy was performed again for lung metastasis and mediastinal lymph nodes in 2013. Radiofrequency ablation (RFA)was performed to lung metastasis in 2016 due to ineffectiveness of chemotherapy. Case 2: 81-year-old man received Hartmann's procedure for rectal cancer with lung and liver metastasis in 2012. After 6 months of chemotherapy, liver partial resection and pulmonary partial resection were performed. In spite of additional chemotherapy, He received partial pneumonectomy in 2013. In 2014, he restart chemotherapy due to lung metastasis. In 2016, he received RFA for lung metastasis because of ineffectiveness of chemotherapy. After that, he received g-knife for brain metastasis. He is going to receive RFA for another lung metastasis.

Malnutrition in rectal cancer patients receiving preoperative chemoradiotherapy is common and associated with treatment tolerability and anastomotic leakage.

PURPOSE: This study assessed the incidence of malnutrition caused by preoperative chemoradiotherapy (CRT) in rectal cancer patients, which is seemingly underestimated; however, malnutrition affects treatment tolerability, postoperative complications, including anastomotic leakage (AL), and oncological outcomes. METHODS: Between January 2008 and December 2014, 54 consecutive patients with T3-4, N0-2, M0-1 resectable rectal cancer received CRT comprising 45 Gy radiotherapy and S-1 alone or with irinotecan for 5 weeks and then underwent curative surgery with diverting or permanent stomas 6-8 weeks after CRT. We assessed malnutrition after completion of CRT (5-6 weeks after CRT start date) and at surgery (11-14 weeks after CRT start date), defining weight loss as ≥5 % of pre-CRT weight; this definition differs from commonly used criteria for adverse events. We evaluated the incidence of malnutrition associated with CRT and influence of malnutrition on treatment tolerability, AL, and disease-free survival (DFS). We also assessed the influence of CRT on the rate of postoperative complications by comparing the study group with 61 patients who had undergone excision with diverting or permanent stomas alone. RESULTS: Malnutrition was observed in 51 % of patients after CRT and in 29 % at surgery. Malnutrition after CRT was associated with treatment tolerability, and malnutrition at surgery was significantly associated with AL, which significantly influenced DFS in stage 1-3 patients. CONCLUSION: Malnutrition caused by CRT is common and is associated with treatment tolerability and AL. Nutritional assessment and support seem indispensable for the rectal cancer patients receiving CRT.

Current topics of colorectal cancer screening.

Despite the recent advancement of the treatment including endoscopic resection, surgery, and systemic chemotherapy, mortality rate of colorectal cancer(CRC) has been increasing in Japan. Therefore, the strategy for CRC should be focused to both the early diagnosis by efficient screening and prevention. The screening using fecal occult blood test and subsequent total colonoscopy has been recognized as a gold standard of CRC screening, however, the checkup rate of these examinations is still very low in Japan. It is considered to be important to improve this checkup rate and now, the new modalities, such as computed tomographic colonography or capsule colon endoscopy, are expected to be involved in the clinical practice of CRC screening.

Prognostic significance of classified extramural tumor deposits and extracapsular lymph node invasion in T3-4 colorectal cancer: a retrospective single-center study.

BACKGROUND: Extramural tumor deposits (TDs) and extracapsular lymph node involvement (ECLNI) are considered to be poor prognostic factors in patients with T3-4, N0-2, M0 colorectal cancer (CRC). Although TDs are known to have multiple origins and pleomorphic features, the prognostic significances of the different type of TDs have not yet been established. METHODS: We performed a retrospective review of 385 consecutive patients with T3-4, N0-2, M0 CRC who received curative resection at our institution between 2006 and 2012. We classified the TDs into two groups: invasive-type TD (iTD), which is characterized by the presence of lymphatic invasion, vascular invasion, perineural invasion, or undefined cancer cell clusters and nodular-type TD (nTD), which is characterized by a smooth or irregular-shaped tumor nodule other than an iTD. ECLNI was defined as invasion of cancer cells into capsular collagen tissues or adipose tissues beyond the capsular collagen. Multivariate analyses were used to assess the prognostic significance of iTD, ND, and ECLNI for relapse-free survival (RFS), disease-specific survival (DSS), and sites of recurrence. RESULTS: In patients without lymph node (LN) metastasis, the incidences of iTD and nTD were both in the range of 2-3 %. Conversely, in patients with LN metastasis, the incidences of iTD, nTD, and ECLNI were 31, 22, and 34 %, respectively. iTD, nTD, and ECLNI were all significant independent adverse factors for RFS in rectal cancer, and were all associated with pT, pN, and LN ratio. iTD was a significant independent adverse prognostic factor for DSS in rectal cancer, metastasis to the liver in colorectal cancer, and distant LN metastasis in colon cancer. ECLNI was a significant independent prognostic factor for RFS in colon cancer. CONCLUSIONS: Classifying TDs and assessing ECLNI may help establish significant prognostic factors for patients with T3-4, N0-2, M0 CRC.

Comparison of the pathological response of the mesorectal positive nodes between short-course chemoradiotherapy with delayed surgery and long-course chemoradiotherapy in patients with rectal cancer.

BACKGROUND: The aim of this study was to compare the pathological response of mesorectal positive nodes between short-course chemoradiotherapy with delayed surgery (SCRT-delay) and long-course chemoradiotherapy (LC-CRT) in patients with rectal cancer. METHOD: The resected primary tumor specimens following the two different approaches were assessed utilizing the tumor regression grade (TRG 0-4), and each positive lymph node was assessed according to the lymph node regression grade (LRG 1-3), with TRG 4 and LRG 3 indicating total regression. The lymph node sizes were measured to elucidate any correlation with LRG scores. RESULTS: Seventy-four patients with ypN-positive rectal cancer had 220 positive lymph nodes following the SCRT-delay, and 48 patients had 141 positive lymph nodes following the LC-CRT. The distribution of LRG 1/2/3 in the two groups was 123/72/25 and 60/31/50 (p < 0.001), respectively, and the distribution of TRG 0/1/2/3/4 in the two groups was 36/19/19/0 and 12/15/20/1 (p = 0.005), respectively. The requirements of total regression of positive lymph nodes were a primary tumor degenerated to TRG 3 with a size less than 6 mm in SCRT-delay (sensitivity, 60.9 %) or a primary tumor degenerated to TRG 2-4 with a size less than 5 mm at TRG 2 (sensitivity, 57.6 %) or 6 mm at TRG 3 and 4 (sensitivity, 84.2 %) in LC-CRT as indicated by the receiver operating characteristic curve analysis. CONCLUSION: The tumor regression effect of LC-CRT on the primary tumor and positive nodes was more favorable than SCRT-delay, and LC-CRT is able to predict the LRG 3 response with a high sensitivity.

The timing of surgery after preoperative short-course S-1 chemoradiotherapy with delayed surgery for T3 lower rectal cancer.

PURPOSE: The purpose of this study was to analyze the influence of variations in clinical practice regarding the timing of surgery with short-course chemoradiotherapy with delayed surgery (SCRT-delay) for lower rectal cancer. METHODS: A total of 171 patients with T3 N0-2 lower rectal cancer treated with SCRT-delay (25 Gy/10 fractions/5 days (S-1); days 1-10) were retrospectively evaluated. The median waiting period of 30 days was used as a discriminator (group A: waiting period, ≤30 days; group B: waiting period, ≥31 days). Preoperative treatment responses and oncological outcomes were analyzed. RESULTS: The mean waiting periods for groups A and B were 24.4 ± 5.3 and 41.4 ± 12.3 days, respectively. There were no statistically significant differences between the two groups in any of the clinical variables. The clinicopathological outcomes were as follows: T downstaging (43.5 vs 37.2 %; p = 0.400), negative yp N (67.1 vs 75.6 %; p = 0.218), pCR (7.1 vs 1.2 %; p = 0.119). The 5-year local recurrence-free survival (89.3 vs 87.6 %; p = 0.956), the recurrence-free survival (82.2 vs 78.8 %; p = 0.662), and the overall survival (88.5 vs 84.4 %; p = 0.741), all of which were similar between the two groups. CONCLUSIONS: The longer waiting period did not increase the tumor downstaging and not improve the oncological outcomes for T3 lower rectal cancer treated with SCRT-delay. In addition, considering that the impaired leukocyte response occurred during the sub-acute period, any time after the sub-acute period (day 12) up to 30 days after radiotherapy would be a suitable waiting period.

[Assessment of malignant grade of colorectal cancer].

In recent years, colorectal cancer has become a very common malignancy in Japan. In the treatment strategy for each patient with colorectal cancer, the evaluation for malignant grade, represented as a recurrence rate, prognosis, etc., is very important. Various biological and/or molecular factor(s) have been investigated in terms of the relationship to malignant phenotype and its predictive value of prognosis, however, none of them has been proved to be clinically useful so far. Recently, several markers have been shown to be useful as the predictive marker for recurrence, especially in Stage II/III colorectal cancer. Among them, microsatellite instability (MSI), gene expression profile analysis, and micro RNA as a topic are briefly introduced in this minireview.

Outcomes of Metastatic and Unresectable Small Bowel Adenocarcinoma in Japan According to the Treatment Strategy: A Nationwide Observational Study.

PURPOSE: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA. METHODS: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests. RESULTS: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively. CONCLUSION: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

Clinicopathological features and prognosis of primary small bowel adenocarcinoma: a large multicenter analysis of the JSCCR database in Japan.

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma.

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma.

[A novel genetic disorder of Lynch syndrome - EPCAM gene deletion].

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, HNPCC, is a cancer-predisposing autosomal-dominant hereditary disorder caused by defects of the mismatch repair(MMR)system during DNA replication. Not only colorectal cancer, but malignancies in various organs, e.g., endometrium, stomach, small intestine, and urinary tract, occur in people of a relatively young age and accumulate in the family; therefore, this syndrome is considered to be a very important clinical entity with regard to the cancer treatment strategy. Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3'part of epithelial cell adhesion molecule(EPCAM) gene which is located upstream of the MSH2 gene, has been reported in recent years. Therefore, it should be kept in mind in genetic testing and/or counseling for Lynch syndrome case with MSH2 defect that there might be a deletion of the EPCAM gene. In this review, the significance of the EPCAM gene defect in the management for Lynch syndrome is briefly introduced.