Makiko Tahara

The Use of Olaparib (AZD2281) Potentiates SN-38 Cytotoxicity in Colon Cancer Cells by Indirect Inhibition of Rad51-Mediated Repair of DNA Double-Strand Breaks

Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)–deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase–specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage–reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy. Mol Cancer Ther; 13(5); 1170–80. ©2014 AACR.

Cell diameter measurements obtained with a handheld cell counter could be used as a surrogate marker of G2/M arrest and apoptosis in colon cancer cell lines exposed to SN-38

In vitro assessment of chemosensitivity are important for experiments evaluating cancer therapies. The Scepter 2.0 cell counter, an automated handheld device based on the Coulter principle of impedance-based particle detection, enables the accurate discrimination of cell populations according to cell size and volume. In this study, the effects of SN-38, the active metabolite of irinotecan, on the colon cancer cell lines HCT116 and HT29 were evaluated using this device. The cell count data obtained with the Scepter counter were compared with those obtained with the (3)H-thymidine uptake assay, which has been used to measure cell proliferation in many previous studies. In addition, we examined whether the changes in the size distributions of these cells reflected alterations in the frequency of cell cycle arrest and/or apoptosis induced by SN-38 treatment. In our experiments using the Scepter 2.0 cell counter, the cell counts were demonstrated to be accurate and reproducible measure and alterations of cell diameter reflected G2/M cell cycle arrest and apoptosis. Our data show that easy-to-use cell counting tools can be utilized to evaluate the cell-killing effects of novel treatments on cancer cells in vitro.

Sigmoid colon carcinoma with focal neuroendocrine differentiation associated with ulcerative colitis: A case report.

Highlights • Colorectal carcinomas with neuroendocrine differentiation in UC are rare entity.• Most of clinical presentations are shared with adenocarcinomas associated with UC. However, malignant potential may be higher.• Surgical treatment should be recommended, if tumors are resectable.• Best chemotherapy for this tumor is unknown, and further studies are required.

Partial duplication of MSH2 spanning exons 7 through 14 in Lynch syndrome

BackgroundLynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs.MethodsA 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently.ResultsNo mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance.ConclusionLarge genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.

Four-directional approach to the meso-transverse attachment combined with preoperative radiological vascular simulation facilitates short-term surgical outcomes in laparoscopic transverse colon cancer surgery: Creative lap transverse colon surgery

Transverse colon resection is one of the most difficult laparoscopic procedures because of anatomic hazards such as variations in the mesenteric vascular anatomy and the complex structure of organs and surrounding membranes.

Utility of preoperative 3-D simulation of laparoscopic lateral pelvic lymph node dissection for advanced rectal cancer: Surgical outcomes of 10 initial cases: 3-D simulation for pelvic node dissection

Laparoscopic lateral pelvic lymph node dissection (LPLD) is technically challenging because of the complicated anatomy of the pelvic wall. To overcome this difficulty, we introduced preoperative 3‐D simulation. The aim of the study is to investigate the usefulness of preoperative 3‐D simulation for the safe conduct of laparoscopic LPLD for rectal cancer.

Metachronous solitary metacarpal bone metastasis from rectal cancer

Abstract Metachronous solitary metacarpal bone metastasis from rectal cancer has not been reported previously. Here, we describe a 54-year-old woman who underwent abdominoperineal resection for rectal cancer following neoadjuvant chemoradiotherapy. The resected specimen contained adenocarcinoma with no lymph node metastases (Stage II, T3N0M0); no adjuvant chemotherapy was administered. Fifteen months after surgery, the patient presented with pain and swelling of the right thumb. Radiography revealed metacarpal bone destruction, and fluorine-18 fluorodeoxyglucose positron emission tomography showed uptake only in the metacarpal bone. Open biopsy revealed an adenocarcinoma, and a right thumb resection was performed. Histological examination indicated features of adenocarcinoma similar to the findings of a rectal lesion, leading to a diagnosis of metachronous solitary metacarpal bone metastasis from rectal cancer. The patient remains free of disease after 6 years of follow-up. Our findings suggest that surgical resection may lead to favorable outcomes in patients with resectable solitary bone metastases.

Synchronous metastatic squamous cell carcinoma to the colon and cervical lymph nodes from a carcinoma of unknown primary site: A case report.

Metastatic squamous cell carcinoma (SCC) from an unknown primary site to the colon has not been reported previously. A 75-year-old woman presented with a mass in the left submandibular region. Biopsy revealed a Class V lesion, but the histologic type was undetermined. Surgical resection of the left submandibular gland with cervical lymph node dissection was performed. However, SCC was seen in the lymph nodes only, with no tumor in the submandibular gland. Three months after surgery, computed tomography revealed that the preoperatively diagnosed lesion in the transverse colon had grown considerably. A laparoscopic right hemicolectomy was performed. Histological examination showed features of SCC, similar to the findings in the cervical lymph nodes. We report a rare case of synchronous metastatic SCC to the colon and cervical lymph nodes from a carcinoma of unknown primary site.