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A submucosal tumor (SMT) was found during a regular health check-up in a 59-year-old man. Following barium meal study the SMT was shown to be growing. He visited our hospital for further examination.
Anastomotic leakage during laparoscopic low anterior resection (Lap-LAR) for rectal cancer remains challenging for colorectal surgeons. Firing linear staplers multiple times has been reported as a risk factor for iatrogenic anastomotic leakage. Our institute usually performs rectal transection using 2 planned stapler fires followed by anastomosis with the double-stapling technique.Between November 2009 and September 2016, a total of 272 consecutive patients underwent Lap-LAR with double-stapling anastomosis for rectal cancer. We inserted a linear 45-mm stapler cartridge from a port in the lower right quadrant of the abdomen. The first transection was made up to three-quarters of the rectal wall, and the remaining rectum was completely resected using a second stapler. During this procedure, the intersection of the 2 staple lines, which might otherwise cause anastomotic leakage, was located in the center of the stump of the distal rectum, so the intersection at the rectal stump was able to be easily removed using a circular stapler.None of our patients were converted to open surgery. Among the 272 Lap-LAR procedures for which use of 2 stapler fires was planned, 3 fires occurred in error only once (0.4%). Rectovaginal fistula and anastomotic leakage occurred in 1 patient (0.4%) and 9 patients (3.3%), respectively, and 49 (18.0%) patients required protective diverting stoma.Rectal transection with 2 planned stapler fires appears safe, practical, and straightforward to standardize, and reduces the need for multiple linear fires and the incidence of anastomotic leakage.
Abstract Background The use of standard chemotherapy regimens has changed the application of chemosensitivity tests from all chemotherapy-eligible patients to those who have failed standard chemotherapy, which includes patients with highly advanced, relapsed, or chemoresistant tumors. Methods We evaluated a total of 43 advanced primary and relapsed gastric cancers for chemosensitivity based on drug dose response curves to improve the objectivity and quality of quantitative measurements. The dose response curves were classified based on seven expected patterns. Instead of a binary chemosensitivity evaluation, we ranked drug sensitivity according to curve shapes and comparison with the peak plasma concentration (ppc) of each drug. Results A total of 193 dose response curves were obtained. The overall informative rate was 67.4%, and 85.3% for cases that had a sufficient number of cells. Paclitaxel (PXL)and docetaxel tended to show a higher rank, while cisplatin (CIS) and 5-fluorouracil (5-FU) tended to show resistance, particularly among the 20 cases (46.5%) that had recurrent disease after receiving chemotherapy with CIS and S-1 (5-FU). As such, we speculate that the resistant pattern of the chemosensitivity test suggests that cells with acquired drug resistance were selected by chemotherapy. Indeed, we observed a change in the chemosensitivity pattern of a sample before and after chemotherapy in terms of PXL sensitivity, which was used after primary chemotherapy. Conclusions These results suggest that: (i) the dose–response pattern provides objective information for predicting chemosensitivity; and (ii) chemotherapy may select resistant cancer cell populations as a result of the therapy.
Abstract [Background] Adjuvant chemotherapy based on 5-FU has been a mainstay of postoperative treatment for the majority of cancers arising in the gastrointestinal tract. Although adjuvant chemotherapy has shown a favorable success rate, there are still considerable numbers of patients who experience cancer relapse following this therapy. Therefore, being able to predict chemosensitivity with data backed by solid molecular evidence would allow us to select biologically reasonable drugs, as well as to avoid adverse effects in those patients who may fail to benefit from chemotherapy. [Materials and Methods] Several candidate markers have been isolated based on the drug-protein association from a “chemosensitivity and protein expression matrix” obtained by a “conventional chemosensitivity assay for 12 drugs” and a “quantitative lysate array for 50 proteins” using a panel of 12 cancer cell lines. The panel of candidate proteins was examined by immunohistochemistry and tissue microarrays of 79 gastrointestinal cancer cases treated with 5-FU based adjuvant chemotherapy after curative operation. A functional assay by siRNA gene knockdown was also performed to confirm whether the protein expression actually affects the chemosensitivity. [Results] The 79 gastrointestinal cancer patients who underwent a curative operation followed by 5-FU based adjuvant chemotherapy were investigated by clinicopathological study and immunohistochemistry. Among the candidate proteins measured in these 79 patients, expression of nuclear NFκB showed a significant association with cancer relapse (median observation period, 2.8 years; p<0.0001, Fisher's exact test). A Kaplan-Meier estimation confirmed that the time to relapse (TTR) was significantly shorter for patients who were positive for nuclear NFκB expression-positive than for negative cases (p<0.0001, Log-Rank test). In a subset analysis, in terms of cancer lesions, the nuclear expression of NFκB showed stronger discriminatory power in predicting the relapse of gastric cancer than of colon cancer. A functional validation study using gene knockdown of NFκB by siRNA revealed increased chemosensitivity for 5-FU in the gastric cancer cell line, MKN45 (p<0.05, t-test). [Discussion] Candidate biomarkers were isolated using a quantitative “chemosensitivity and protein expression matrix,” which has been used for small molecule screening in anti-cancer drug discovery. In the present study, we adopted the technologies using clinically “approved” drugs to predict chemosensitivity in terms of cancer relapse. Our results indicate that nuclear expression of NFκB may be a good marker for consideration of alternative adjuvant chemotherapeutic regimens for post-operative gastrointestinal cancer patients immediately after the operation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4129. doi:10.1158/1538-7445.AM2011-4129
Abstract [Background] Anti-human EGFR monoclonal antibody (cetuximab) has been widely used in the treatment of colorectal cancer (CRC). However it is thought that a reliable predictor for therapeutic efficacy should be established because the benefit of cetuximab treatment is often still uncertain. Our preliminary study showed that the prediction of therapeutic efficacy using a conventional chemosensitivity test using growth suppression assay is generally not informative because cetuximab does not seem to have as strong a cytotoxicity as other anticancer drugs. KRAS mutation status has been used as a biomarker to predict therapeutic efficiency but it is not sensitive enough to determine the absolute indication. [Purpose] We hypothesized that we could predict therapeutic efficacy by evaluating expected molecular reaction when cetuximab is administrated in vitro. In the present study, we build up an in vitro EGFR signaling model for a new chemosensitivity test based on protein monitoring in response to cetuximab administration. [Materials and Methods] Three growth factors (EGF, TGF-α, and IGF) and the inhibitor (cetuximab) were added to HT29 (KRAS wild type, EGFR positive) in six combinations. Cell pellets were harvested at 5 time points over a 15min time course, each of which was processed for cell lysate. The lysates were analyzed by Western blotting to see if the proteins involved in the EGFR signaling pathway responded over time. [Results] We confirmed the activation of signaling stimulated by EGF, TGF-α, and IGF; and the effect on signaling by cetuximab in HT29 with Western blotting. Intriguingly, the phosphorylation level of EGFR was rapidly elevated and declined by EGF stimulating in the absence of cetuximab whereas dephosphorylation was prolonged in the presence of cetuximab. In the administration of either TGF-α or IGF, the phosphorylation pattern of EGFR, c-RAF, MEK, MAPK, ERK, PI3K, AKT, PTEN, and STAT was different from that of EGF alone. [Conclusions] These results shows that:(i) EGF is not EGFR's only ligand; (ii) cetuximab can't inhibit every signaling pathway starting from EGFR; and (iii) TGF-α and IGF activate signaling pathway starting from EGFR partially but not thoroughly. An additional reliable predictor of cetuximab efficacy should be identified based on functional protein characteristics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4146.
To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(−) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2–43.4; JNK(−), p = 0.0302, HR4.4, 95%CI 1.2–16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2–426.0; JNK(−), p = 0.0098, HR3.2, 95%CI 1.3–7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.
