Laparoscopic colectomy for persistent descending mesocolon in sigmoid colon cancer: A case report.

A 55-year-old-man underwent laparoscopic sigmoidectomy for sigmoid colon cancer. Preoperative barium enema showed a slightly medial displacement of the descending colon, and the sigmoid colon was quite long. The operative findings showed that the descending colon was not fused with the retroperitoneum and shifted to the midline and the left colon adhered to the small mesentery and right pelvic wall. Thus, a diagnosis of persistent descending mesocolon (PDM) was made. The left colon, sigmoid colon, and superior rectal arteries often branch radially from the inferior mesenteric artery. The sigmoid mesentery shortens, and the inferior mesenteric vein is often close to the marginal vessels. By understanding the anatomical feature of PDM and devising surgical techniques, laparoscopic sigmoidectomy for sigmoid colon cancer with PDM could be performed without compromising its curative effect and safety.

Early renal dysfunction after temporary ileostomy construction.

PURPOSE: Loop ileostomy is often used to prevent complications after colorectal surgery, but it has been reported to cause renal impairment. This study aimed to evaluate the changes in the renal function after ileostomy and to compare these with the renal function after low anterior resection without ileostomy (low-ANT). METHODS: The subjects included 58 patients who underwent ileostomy construction and closure for rectal cancer. The estimated glomerular filtration rate (eGFR) was calculated at specific time points after the index surgery. In addition, we conducted a case-matched study on 147 patients who underwent low-ANT. RESULTS: The eGFR was significantly lower at 1 month after ileostomy than at the time of ileostomy construction (78.8 vs. 84.0, p < 0.0001) and did not improve after ileostomy closure. The only risk factor for a reduced eGFR was preoperative chemotherapy or chemoradiotherapy. In the case-matched study, 36 patients were allocated for each of the two groups. The number of ileostomy patients with a reduced eGFR was significantly increased 1 month after the index surgery (p = 0.005). CONCLUSIONS: The eGFR began to decrease at one month after ileostomy construction and did not improve after ileostomy closure.

Laparoscopic Low Anterior Resection with Two Planned Stapler Fires.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[COMPLETE RESECTION OF URACHAL CARCINOMA WITH SIGMOID COLON INVASION AFTER FOLFOX CHEMOTHERAPY: A CASE REPORT].

A 45-years-old man presented discharge of abscess from the umbilicus with lower abdominal pain. CT scan showed huge tumor from the bladder to the umbilical part with sigmoid colon invasion. He was diagnosed as urachal carcinoma, which was confirmed by pathological examination. We started FOLFOX chemotherapy according to advanced colon cancer. Approximately 80% of reduction was accomplished after 11 courses of FOLFOX. We performed radical cystectomy with sigmoid colon resection. Pathological examination revealed complete resection with negative surgical margin. No recurrence and metastasis were observed after 30 months of surgery. Urachal carcinoma is often advanced cancer when diagnosed. Effective chemotherapy is not established well. FOLFOX chemotherapy demonstrated the well antitumor effect in this case.

Transumbilical abdominal incision for laparoscopic colorectal surgery does not increase the risk of postoperative surgical site infection.

PURPOSE: Besides antibiotic prophylaxis, antiseptic skin preparation is an important measure to prevent surgical site infection (SSI). No reports have detailed the relationship between SSI and umbilical microflora following laparoscopic colorectal cancer with a transumbilical longitudinal incision. METHODS: Risk factors and the rate of SSI were investigated in 453 patients who underwent laparoscopic colorectal resection over a 3-year period. Microbiological samples were collected from the umbilicus and SSI areas. RESULTS: After laparoscopic procedure, we observed SSIs in approximately 5% of cases, with superficial SSI in 15 (3.3%) patients and organ/space SSIs 7 (1.5%). In univariate analysis, preoperative albumin (Alb) value and anastomosis of enterocolostomy were significantly associated with superficial SSI development. Also, age, blood loss, stoma, tumor site (rectum), and Hartmann/abdominal perineal resection (APR) were significant risk factors for organ/space SSI. In multivariate analysis, the preoperative Alb value was the most significant factor associated with a predisposition to superficial SSI. The bacteria detected in SSI were mostly different from those at wound closure. Antibiotic-resistant bacteria were included in organ/space SSI all cases. CONCLUSIONS: SSI development with laparoscopic surgery reportedly occurs in about 3-15% cases. The SSI rate in this study and other reports was comparable. Using small transumbilical longitudinal incision in laparoscopic colorectal surgery is less likely to cause SSI when sufficient control measures are enacted, even though the umbilicus contains resident bacteria in abundance.

[A Case of Para-Aortic Lymph Node Metastasis of Rectal Cancer Successfully Treated Using Multidisciplinary Therapy].

A 66-year-old man diagnosed with rectal cancer underwent high anterior resection and received adjuvant chemotherapy (UFT plus UZEL). One year after the surgery, lung and para-aortic lymph node(PLN)metastases were identified. We chose mFOLFOX6 for first-line chemotherapy. After 7 courses, we changed the regimen to sLV5FU2 because of Grade 3 neuropathy. After 5 courses, to treat progressive disease(PD), we changed the regimen to FOLFIRI. Then, the patient had stable disease (SD), and surgical excision was performed for both lung and lymph node recurrence without adjuvant chemotherapy. Six years after the excision, a CT scan revealed PLNagain. We chose FOLFIRI plus cetuximab. After 9 courses, the lymph nodes decreased in size and there was no other recurrence; thus we performed resection. However, a third PLNrecurrence was identified 20 months after the resection. Chemotherapy has continued for 47 courses, and he has maintained SD for more than 2 years.

[A Case of More Than Five-Year Survival of Carcinoma Associated with Anal Fistula Effectively Treated by Combined Modality Therapy].

The patient was a 56-year-old man who presented with perianal pain and a perianal abscess. After admission, he underwent debridement and colostomy due to poor control of the perianal abscess. Following a biopsy of the resected specimens, he was diagnosed with adenocarcinoma in the anorectal fistula. CT and MRI revealed that the tumor had invaded into the internal obturator muscle. Therefore, preoperative chemoradiotherapy and chemotherapy were given for locally advanced cancer. Subsequent to tumor shrinkage, we performed an abdominoperineal resection. Histopathologically, no cancer cells were detected on the surgical margin, and the effect of the preoperative therapy was judged to be Grade 1b. There has been no indication of recurrence of cancer after 5 years.

Comparative benefits of laparoscopic surgery for colorectal cancer in octogenarians: a case-matched comparison of short- and long-term outcomes with middle-aged patients.

PURPOSE: The aim of this study was to compare the postoperative short- and long-term outcomes after laparoscopic colorectal surgery (LCS) between octogenarians and healthy middle-aged patients. METHODS: Between January 1997 and July 2009, 655 consecutive laparoscopic surgeries for colorectal cancer patients were operated by 1 colorectal surgeon. Ninety-three patients were octogenarians (≥80 years), and 133 patients were case-matched middle-aged (60-69 years) patients. We analyzed the mean operative time, blood loss, type of surgery for rectal cancer, length of hospital stay, mortality, and morbidity. The overall survival curve was constructed using the Kaplan-Meier method. RESULTS: The American Society of Anesthesiologists classification was significantly higher in the octogenarians than in the middle-aged controls. However, there were no significant differences between the two groups in terms of the incidence of morbidities (11.7 vs. 9.2 %) and length of hospital stay (12.1 vs. 10.9 days). The number of lymph nodes harvested was significantly fewer (p < 0.05) and the operative time significantly shorter (p < 0.05) in the octogenarians than in the middle-aged controls. At a mean follow-up of 38.2 months, the overall 5-year survival rate was 64.8 % in the octogenarians and 92.4 % in the middle-aged group, whereas the cancer-specific 5-year survival rate was 91 % in the octogenarians and 95.7 % in the middle-aged group. CONCLUSIONS: We suggest that advanced age should not be a contraindication for LCS, even for complex procedures, such as laparoscopic rectal resection.

Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel.

BACKGROUND: Circulating tumor DNA (ctDNA) carries information on tumor burden. However, the mutation spectrum is different among tumors. This study was designed to examine the utility of ctDNA for monitoring tumor burden based on an individual mutation profile. METHODOLOGY: DNA was extracted from a total of 176 samples, including pre- and post-operational plasma, primary tumors, and peripheral blood mononuclear cells (PBMC), from 44 individuals with colorectal tumor who underwent curative resection of colorectal tumors, as well as nine healthy individuals. Using a panel of 50 cancer-associated genes, tumor-unique mutations were identified by comparing the single nucleotide variants (SNVs) from tumors and PBMCs with an Ion PGM sequencer. A group of the tumor-unique mutations from individual tumors were designated as individual marker mutations (MMs) to trace tumor burden by ctDNA using droplet digital PCR (ddPCR). From these experiments, three major objectives were assessed: (a) Tumor-unique mutations; (b) mutation spectrum of a tumor; and (c) changes in allele frequency of the MMs in ctDNA after curative resection of the tumor. RESULTS: A total of 128 gene point mutations were identified in 27 colorectal tumors. Twenty-six genes were mutated in at least 1 sample, while 14 genes were found to be mutated in only 1 sample, respectively. An average of 2.7 genes were mutated per tumor. Subsequently, 24 MMs were selected from SNVs for tumor burden monitoring. Among the MMs found by ddPCR with > 0.1% variant allele frequency in plasma DNA, 100% (8 out of 8) exhibited a decrease in post-operation ctDNA, whereas none of the 16 MMs found by ddPCR with < 0.1% variant allele frequency in plasma DNA showed a decrease. CONCLUSIONS: This panel of 50 cancer-associated genes appeared to be sufficient to identify individual, tumor-unique, mutated ctDNA markers in cancer patients. The MMs showed the clinical utility in monitoring curatively-treated colorectal tumor burden if the allele frequency of MMs in plasma DNA is above 0.1%.

Evaluation of chemosensitivity prediction using quantitative dose-response curve classification for highly advanced/relapsed gastric cancer.

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.

Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

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.

[A novel Cisplatin delivery system for malignant ascites-bearing mice-a basic experimentation].

The authors used 70% deacetylated chitin and cisplatin (CDDP) to devise a novel anticancer drug delivery system (DDS). We examined in vitro release of the CDDP from the system. The novel system was intraperitoneally( ip) given to malignant ascites-bearing mice, and the survival time of each animal was recorded. The related oncolytic mechanism was immunologically investigated. More than 70-90% of the CDDP was gradually delivered from the system in 24 hours. Nineteen animals among 30 treated with our system survived for longer than 4 weeks, and a recurrence of ascites was nil. A 4- week survival rate of the animals with ip injected conventional CDDP was 5/14. All non-treated animals had massive ascites and died within 4 weeks. Immunologic studies suggested that cytotoxic immunoresponse was induced in the mice treated with the novel system. Our newly devised system warrants for clinical applications in the treatment of malignant ascites.

[A novel gemcitabine delivery system].

Indocyanine green (ICG) is specifically excreted through the biliary tracts. The authors applied ICG as a carrier of gemcitabine (GEM) to devising a novel drug delivery system. Our newly devised chitin flakes, ICG and GEM were mixed together. Then physiological saline solution was added to the mixture to form the system. The release profiles of GEM and ICG from the system were examined at various times in vitro. Anticancer activities of the GEM and ICG delivered from the system were detected by MTT assay method using human pancreatic cancer cell lines. The novel system was visco-elastic green sol at room temperature and changed to gel at body temperature. Seventy to 80% of GEM was gradually delivered from the system in 24 hours, and 30 to 50% of ICG was slowly released over 24 hours. The released GEM favorably demonstrated anticancer activities against the cancer cells, while the ICG released from the system showed no oncolytic activities. These suggested that our devised system would be clinically useful as a novel tool in cancer chemotherapy.

Analysis of the anti-tumor effect of cetuximab using protein kinetics and mouse xenograft models.

BACKGROUND: The binding of EGFR and its ligands leads to autophosphorylation of receptor tyrosine kinase as well as subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. An EGFR inhibitor, cetuximab binds to EGFR and consequently blocks a variety of cellular processes. KRAS/BRAF mutations are known to be associated with a low response rate to cetuximab. In the present study, to clarify the anti-tumor mechanisms of cetuximab, we evaluated the KRAS/BRAF status, phosphorylation level of the EGFR pathway, and the tumor suppression effect in vivo, using a human colon cancer cell line HT29, which exhibited the highest EGFR expression in response to the cetuximab therapy among the 6 colorectal cancer cell lines tested. FINDINGS: The conventional growth suppression assay did not work efficiently with cetuximab. EGF, TGF-α, and IGF activated the EGFR/MAPK cell signaling pathway by initiating the phosphorylation of EGFR. Cetuximab partially inhibited the EGFR/MAPK pathway induced by EGF, TGF-α, and IGF. However, cetuximab exposure induced the EGFR, MEK, and ERK1/2 phosphorylation by itself. Mouse xenograft tumor growth was significantly inhibited by cetuximab and both cetuximab-treated and -untreated xenograft specimens exhibited phosphorylations of the EGFR pathway proteins. CONCLUSIONS: We have confirmed that cetuximab inhibited the EGFR/MAPK pathway and reduced tumor growth in the xenografts while the remaining tumor showed EGFR pathway activation. These results suggest that: ( i ) The effect of cetuximab in growth signaling is not sufficient to induce complete growth suppression in vitro; ( ii ) time-course monitoring may be necessary to evaluate the effect of cetuximab because EGFR signaling is transmitted in a minute order; and ( iii ) cetuximab treatment may have cells acquired resistant selectively survived in the heterogeneous cancer population.

[Anticancer efficacy with cisplatin delivery systems].

The authors devised two different types of cisplatin (CDDP) delivery systems; namely, System A and System B. The anticancer efficacy with each system was examined using cancer-bearing animals. Seventy-percent deacetylated chitin (DAC-70) was used as the drug carrier in the system. Cancer-bearing animals were prepared by intra-peritoneally (ip) inoculating the MM-46 cancer cells to C3H mice. Each novel system was also ip injected to the cancer-bearing mouse, and then survival time of each animal was recorded to evaluate the anti-cancer efficacy of the system. Both Systems A and B were viscoelastic sol at 25°C and slowly changed to gel at 37°C. Four-week survival rate of each animal treated with the System was as follows: System A 6/10 (60%), System B 10/11 (90.9%), conventional CDDP alone 3/9 (33.3%) and non-treated 0/7 (0%). No signs of recurrence of ascites were encountered in the long-term survived animals treated with System A and B. Our newly devised systems provided a favorable antitumor efficacy in vivo. Now, we will carry out further studies by making a clinically applicable novel conjugated system, DAC-70 and CDDP.