The COMET Open-label Phase II Study of Neoadjuvant FOLFOX or XELOX Treatment Combined with Molecular Targeting Monoclonal Antibodies in Patients with Resectable Liver Metastasis of Colorectal Cancer.

BACKGROUND: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. METHODS: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. CONCLUSIONS: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

Preoperative Serum Interleukin-6 Is a Potential Prognostic Factor for Colorectal Cancer, including Stage II Patients.

Aims. To evaluate the prognostic significance of serum interleukin-6 (IL-6) in colorectal cancer (CRC). Patients and Methods. Preoperative serum IL-6 was measured in 233 CRC patients and 13 healthy controls. Relationships between IL-6 and various clinicopathological factors were evaluated, and the overall survival (OS) and disease-free survival (DFS) rates according to IL-6 status were calculated for all patients and according to disease stage. Results. The mean IL-6 level was 6.6 pg/mL in CRC patients and 2.6 pg/mL in healthy controls. Using a cutoff of 6.3 pg/mL, obtained using receiver operating characteristic curve analysis, 57 patients had a high IL-6 level. The mean value was higher for stage II disease than for stage III disease. IL-6 status correlated with C-reactive protein (CRP) and carcinoembryonic antigen levels, obstruction, and pT4 disease. The OS differed according to the IL-6 status for all patients, whereas the DFS differed for all patients and for those with stage II disease. The Cox proportional hazards model showed that pT4 disease was an independent risk factor for recurrence in all CRC patients; IL-6, CRP, and pT4 were significant risk factors in stage II patients. Conclusions. The preoperative IL-6 level influences the risk of CRC recurrence.

Inflammatory pseudotumor of the liver diagnosed as metastatic liver tumor in a patient with a gastrointestinal stromal tumor of the rectum: report of a case.

BACKGROUND: Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion. A case of IPT of the liver found in association with a malignant gastrointestinal stromal tumor (GIST) is reported. CASE REPORT: A 74-year-old man was admitted to our hospital for a liver tumor. He previously underwent rectal amputation for a malignant GIST. Computed tomography (CT) revealed a low-density area in the liver and dynamic contrast-enhanced MRI (EOB-MRI) showed that the tumor was completely washed out in the delayed phase. 18Fluorine-fluorodeoxyglucose positron emission tomography (FDG-PET) showed strong uptake in the liver. A diagnosis of liver metastasis was made and partial hepatectomy was performed. Microscopic examination showed that the tumor was an IPT. CONCLUSION: Differential diagnosis between IPT and malignant neoplasms is difficult. Moreover, FDG-PET revealed strong uptake in the tumor. To our knowledge, this is the first patient reported to have an IPT in association with a rectal GIST. This patient is discussed along with a review of the literature.

Single-incision endoscopy-assisted ileocecal resection.

BACKGROUND: Minimally invasive laparoscopic surgery was widely performed for colectomies. In recent years, as a new approach, the sigmoid colon or rectum is removed through the anus, minimizing the need for skin incisions. However, the resected ileocecal portion or the right side of the colon may be difficult to remove from the anus. Therefore, it usually needs to be removed using a skin incision, which typically restricts the size of the tissue. In these cases, we applied a less-invasive single-incision endoscopy-assisted colectomy to avoid forceps interference and reduce the port size required for the energy device. In this study, we introduce an ideal single-incision technique. METHODS: We performed surgeries on 3 patients with cecal or proximal ascending colon cancer (1 early and 2 advanced cases). Under general anesthesia, we initially made a right pararectal incision (3 to 5 cm), which was dependent on the tumor size and fixed a GelPort (Applied Medical, Orange County, CA) and inserted 12- and 5-mm trocars. Through the 12-mm trocar, we inserted a gastrointestinal scope for dissecting the ileocecal area from the retroperitoneum using a hook knife, similar to the endoscopic submucosal dissection technique. After mobilization, all other maneuvers were performed by an open method. RESULTS: The mean surgery time was 185 minutes. There were no major complications among the patients. DISCUSSION: This single-incision endoscopy-assisted dissection needs no additional suction, irrigation, or electrocoagulator and is a realistic and idealistic technique at present. Transvaginal and transanal retrieval methods are still controversial. CONCLUSION: We believe that this endoscopic technique may be essential for advancement to minimally invasive laparoscopic surgery toward natural orifice transluminal endoscopic surgery.

Multicenter phase II study of modified FOLFOX6 as neoadjuvant chemotherapy for patients with unresectable liver-only metastases from colorectal cancer in Japan: ROOF study.

BACKGROUND: Neoadjuvant chemotherapy for unresectable colorectal liver metastases can reduce tumor size, which sometimes leads to curative resection. The aim of the present study was to identify and describe patients with initially unresectable liver-only metastases from colorectal cancer who obtained sufficient chemotherapeutic benefit that eventually lead to the removal of the metastatic diseases in the liver. METHODS: A phase II multicenter cooperative study was conducted in 38 medical institutions using modified FOLFOX6 (mFOLFOX6) as neoadjuvant chemotherapy from January 2008 to June 2009. Patients with liver-only metastases from colorectal cancer that was deemed not optimally resectable by liver surgeons received mFOLFOX6 as preoperative neoadjuvant chemotherapy for 6-8 cycles. Patients were reassessed for resectability after 6 cycles of mFOLFOX6. Surgery was carried out 3-6 weeks after chemotherapy. The primary endpoint was the rate of macroscopic curative surgery including liver resection. RESULTS: 36 patients (23 male/13 female, ECOG performance status 0-1) were enrolled. The median age of the patients was 62.5 years; 78% (28 patients) had 5 or more metastatic tumors, and 50% (18 patients) had metastatic tumors over 5 cm diameter. The mFOLFOX6 regimen was safety administered resulting in 18 partial responses (50%), 12 stable disease, and 4 progressive disease. There was no grade 3/4 neurotoxicity. Fourteen patients (38.9%) underwent surgery (R0: 13; R1: 1). Of these, thirteen patients (36.1%) underwent R0 surgery. CONCLUSIONS: Our data suggest that mFOLFOX6 has a high response rate in patients with liver-only metastases from colorectal cancer, allowing for R0 resection of liver metastases in a proportion of patients initially not judged to be optimally resectable.

Comparative analysis of MRSA strains isolated from cases of mupirocin ointment treatment in which eradication was successful and in which eradication failed.

Nasal decolonization in methicillin-resistant Staphylococcus aureus (MRSA) carriers using mupirocin (MUP) is a strategy that complements barrier precautions and contact isolation. However, eradication failure cases have been observed despite isolates being susceptible to MUP. This would suggest that the minimum inhibitory concentration (MIC) alone is not the only determinant of successful eradication. In this study, we undertook a comparative analysis of MRSA isolates from cases of successful and unsuccessful MUP-eradication treatment. The analyses we carried out were: determination of mupirocin MICs, sequencing of the isoleucyl-tRNA synthetase (ileS) gene, staphylococcal cassette chromosome mec typing, and the assessment of slime production. MICs for all 14 of the successful nasal decolonization cases showed susceptibility to MUP, whereas 21 (87.5 %) of the 24 unsuccessful cases were MUP-susceptible, with low-level resistance seen in 3 (12.5 %) strains. In the analysis of mutations in the ileS gene, one strain with an MIC of 4 µg/ml exhibited a G1778A point mutation that has not been previously reported. In the 14 successful nasal decolonization cases, only 1 strain (7.1 %) was an MRSA slime-producer, compared with 19 (79.7 %) of the 24 MRSA strains that could not be eradicated after MUP treatment (p < 0.05). For the eradication of MRSA by MUP, it is possible that slime may affect drug penetration. In conclusion, slime production was the only significant difference between isolates recovered from successful and unsuccessful eradication cases.

Curatively resected isolated inguinal lymph node metastasis from cecum cancer: report of a case.

We herein report the case of a curatively resected solitary inguinal lymph node metastasis from cecum cancer. Our patient was a 67-year-old male with cecum cancer with abdominal wall invasion. Three years after surgery, inguinal lymph node swelling was detected by a computed tomography examination. Further examination revealed no other metastases. Surgical resection was performed to remove the lesion, and microscopic examination revealed that cancer cells had metastasized. No recurrence was detected 3 years after the salvage surgery. Inguinal lymph node metastasis of cecum cancer has not been reported in the literature, but in our case salvage surgery resulted in a good outcome.

A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies.

PURPOSE: Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands. METHODS: Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes. RESULTS: Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand. CONCLUSIONS: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-α, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC.

Carcinoembryonic antigen elevation in post-hepatectomy patients with colorectal cancer liver metastasis indicates recurrence with high accuracy.

BACKGROUND/AIMS: We aimed to retrospectively determine the accuracy of postoperative serum carcinoembryonic antigen (CEA) monitoring to detect or rule out recurrence in post-hepatectomy colorectal cancer patients by using a new statistical technique, likelihood ratio and post-test probability. METHODS: A total of 110 colorectal cancer patients who underwent curative hepatectomy were enrolled. A serum CEA assay and radiological examination were performed routinely for 5 years after surgery or until recurrence was detected. Yearly recurrence rates, sensitivities, specificities, and likelihood ratios were calculated. Post-test probabilities were calculated using these values. RESULTS: All episodes of recurrence occurred within 3 years after hepatectomy. The most frequent recurrence site was the liver, with a recurrence rate of 61.4% of all recurrence. The post-test probabilities of recurrence in post-hepatectomy colorectal cancer patients with positive and negative serum CEA were approximately 70-90% and 10%, respectively. CONCLUSIONS: CEA elevation in colorectal cancer patients who underwent curative resection indicated recurrence with high accuracy because of the high recurrence rate in the liver, in which CEA elevation is more frequent than in other recurrent sites. The elevation of CEA in post-hepatectomy patients necessitates frequent examination using imaging techniques to reveal undetected metastasis as soon as possible.

Simple laparoscopic technique of transverse loop colostomy prolapse.

Prolapse of loop colostomy or ileostomy is a common complication and markedly reduces patient quality of life. Many techniques have been reported for surgical or nonsurgical management of prolapse. We here report a simple laparoscopic technique for loop stoma prolapse. The prolapsed intestine (usually distal limb) was fixed to the abdominal wall by laparoscopic suturing. This technique should represent a good option for management of loop colostomy prolapse and can be applied to loop ileostomy or single stoma prolapse.

Laparoscopic intersphincteric resection with a SILS port for very low rectal cancer: a case report.

Since intersphincteric resection (ISR) for rectal cancer was established in the 1990 s, this technique has been applied to very low rectal cancer. This procedure requires advanced techniques for anorectal surgery. However, it is indicated only for early lesions and should be as minimally invasive as possible. We describe a minimally invasive ISR with a single-incision laparoscopic surgery (SILS) port. Our case involves a 59-year-old man with hemorrhage from the rectum. Pathologic examination of the transanally resected specimen revealed that the tumor had invaded into the deeper submucosa. To minimize surgical incisions, a SILS port was utilized in place of a 10- and a 5-mm trocar. The SILS port was inserted through a 2.5 cm transverse incision in the right lower abdomen, where a diverting stoma would be created. Two flexible or straight forceps introduced through this port afforded an easier dissection of the rectum to the levator ani muscle, and transanal dissection of the internal sphincter was performed in the standard manner to connect with the abdominal dissection. The only postoperative incision other than a stoma and surgical drain was one 10-mm incision above the umbilicus. Our technique of ISR with the SILS port is a useful clinical application of minimally invasive surgery.

Transvaginal resection of a rectal gastrointestinal stromal tumor.

We herein report a case in which a rectal gastrointestinal stromal tumor (GIST) was resected transvaginally. The patient, a 45-year-old female, had a rectal GIST on the anterior wall of the lower rectum. The tumor was within 6 cm of the anal verge, a location which would normally require performing an ultra-low anterior resection using the Double Staple Technique, and a diverting stoma. To minimize the invasiveness of treatment and to reduce the postoperative morbidity, a transvaginal resection was performed. Under general anesthesia, the posterior vaginal mucosa was incised vertically. The tumor was then excised en bloc with the overlying rectovaginal septum and rectal mesenchymal tissue. The defect was repaired primarily, and a diverting stoma was not required. The procedure was uncomplicated, and the patient was discharged home with an intact anal sphincter function and no abdominal incisions. In female patients, transvaginal resection of low anterior rectal lesions may provide a minimally invasive alternative to the traditional ultra-low anterior resection.

Hybrid natural orifice transluminal endoscopic surgery for ileocecal resection.

Although laparoscopic colectomy is commonly performed around the world, an operative wound formed during the surgery is large but not sufficient enough to convert for the majority of open surgery. Thus, a certain sized skin incision is required to remove the resected colon. Here we report the case of a pure laparoscopic ileocecal resection which involves transanal specimen extraction. We present a case characterized by a laterally spreading type of tumor of the cecum. We performed a pure laparoscopic ileocecal resection and the resected specimen was removed transanally using colonoscopy. Intracorporeal functional anastomosis was then performed using a flexible linear stapling device under supporting barbed suture traction. The patient was discharged without complications on postoperative day 4. Laparoscopic colectomy performed with minimal incision could essentially increase the usage of this surgical technique. Although our method is restricted to flat or small lesions, we think it is a feasible and realistic solution for minimization of operative invasion because it involves specimen extraction through a natural orifice.

Laparoscopic anterior resection for colorectal cancer without minilaparotomy using transanal bowel reversing retrieval.

PURPOSE: In laparoscopic colon resection for rectosigmoid colon cancer, minilaparotomy is usually necessary for specimen retrieval and completion of primary anastomosis. This incision may increase postoperative pain, and cause wound infection or other complications. We describe a new technique of laparoscopic anterior colon resection without requiring a minilaparotomy incision. PATIENTS AND METHODS: We attempted this procedure on 9 patients with sigmoid colon or rectal cancer. We ligated the inferior mesenteric artery and divided the bowel proximally, similar to conventional laparoscopic technique. We pulled out the specimen and the rectum transanally, and performed distal colon division extracorporeally. An anvil was inserted transanally into corporeal cavity and then, inserted into the proximal stump of the colon lumen laparoscopically. We placed a purse-string suture extracorporeally around the distal colon stump, and then completed a side-to-end anastomosis intracorporeally. RESULTS: The procedure was successfully completed in 8 of the 9 patients. Median operative time was 293 minutes and median blood loss was 47.2 mL. No major complications were observed. CONCLUSIONS: This novel technique of transanal specimen retrieval and intracorporeal anastomosis with extracorporeal purse-string placement can be performed safely and easily in patients with rectosigmoid colon cancer.

Accuracy of monitoring serum carcinoembryonic antigen levels in postoperative stage III colorectal cancer patients is limited to only the first postoperative year.

PURPOSE: The aim of the present study was to determine the accuracy of yearly postoperative monitoring of serum tumor markers to either detect or rule out recurrence in colorectal cancer patients. METHODS: A total of 127 colorectal cancer patients who underwent curative surgery were enrolled. The serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were assayed, and radiological examinations were performed routinely for 5 years after surgery or until recurrence was detected. Yearly recurrence rates (number of recurrences/number of patients assessed in a given year), sensitivities, specificities, and likelihood ratios were calculated. Post-test probabilities were calculated from these values. RESULTS: Recurrences tended to show almost the same frequencies in the first and second year after surgery (20 of 127 patients and 18 of 107 patients, respectively). However, the post-test probability of recurrence in patients with positive and negative serum CEA levels was significantly lower in the second year than in the first year (test positive: 40.0% and 76.0%; test negative: 9.3% and 0.5%, respectively). CONCLUSIONS: Measuring CEA can help to identify patients likely to demonstrate recurrence with high accuracy only within the first year after surgery. Another examination, such as imaging, is therefore necessary for monitoring patients at 2 or more years after surgery.

Single-port retrieval of peritoneal foreign body using SILS port: report of a case.

Foreign body retrieval surgery sometimes does not need excision and reconstruction of the gastrointestinal tract. To avoid unnecessarily large incisions is now feasible for such retrieval surgery. We report herein a case of a patient who underwent retrieval surgery with a single-incision laparoscopic surgery (SILS) to minimize surgical incision. Our case concerns a 72-year-old female with a 3 cm length needle incidentally discovered as a peritoneal foreign body without any apparent symptoms. Retrieval was performed safely with SILS port inserted through a 2.5 cm transverse incision below the umbilicus. Two flexible forceps introduced through the SILS port offer easy operation for retrieving foreign bodies even if dissection or other surgical maneuvers are required. Our technique of abdominal foreign body retrieval with the SILS port is a useful clinical application of minimally invasive surgery for such cases.

Does serum carcinoembryonic antigen elevation in patients with postoperative stage II colorectal cancer indicate recurrence? Comparison with stage III.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the accuracy of postoperative monitoring of serum carcinoembryonic antigen (CEA) to detect or rule out recurrence in patients with stage II colorectal cancer (CRC) by comparing results with stage III. METHODS: A total of 303 patients with CRC who underwent curative surgery were enrolled. Serum CEA was assayed, and radiological examination was performed routinely for 5 years after surgery. Yearly recurrence rates, sensitivities, specificities, likelihood ratios, and posttest probabilities were calculated. RESULTS: Sensitivity and specificity of CEA monitoring in stage II patients are almost same as those in stage III. Whereas recurrences occurred early in stage III, they occurred almost as frequently in both early and late stage II. The obtained posttest probability of recurrence in stage II patients with CEA elevation was significantly lower (only 30% or less) than those in stage III (approximately 80%). CONCLUSION: Elevation of CEA in patients with stage II CRC does not represent recurrence with high probability. One of the reasons for the unreliability of CEA monitoring was its high false-positive rate. Another tumor marker with a lower false-positive rate is necessary to follow-up stage II CRC patients.

IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3K/Akt signaling pathway in pancreatic cancer cells.

BACKGROUND: Type-1 insulin-like growth factor (IGF-1) up-regulates cell proliferation and invasiveness through activation of PI3K/Akt signaling pathway. IGF-1 also down-regulates the tumor suppressor chromosome 10 (PTEN). We investigated the mechanism by which IGF-1 affects cell proliferation and invasion by suppression of PTEN phosphorylation and interaction with PI3K/PTEN/Akt/NF-small ka, CyrillicB signaling pathway in pancreatic cancer. MATERIALS AND METHODS: The expression of IGF-1 receptor (IGF-1R) and PTEN in five pancreatic cancer cell lines was determined by RT-PCR and Western blot. Proliferation and invasion were investigated by WST-1 assay and Matrigel-double chamber assay. Pancreatic cancer cells were transfected with PTEN siRNA to investigate which signaling pathway correlates in regulation of cancer cell proliferation and invasion. RESULTS: Five pancreatic cancer cell lines expressed PTEN and IGF-1R in mRNA and protein levels. Suppression of PTEN phosphorylation strongly enhanced cell proliferation and invasion stimulated with IGF-1 via activation of PI3K/Akt/NF-small ka, CyrillicB signaling pathway. In addition, knockdown of PTEN by siRNA transfection also enhanced activation of PI3K/Akt/NF-small ka, CyrillicB pathway, subsequently up-regulating cell invasiveness and proliferation. CONCLUSIONS: The IGF-1/PI3K/PTEN/Akt/NF-small ka, CyrillicB cascade may be a key pathway stimulating metastasis of pancreatic cancer cells. We suggest that interfering with the functions of IGF-1/PI3K/Akt/NF-small ka, CyrillicB might be a novel therapeutic approach to inhibit aggressive spread of pancreatic cancer.