Phase III randomised trial comparing 6 vs. 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study.

BACKGROUND: Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. METHODS: A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. RESULTS: The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732-1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670-0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575-0.919). The incidence of overall grade 3-4 adverse events was almost comparable in both groups. CONCLUSIONS: Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.

Lobulated esophageal schwannoma resected with concurrent approach from the thorax and cervix.

BACKGROUND: Esophageal schwannomas are rare esophageal submucosal tumors. We herein report a case of a lobulated esophageal schwannoma resected with concurrent approach from the thorax and cervix. CASE PRESENTATION: A 74-year-old woman visited our hospital with complaint of loss of consciousness, and a lobulated mediastinal tumor was discovered by chance in computed tomography. Upper gastrointestinal endoscopy showed a smooth elevated lesion at a position of 23-28 cm from the incisor teeth. A hypermetabolic appearance was noted on positron emission tomography. Based on these data, a gastrointestinal stromal tumor was suspected. The tumor was enucleated at the thoracic cavity while being pushed from the cervical incision. Pathological examination showed an esophageal schwannoma. CONCLUSIONS: We experienced a case of lobulated esophageal schwannoma with fluorodeoxyglucose accumulation. We resected the tumor with concurrent approach from the thorax and cervix.

Randomized phase III trial comparing surgery alone to UFT + PSK for stage II rectal cancer (JFMC38 trial).

BACKGROUND: We conducted a randomized phase III trial comparing tegafur/uracil (UFT) and Polysaccharide-K (PSK) to surgery alone in curatively resected stage II rectal cancer patients. METHODS: Patients were randomly assigned to receive either UFT and PSK or surgery alone in a 1:1 ratio with a minimization method to balance the treatment allocation. The primary end point of this study was the disease-free survival (DFS). The secondary end point was the overall survival (OS). RESULTS: From October 2011 to February 2013, 111 patients were registered from 62 institutions. The study was prematurely closed due to poor accrual after reaching 20% of its goal. The patients' characteristics were similar between the UFT and PSK group and the surgery-alone group. The DFS rate was 76.0% at 3 years and 65.1% at 5 years in the UFT and PSK arm and 84.0% at 3 years and 77.2% at 5 years in the surgery-alone arm. The DFS was slightly worse in the UFT + PSK arm than in the surgery-alone arm, but the difference did not reach statistical significance (log rank p = 0.102). The OS rate was 100% at 3 years and 97.9% at 5 years in the UFT + PSK arm, while that was 100% at 3 years and 93.4% at 5 years in the surgery-alone arm. The OS was similar in the UFT + PSK arm and surgery-alone arm (p = 0.533). CONCLUSION: The present study suggests that UFT and PSK are not attractive candidates to advance to the next phase III study because the DFS was slightly worse in the UFT and PSK arm than in the surgery-alone arm.

Planned Safety Analysis of the ACTS-CC 02 Trial: A Randomized Phase III Trial of S-1 With Oxaliplatin Versus Tegafur and Uracil With Leucovorin as Adjuvant Chemotherapy for High-Risk Stage III Colon Cancer.

BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.

Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.

A case of carcinoma of the papilla of Vater in a young man after subtotal colectomy for familial adenomatous polyposis.

BACKGROUND: Carcinoma and adenoma of the duodenum, including the papilla of Vater, are problematic diseases in patients with familial adenomatous polyposis (FAP). CASE PRESENTATION: A 36-year-old man underwent a periodic medical examination for early colon cancer originating from FAP for which laparoscopic-assisted subtotal colectomy with a J-shaped ileal pouch-rectal anastomosis was performed 3 years earlier. A tumor was detected at the papilla of Vater along with elevation of total bilirubin and hepatobiliary enzymes. Although cytology did not determine the tumor to be an adenocarcinoma, we suspected adenocarcinoma due to its hypervascularity shown by contrast-enhanced computed tomography. Pylorus-preserving pancreaticoduodenectomy with modified Imanaga reconstruction and regional lymph node dissection (D2) was performed. The pathological study showed that the tumor was a papillary and moderately differentiated tubular adenocarcinoma. The patient is currently in good health without recurrence, weight loss, or severe diarrhea at 12 months after surgery. CONCLUSIONS: Awareness of biliary-pancreatic symptoms and periodic gastroduodenoscopy might contribute both to the early detection of duodenal or periampullary polyps and cancer and to the radical treatment of FAP. Modified Imanaga reconstruction has the potential to become one of the more effective procedures for providing good quality of life to FAP patients with duodenal or periampullary cancer.

Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study (JFMC39-0902).

OBJECTIVE: This exploratory trial was performed to determine whether Daikenchuto accelerates recovery of gastrointestinal function in patients undergoing open colectomy for colon cancer. METHODS: A total of 386 patients undergoing colectomy at 1 of the 51 clinical trial sites in Japan from January 2009 to June 2011 were registered for the study (JFMC39-0902). Patients received either placebo or Daikenchuto (15.0 g/day, t.i.d) between post-operative day 2 and post-operative day 8. Primary end-points included time to first bowel movement, frequency of bowel movement and stool form. The incidence of intestinal obstruction was evaluated post-operatively. The safety profile of Daikenchuto until post-operative day 8 was also evaluated. RESULTS: The results for 336 patients (Daikenchuto, n = 174; placebo, n = 162) were available for statistical analysis. The time to first bowel movement did not differ significantly between the two groups. All patients reported having diarrhea or soft stools immediately after surgery, and the time until stool normalization (50th percentile) in the Daikenchuto and placebo groups was 6 days and 7 days, respectively. The placebo group had a significantly greater number of hard stools at post-operative day 8 (P = 0.016), and bowel movement frequency continued to increase until post-operative day 8 as well. In contrast, bowel movement frequency in the Daikenchuto group increased until post-operative day 6, however decreased from post-operative day 7 and was significantly lower at post-operative day 8 compared with the placebo group (P = 0.024). CONCLUSION: The moderate effects of Daikenchuto were observed ∼1 week after the operation. Although Daikenchuto had an effect on gastrointestinal function after open surgery in patients with colon cancer, this study did not show its clinical benefits adequately.

Giant left-sided inguinoscrotal hernia containing the cecum and appendix (giant left-sided Amyand's hernia).

KEY CLINICAL MESSAGE: The present case involved a 62-year-old male with a large left-sided inguinoscrotal hernia. A CT scan and a clinical examination led to a diagnosis of a giant left-sided Amyand's hernia. The hernia was repaired using the ULTRAPRO Hernia System (UHS), and the patient exhibited an uneventful postoperative course.

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.

V-shaped lymph node dissection in laparoscopic distal gastrectomy; new technique of intra-abdominal dissection and surgical outcomes.

BACKGROUND: Recently, laparoscopic-assisted distal gastrectomy (LADG) has become popular for the treatment of early gastric cancer. Furthermore, the use of totally laparoscopic gastrectomy (TLG), a more difficult procedure than LADG, has been increasing in Japan. Laparoscopic-assisted distal gastrectomy is currently performed more frequently than laparoscopic distal gastrectomy (LDG) in hospitals in Japan. METHOD: Reconstruction after LDG is commonly performed extra-abdominally and lymph node dissection of the lesser curvature is performed at the same time. We have developed a new method of intra-abdominal lymph node dissection for the lesser curvature. RESULTS: Our technique showed positive results, is easy to perform, and is reasonable in terms of general oncology theory. CONCLUSION: In oncological therapy, this technique could be a valuable surgical option for totally laparoscopic surgery.

A patient with spontaneous rupture of the esophagus and concomitant gastric cancer whose life was saved: case of report and review of the literature in Japan.

A 71-year-old man suddenly developed abdominal pain and vomiting on drinking soda after a meal, and visited a physician. Cervical subcutaneous and mediastinal emphysemas were observed on CT, and the patient was transferred to the emergency medical center of our hospital on the same day. Esophagography was performed at our department. A ruptured region was identified on the left side of the lower thoracic esophagus, and surgery was emergently performed employing sequential left thoracoabdominal incision. The chest wall was adhered due to inflammation, and large amounts of residual food and sloughing were present in the thoracic cavity and mediastinum. Moreover, necrotic changes were noted in the superior through inferior mediastinum. An about 2-cm rupture site was confirmed on the left side of the lower thoracic esophagus and closed by suture and filling with pediculate omentum. The presence of a tumorous lesion located mainly in the body of the stomach and lymph node enlargement were also diagnosed before surgery, for which gastric and intestinal fistulae were inserted to prepare for the second-stage surgery. The patient was admitted to an ICU after surgery. ARDS and MRSA-induced pneumonia and enteritis concomitantly developed but remitted. Curative surgery for gastric cancer was performed at 40 POD. Spontaneous rupture of the esophagus is relatively rare and that complicated by gastric caner is very rare, with only six cases being reported in Japan. Herein, we report the case.

[A case of advanced colon cancer with metastases to both supraclavicular and para-aortic lymph nodes effectively treated by radiation and S-1 therapy].

We report the case of a 60-year-old woman with multiple lymph node metastases after ascending colon cancer who received radiation therapy and then chemotherapy with S-1. She was diagnosed with lymph node metastasis of the para aorta and left upper clavicle 10 months after surgery. We performed radiation therapy for the left upper clavicle (64 Gy)and para aorta (40 Gy). Consequently, we administered S-1(100mg/day)orally. After three months, the upper clavicle lymph nodes had disappeared and the para-aortic lymph nodes reduced. All metastatic lesions disappeared after 10 months. She survived for 32 months after the radiation therapy.

[Three cases of gastric cancer with para-aortic lymph node metastases succesfully treated by S-1/CDDP combination therapy followed by curative resection].

Due to advanced gastric cancer with abdominal para-aortic lymph node metastases, we performed a curative operation in three cases in which S-1/CDDP combination therapy proved effective. In case 1, after only one course of this chemotherapy, the reduction of the primary lesion was slight, but para-aortic metastatic lymph nodes were remarkably reduced. We performed a curative operation with complete D3 lymph node dissection. In case 2, after two courses the reduction of the primary lesion was remarkable, and para-aortic metastatic lymph nodes almost disappeared. Therefore, we performed a curative operation with D2 lymph node dissection. In case 3, after two courses the reduction of the primary lesion was cicatrized. Although para-aortic metastatic lymph nodes were gradually reduced, one of them increased after the third period of treatment. Therefore, we performed a curative operation with complete D2 lymph node dissection and 16b1 lateral lymph node dissection. All underwent postoperative adjuvant chemotherapy, and have been surviving for 58 months, 42 months, and 18 months, respectively. In advanced gastric cancer with para-aortic lymph node metastases without other non-curative factors, long-term survival can be expected by combining a curative operation with S-1/CDDP combined therapy.

Large solitary fibrous tumor of the retroperitoneum: report of a case.

We report an unusual case of a large solitary fibrous tumor (SFT) in the retroperitoneum. A 53-year-old man was referred to our hospital for surgical treatment of a swelling in the right flank with dull pain. Abdominal computed tomography (CT) and echograms showed a large encapsulated tumor compressing the right kidney and liver. At laparotomy, the tumor was found to be encapsulated but fixed to the capsule of the right kidney within a small area. Therefore, complete removal was achieved. The resected specimen was an encapsulated elastic hard tumor, 14 x 13 x 10 cm in size. Immunohistochemical studies revealed reactivity for CD34 and vimentin, but no staining for keratin, S-100, or alpha-smooth muscle actin, confirming a diagnosis of SFT. Although SFT is usually associated with a favorable prognosis, close follow-up is recommended because of the limited information on its long-term behavior.

Evaluation of carcinoembryonic antigen mRNA in living, necrotic, and apoptotic gastric cancer cells by reverse transcriptase-polymerase chain reaction.

PURPOSE: Positive mRNA expression of carcinoembryonic antigen (CEA) is often found in histologically negative lymph nodes, even in early gastric cancer. Therefore, we examined the differences in mRNA expression in MKN45 gastric cancer cells obtained under various cell conditions, namely, living cells, necrosis, and apoptosis, and assessed the possibility of detecting micrometastasis from these results. METHODS: MKN45 cells were cultured with low-dose anticancer drugs (5-fluorouracil (5FU) + cisplatin (CDDP)) or cytokines (tumor necrosis factor alpha (TNFAlpha) + interferon gamma (INFGamma)) to induce apoptosis, or subjected to freezing-thawing to induce necrosis. All the treated cells were stained with propidium iodide and Hoechst and the numbers of living, apoptotic, and necrotic cells were counted. CEA mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and DNA fragmentation was confirmed. RESULTS: mRNA expression of CEA and CEA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) tended to decrease as the apoptotic index (AI) increased in the 5FU + CDDP group. On the other hand, almost no change was seen, even when the AI increased, in the TNFAlpha + IFNGamma group. mRNA expression in the necrotic cells was the almost same as that in the living cells. CONCLUSION: Positive CEA mRNA expression by RT-PCR could suggest the existence of living cancer cells.

Significance of apoptosis induced by tumor necrosis factor-alpha and/or interferon-gamma against human gastric cancer cell lines and the role of the p53 gene.

PURPOSE: The expression of the p53 gene in target cells plays an important role in the induction of apoptosis by tumor necrosis factor (TNF)-Alpha and interferon (IFN)-Gamma. We herein present a study suggesting the existence of a caspase-independent pathway from p53 via insulin-like growth factor binding protein 3 (IGF-BP3) which acts as an apoptosis induction mechanism. METHODS: MKN-45 (wild-type p53) or MKN-28 (mutant-type p53) was cultured with TNF-Alpha or IFN-Gamma either alone or together. After 24 and 48 h, the apoptotic index (AI) was determined by Hoechst staining and then compared. To clarify whether the mechanism of apoptosis is induced by TNF-Alpha and/or IFN-Gamma, apoptosis-related genes were examined by a cDNA on microarray analysis and a Western blot analysis. RESULTS: (1) The AI for MKN-45 increased at 48 h in the presence of TNF-Alpha or IFN-Gamma alone. (2) In the case of combination treatment using TNF-Alpha and IFN-Gamma, the AI for MKN-45 was higher than those in the groups with a single treatment. (3) A cDNA microarray analysis showed that IGF-BP3, the TNF superfamily, and caspase 1 were all upregulated after treatment with the combination of TNF-Alpha and IFN-Gamma. (4) A Western blot analysis of MKN-45 showed a reaction with an anti-IGF-BP3 antibody. CONCLUSIONS: These results suggest that the induction mechanism underlying apoptosis induced by TNF-Alpha and IFN-Gamma might therefore involve the caspase-independent pathway via IGF-BP3.

Prediction of 5-fluorouracil and cisplatin synergism for advanced gastrointestinal cancers using a collagen gel droplet embedded culture.

PURPOSE: The combination effects of 5-fluorouracil (5-FU) and cisplatin (CDDP) are herein reported using a drug sensitivity assay, with a special focus on the induction of apoptosis. METHODS: The combination effects of 5-FU and CDDP were examined using in vitro chemosensitivity testing by means of the collagen gel droplet embedded culture drug sensitivity test (CD-DST) in MKN45 and GSS cell lines, and primary gastrointestinal cancer cells ob-tained from 40 patients. Apoptosis was assayed using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin neck end labeling (TUNEL) method. RESULTS: The combination of 5-FU with CDDP increased the efficacy of 5-FU 1.16-1.35-fold with the GSS cell line and 1.10-2.01-fold with primary gastric and colorectal cancers when the exposure time was 7 days. In primary tumor cells a synergistic action was noted in 15 of 40 (38%) gastric and colorectal cancers. Both 5-FU and CDDP were found to induce apoptosis in GSS and MKN45 cells, and the number of apoptotic cells increased synergistically after the combined treatment in the GSS cases and showed a correlation with the results of CD-DST. CONCLUSIONS: Our findings suggested that the efficacy of the combined treatment with 5-FU and CDDP can be predicted by the in vitro chemosensitivity test and that a synergistic effect might be associated with the induction of apoptosis.

Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers.

PLK (polo-like kinase), the human counterpart of polo in Drosophila melanogaster and of CDC5 in Saccharomyces cerevisiae, belongs to a family of serine/threonine kinases. It is intimately involved in spindle formation and chromosome segregation during mitosis. The purpose of this study was to determine whether PLK1 is overexpressed in primary colorectal cancer specimens as compared with normal colon mucosa and to assess its relation to other kinases as a potential new tumor marker. In the present study, immunohistochemical analyses were performed of PLK1 expression in 78 primary colorectal cancers as well as 15 normal colorectal specimens. Furthermore, we examined the relationship between other kinases, Aurora-A and Aurora-C, and PLK1 expression. In normal colon mucosa, some crypt cells showed weakly positive staining for PLK1 in 13 out of 15 cases, the remaining cases being negative. Elevated expression of PLK1 was observed in 57 (73.1%) of the colorectal cancers, statistically significant associations being evident with pT (primary tumor invasion) (P=0.0006, Mann-Whitney U test), pN (regional lymph nodes) (P=0.008, chi2 test) and the Dukes' classification (P=0.0005, Mann-Whitney U test). Mean proliferating cell nuclear antigen-labeling index was 52.3%, with a range of 24.1% to 77.3%. Values for lesions with high and low PLK1 expression were 54.7+/-10.3% (mean+/-SD) and 45.9+/-11.9% (P=0.002, Student's t test). PLK1 was significantly associated with Aurora-A, but PLK1 staining was more diffuse and extensive than for Aurora-A or Aurora-C. Interestingly, PLK1 overexpression was significantly associated with p53 accumulation in colorectal cancers. Our results suggest overexpression of PLK1 might be of pathogenic, prognostic and proliferative importance, so that this kinase might have potential as a new tumor marker for colorectal cancers.