Prognostic impact and survival outcomes of colon perforation in patients with metastatic colorectal cancer: a multicenter retrospective cohort study.

BACKGROUND: Colon perforation caused by colorectal cancer (CRC) is a fatal condition requiring emergency intervention. For patients with metastatic lesions, surgeons face difficult decisions regarding whether to resect the primary and metastatic lesions. Moreover, there is currently no established treatment strategy for these patients. This study aimed to investigate the clinical practice and long-term outcomes of patients with metastatic CRC diagnosed with the onset of colon perforation. METHODS: We performed a population-based multicenter cohort study. Consecutive patients diagnosed with stage IV CRC between 2008 and 2015 at all designated cancer hospitals in Fukushima Prefecture, Japan, were enrolled in this study. We evaluated the impact of colon perforation on the survival outcomes of patients with metastatic CRC. The main outcome was the adjusted hazard ratio (aHR) of perforation for overall survival (OS). Survival time and HRs were estimated using Kaplan‒Meier and Cox proportional regression analyses. RESULTS: A total of 1258 patients were enrolled (perforation: n = 46; non-perforation: n = 1212). All but one of the patients with perforation underwent primary resection or colostomy and 25 cases were able to receive chemotherapy. The median OS for the perforation and non-perforation groups was 19.0 and 20.0 months, respectively (p = 0.96). Moreover, perforation was not an independent prognostic factor (aHR: 0.99; 95% confidence interval: 0.61-1.28). CONCLUSIONS: In metastatic CRC, perforation is not necessarily a poor prognostic factor. Patients with perforation who undergo primary tumor resection or colostomy and prompt initiation of systemic chemotherapy might be expected to have a survival time similar to that of patients with non-perforated colon.

Clinical impact of gastrectomy for gastric cancer patients with positive lavage cytology without gross peritoneal dissemination.

BACKGROUND: The prognosis of gastric cancer patients with positive lavage cytology without gross peritoneal dissemination (P0CY1) is poor. The survival benefit of gastrectomy for these patients has not been established. PATIENTS AND METHODS: In this population-based cohort study, we investigated the impact of radical gastrectomy with lymph node dissection for P0CY1 patients. Patients who were diagnosed with Stage IV gastric cancer from 2008 to 2015 in all nine cancer-designated hospitals in a tertiary medical area were listed. Patients who were diagnosed with histologically proven adenocarcinoma in both the primary lesion and lavage cytology during the operation or a diagnostic laparoscopic examination were enrolled. Patients with a gross peritoneal lesion or other metastatic lesions were excluded. The primary outcome was the adjusted hazard ratio (aHR) of gastrectomy for overall survival. We also evaluated the survival time in patients who underwent gastrectomy or chemotherapy in comparison to patients managed without primary surgery or with best supportive care. RESULTS: One hundred patients were enrolled. The aHR (95% confidence interval) of gastrectomy was 0.677 (0.411-1.114, p = 0.125). The median survival time in patients who received gastrectomy (n = 74) was 21.7, while that in patients managed without primary surgery (n = 30) was 20.5 months (p = 0.155). The median survival time in patients who received chemotherapy (n = 76) was 23.0 months, while that in patients managed without chemotherapy was 8.6 months (p < 0.001). CONCLUSION: Gastrectomy was not effective for improving the survival time in patients with P0CY1 gastric cancer. Surgeons should prioritize the performance of chemotherapy over surgery as the initial treatment.

A grading system for predicting the prognosis of gastric cancer with liver metastasis.

OBJECTIVE: The prognosis of patients with liver metastases from gastric cancer is determined using tumor size and number of metastases; this is similar to the factors used for the prediction of liver metastases from colorectal cancer. The relationship between the degree of liver metastasis from gastric cancer and prognosis with reference to the classification of liver metastasis from colorectal cancer was investigated. METHODS: This was a multi-institutional historical cohort study. Among patients with stage IV gastric cancer, who visited the cancer hospitals in Fukushima Prefecture, Japan, between 2008 and 2015, those with simultaneous liver metastasis were included. Abdominal pretreatment computed tomography images were reviewed and classified into H1 (four or less liver metastases with a maximum diameter of ≤5 cm); H2 (other than H1 and H3) or H3 (five or more liver metastases with a maximum diameter of ≥5 cm). The hazard ratio for overall survival according to the H grade (H1, H2 and H3) was calculated using the Cox proportional hazards model. RESULTS: A total of 412 patients were analyzed. Patients with H1, H2 and H3 grades were 118, 162 and 141, respectively, and their median survival time was 10.2, 5.7 and 3.1 months, respectively (log-rank P < 0.001). The adjusted hazard ratio for overall survival was H1: H2: H3 = reference: 1.39 (95% confidence interval: 1.04-1.85): 1.69 (95% confidence interval: 1.27-2.27). CONCLUSIONS: The grading system proposed in this study was a simple and easy-to-use prognosis prediction index for patients with liver metastasis from gastric cancer.

Benefit of intensive chemotherapy for elderly patients aged 80 years or older with metastatic colorectal cancer: a state-wide multicenter cohort study.

BACKGROUND: It remains unclear whether intensive chemotherapy for Stage IV colorectal cancer (CRC) patients aged 80 years or older is beneficial prognostically. This study aimed to investigate the overall survival of Stage IV CRC patients aged ≥ 80 years receiving intensive chemotherapy. METHODS: The study design was a population-based, multicenter, historical cohort study. The extracted participants' data were consecutive patients diagnosed as Stage IV CRC between January 2008 and May 2015 in nine hospitals in Japan. Patients were classified into two groups according to age: aged group (≥ 80 years) and younger group (< 80 years old). Intensive chemotherapy was defined as at least two courses of doublet chemotherapy with oxaliplatin-or irinotecan-based regimens. The primary outcome was the adjusted hazard ratio (HR) of age ≥ 80 years in patients who undergoing intensive chemotherapy. RESULTS: During the study period, 1259 patients were treated for Stage IV CRC in the participating hospitals. In total, 231 patients (18.3%) were in the aged group, and 1028 (81.7%) were in the younger group, and 788 (62.6%) underwent intensive chemotherapy. The median overall survival for the aged and younger group patients was 21.0 months (interquartile range (IQR), 10.6-34.1 months) and 24.3 months (IQR 12.6-39.3 months), respectively. The adjusted HR of age ≥ 80 years was 1.29 (confidence intervals 0.84-2.00). CONCLUSION: Stage IV CRC patients aged 80 years or older receiving intensive chemotherapy had a similar prognosis to those aged < 80 years. Avoiding intensive chemotherapy for mCRC patients simply because they are ≥ 80 years old is not recommended.

Necrotizing fasciitis wound after debridement could be successfully treated with negative-pressure wound therapy with instillation and dwelling: A case report.

Background: Necrotizing fasciitis (NF) is associated with a high mortality rate. Adequate incision and drainage and repeated debridement are necessary for NF management. After drainage, daily local irrigation should be performed. Case presentation: A 72-year-old male patient complained of left lower quadrant pain. Computed tomography revealed a 7 cm mass in the descending colon, with retroperitoneal penetration. Hence, he underwent emergency surgery. The left abdomen was widely incised, and a transverse colostomy was performed for local wound control. Daily debridement of necrotic tissue and wound irrigation were continued. On postoperative day 48, the wound was extensive and complex and obtained a positive bacterial culture. Subsequently, we began a negative-pressure wound therapy with instillation and dwelling (NPWTi-d), which was very effective for extensive and complicated wounds with infection. Thereafter, a split-thickness skin was grafted, and the skin graft survived well. Ultimately, the wound successfully closed. Conclusions: NPWT is contraindicated for infected wounds, and an infection control period is required. However, NPWTi-d enables early initiation of wound care despite the presence of infection. Therefore, NPWTi-d is effective for extensive and complicated wounds with infection after NF debridement.

Clinical Features and Survival of Young Adults with Stage IV Gastric Cancer: a Japanese Population-Based Study.

PURPOSE: With the aging of society, the mean age of patients with gastric cancer (GC) in Japan has increased. However, there are few documented outcomes for young patients with stage IV GC. We investigated the clinical characteristics and prognosis of such patients aged < 40 years using a dataset from an integrated population-based cohort study. METHODS: We conducted this multicenter population-based cohort study to determine whether earlier onset of GC was a poor prognostic factor. We enrolled patients with metastatic GC aged < 40 years (young group) and those aged between 60 and 75 years (middle-aged group). Patients were histologically diagnosed as having gastric adenocarcinoma. We evaluated the overall survival (OS) of both groups and the hazard ratio (HR) for OS based on age. The adjusted HR with 95% confidence interval (CI) was evaluated using the Cox proportional hazards model after adjusting for confounding factors, including sex, histology, number of metastatic lesions, surgical resection, and chemotherapy. RESULTS: This study enrolled 555 patients. The patients were classified into the young (n = 20) and the middle-aged group (n = 535). The median OS durations were 5.7 and 8.8 months in the young and middle-aged groups, respectively (p = 0.029). The adjusted HR (95% CI) of the young group was 1.88 (1.17-3.04, p = 0.009). CONCLUSION: Age was an independent prognostic factor in patients with stage IV GC. Further studies investigating the genomic characteristics of GC and exploring more effective chemotherapeutic agents are required.

A case of strongly suspected Lynch syndrome with colorectal neuroendocrine carcinoma.

BACKGROUND: Neuroendocrine cell carcinomas (NEC) of the colon and rectum are uncommon, representing ~ 0.1% of all colorectal carcinomas. They are associated with a much worse prognosis compared to adenocarcinoma of the colon and rectum, as death occurs in approximately half of all patients within 1 year. Lynch syndrome (LS) is the most common cause of inherited colorectal cancer, accounting for 2-4% of newly diagnosed colorectal cancer cases. This case is extremely rare which was strongly suspected LS as the background, and NEC as the histological type of colorectal cancer. CASE PRESENTATION: The patient was a 44-year-old man presenting with vomiting as the main complaint. He had undergone ileocecal resection for cecal cancer at age 29. The diagnosis was obstructive descending colorectal cancer, and colonoscopy revealed tumors in the rectum and sigmoid colon in addition. Due to multiple occurrences of colorectal cancer and its prevalence in the patient's family, LS was suspected. The operation which was a subtotal proctocolectomy was performed. Pathological analysis revealed complete curative resection and the descending colon cancer of the obstructed portion was at the most advanced pathological Stage IIIC in UICC TNM classification, and the tissue type was a NEC. The Ki-67 index was 70%. The results of the microsatellite instability (MSI) test showed high-frequency MSI. The BRAF V600E variant was negative. The immunoexpression of MLH1 was positive, MSH2 was negative, PMS2 was positive, and MSH6 was negative. CONCLUSIONS: Extended surgery is recommended for incipient colorectal cancer in LS cases in order to reliably reduce the risk of developing metachronous colorectal cancer. The survival outcome of surgery alone on digestive tract NECs, even locoregional lesions that are completely resection, is extremely poor. It is currently unclear if digestive tract NECs develop more readily in patients with LS. The accumulation of additional cases is necessary.

Impact of histological subtype on prognosis in stage IV colorectal cancer: A population-based cohort study.

BACKGROUND: There are a few established prognostic factors for stage IV colorectal cancer. Thus, this study aimed to evaluate the impact of histological subtypes on prognosis and metastatic patterns in patients with stage IV colorectal cancer. METHODS: This was a population-based, multicenter, cohort study. We included consecutive patients diagnosed with stage IV colorectal cancer between 2008 and 2015 at all designated cancer hospitals in Fukushima prefecture, Japan. Patients were classified into two groups according to histological subtypes as follows: poorly differentiated adenocarcinoma (Por), mucinous adenocarcinoma (Muc), or signet-ring cell carcinoma (Sig) and well (Wel) or moderately differentiated adenocarcinoma (Mod). We evaluated the relationship between these histological groups and survival time. After adjusting for other clinical factors, we calculated the hazard ratio for Por/Muc/Sig. RESULTS: A total of 1,151 patients were enrolled, and 1,031 and 120 had Wel/Mod and Por/Muc/Sig, respectively. The median overall survival was 19.2 and 11.9 months for Wel/Mod and Por/Muc/Sig, respectively (p < 0.001). The adjusted hazard ratio for Por/Muc/Sig with regard to survival time was 1.42 (95% confidence interval: 1.13-1.77). Por/Muc/Sig had a lower incidence of liver and lung metastases and a higher incidence of peritoneal dissemination and metastasis to rare organs, such as the bone and brain. CONCLUSIONS: The Por/Muc/Sig histological subtype was an independent prognostic factor for poor prognosis among patients with stage IV colorectal cancer. The histological subtype may be useful for predicting the prognosis of patients with stage IV colorectal cancer and designing the treatment strategy.

Clinical Impact of Primary Tumor Site in Stage IV Colorectal Cancer: A Statewide Cohort Study.

BACKGROUND/AIM: We investigated the clinical impact of the primary tumor site in stage IV colorectal cancer (CRC). PATIENTS AND METHODS: In this statewide multicenter retrospective cohort, patients with stage IV CRC from nine hospital-based cancer registries across the Fukushima Prefecture (2008-2015) were categorized based on three primary tumor sites: right colon cancer (RCC), left colon cancer (LCC), and rectal cancer. Overall survival was assessed using Cox regression analysis. RESULTS: A total of 1,211 patients were included. The most common clinical symptom was obstruction in LCC and bleeding in rectal cancer. Liver metastases were multiple and larger in LCC, while lung metastases were multiple in rectal cancer. Compared to LCC, the adjusted hazard ratio (HR) for overall survival was 1.19 [95% confidence interval (CI)=1.01-1.39, p=0.032] in RCC and 1.03 (95% CI=0.86-1.23, p=0.77) in rectal cancer. CONCLUSION: RCC was independently associated with a worse prognosis in stage IV CRC.

An ascites grading system for predicting the prognosis of gastric cancer with peritoneum dissemination.

AIM: Gastric cancer with peritoneum dissemination is intractable with surgical resection. The evaluation of the degree of dissemination using computed tomography (CT) is difficult. We focused on the amount of ascites based on CT findings and established a scaling system to predict these patients' prognoses. METHODS: We extracted individual data from a population-based cohort. Patients diagnosed with histologically proven gastric adenocarcinoma with peritoneum dissemination were enrolled. Two raters evaluated the CT images and determined the grade of ascites in each patient: grade 0 indicated no ascites in all slices; grade 1 indicated ascites detected only in the upper or lower abdominal cavity; grade 2 indicated ascites detected in both the upper and lower abdominal cavities; and grade 3 indicated ascites extending continuously from the pelvic cavity to the upper abdominal cavity. We evaluated the relationship between the ascites grade and survival time. After adjusting for other clinical factors, we calculated hazard ratios of each ascites grade. RESULTS: A total of 718 patients were enrolled. The number of patients with grades 0, 1, 2, and 3 were 303, 223, 94, and 98, respectively. The median overall survival times were 16.0, 8.7, 5.4, and 3.0 months for ascites on CT grades 0, 1, 2, and 3, respectively (P < .001). The adjusted hazard ratios for the survival time were 1.74 (1.33-2.26, P < .001), 3.20 (2.25-4.57, P < .001), and 4.76 (3.16-7.17, P < .001) for grades 1, 2, and 3, respectively. CONCLUSION: We established a new grading system of pretreatment ascites to better predict the prognosis of gastric cancer.

Overexpression of adenovirus-mediated p27kip1 lacking the Jab1-binding region enhances cytotoxicity and inhibits xenografted human cholangiocarcinoma growth.

The cyclin-dependent kinase inhibitor (CDK1) p27(kip1) is a negative regulator of cell cycling and has antitumor effects. In our previous study, the recombinant adenovirus expressing wild-type p27(kip1) (Adp27-wt) induced cell cycle arrest and apoptosis, and proved that p27 is a tumor suppressor gene like p53. Another adenovirus vector expressing mutant p27(kip1) (Adp27-mt), which inhibited degradation by the ubiquitin-proteasome system, showed increased protein stability and caused a stronger induction of apoptosis. Recently, the p27(kip1) protein binding with Jab1 (Jun activating binding protein 1) was found to translocate from the nucleus into the cytosol, and then become degraded by the 26S proteasome system. The inhibition of nuclear-cytoplasmic translocation increases the protein stability of p27(kip1) and p27(kip1) with a deletion of the Jab1-binding region (p27-jab-d) is not translocated and not degraded. Therefore, a new recombinant adenovirus (Adp27-jab-d) expressing p27-jab-d was made which was able to induce greater cytotoxicity. Adp27-jab-d inhibited the growth of human cholangiocarcinoma cell line (TFK-1) cells in vitro at 3.3 times (IC(50)) lower concentration than Adp27-wt. Moreover, in a xenografted severe combined immuno-deficient (SCID) mouse model injected with TFK-1 cells in the subcutaneous tissue, treatment by intratumor injection of Adp27-jab-d once a day for 3 days after the tumor was established, inhibited tumor growth more strongly than Adp27-wt or Adp27-mt and even induced tumor regression. However, the flow cytometric TUNEL assay showed little enhancement of apoptosis. Adp27-jab-d was thought to induce not only apoptosis but also necrosis, which was due to a specific effect of the Adp27-jab-d. Thus, by enhancing the cytotoxicity through inhibiting the translocaton of p27(kip1), p27(kip1) lacking the Jab1-binding region might be useful for cancer therapy. The control protein localization might also be a new target not only for cancer treatment, but also other diseases.

Up-regulated p27Kip1 reduces matrix metalloproteinase-9 and inhibits invasion of human breast cancer cells.

BACKGROUND: p27Kip1 is a cyclin-dependent kinase inhibitor which has been reported to be associated with invasion, metastasis and angiogenesis in malignant tumors, but its mechanism of action remains unknown. Here, it was examined whether p27Kip1 has an inhibitory effect on cancer cell invasion and correlates with matrix metalloproteinase expression (MMPs). MATERIAL AND METHODS: The human breast cancer cell line MDA-MB-231 and MDA-MB-231 transfectedp27Kip1 MDA-MB-p27 were used for the invasion assay, Western blotting and real-time quantitative RT-PCR. RESULTS: In the invasion assay, the invasion of MDA-MB-p27 was significantly less than that of the parent cell line. In Western blotting analyses, the protein level of MMP-9 was also reduced in MDA-MB-p27. Furthermore, the activity of MMP-9 in cell culture supernatants was lower in MDA-MB-p27 as compared with enzyme-linked immunosorbent assays. In real-time quantitative RT-PCR, the mRNA level of MMP-9 was lower in MDA-MB-p27 cells. CONCLUSION: Up-regulation of p27Kip1 remarkably inhibited the invasion of the breast cancer cells, in part due to the reduced expression of MMP-9. This is the first report of p27Kip1 modulating MMP-9 and indicating that p27Kip1 might play a key role in tumor cell invasion.

Adenovirus expressing p27KIP1 induces apoptosis against cholangiocarcinoma cells by triggering Fas ligand on the cell surface.

BACKGROUND/AIMS: The prognosis of patients with cholangiocarcinoma is poor because of the difficulty of surgical curative resection. Therefore, other effective treatments must be developed especially those involving gene therapy. p27kip1, one of the cyclin-dependent kinase inhibitors, is known to limit proliferation of the cells. Our previous reports have shown that the overexpression of p27kip1 by a recombinant adenoviral vector expressing p27kip1 (Adp27) induces apoptosis. However, the mechanism of the Adp27-mediated apoptosis is not still resolved. Activation of the Fas pathway is one of the important gates for apoptosis. In this report, we examined whether p27kip1-induced apoptosis is closely related to the Fas/Fas ligand (FasL) system. RESULTS: After infection of Adp27, flow cytometric analysis showed that Fas ligand was expressed on the cell surface of cholangiocarcinoma cell lines (TFK-1). In spite of detecting the cell surface expression of Fas ligand, overexpression of p27kip1 increased no amount of Fas ligand in mRNA by quantitative RT-PCR and protein level by Western blot. In addition, the immunocytochemical analysis showed that Fas ligand was adequately stored within the cytosol of TFK-1 cells. More interestingly, Adp27-induced apoptosis was completely inhibited by the neutralizing antibody of Fas ligand (NOK-1). This result suggests that overexpression of p27kip1 may deliver Fas ligand to the cell surface and mainly utilizes the Fas pathway as a gate of apoptosis. CONCLUSIONS: This is the first report to prove that Adp27-mediated apoptosis utilizes the Fas pathway by delivering Fas ligand to the cell surface.

Adenovirus expressing mutant p27kip1 enhanced apoptosis against cholangiocarcinoma than adenovirus-p27kip1 wild type.

BACKGROUND/AIMS: The prognosis of cholangiocarcinoma is extremely poor despite the aggressive multidisciplinary cancer therapies that have been used clinically. Thus, it is imperative to develop new and effective treatments, such as gene therapy in order to treat this disease. p53 is the most common target for cancer gene therapy treatment. However, cholangiocarcinoma has a low frequency of p53 mutation, which makes this protein a poor candidate for gene therapy in this disease and another suitable gene therapy target must be found. p27kip1 is a universal cyclin-dependent kinase (CDK) inhibitor that blocks cell cycle progression and inhibits proliferation. Our previous reports have demonstrated the role of p27kip1 in the induction of apoptosis using a recombinant adenoviral vector expressing p27kip1 (Adp27) in several different human cancer cells. p27kip1 is regulated by two mechanisms composed of a ubiquitin-proteasome system and proteolytic processing system that requires the phosphorylation of p27kip1 on Thr-187 by the cyclinE/Cdk2 complex followed by proteolytic degradation. METHODOLOGY: In this study, we focused our aim on the degradation of p27kip1 protein mediated by a recombinant adenoviral expressing a mutant p27kip1 (Adp27-mt), which has a mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC). RESULTS: We observed that the mutated p27kip1 markedly inhibited ubiquitination and the subsequent degradation of p27kip1 when compared to wild type p27kip1. Consequently, we found that mutated p27kip1 induced a stronger induction of apoptosis and cell growth inhibition than wild type p27kip1 in cholangiocarcinoma cell lines TFK-1 and HuCCT-1. Furthermore, we demonstrated that Adp27-mt mainly caused G2/M arrest in the cell cycle progression and a decreased cyclinB1 and Cdc2 protein where as Adp27-wt mediated a G1/S arrest at 48 hours after infection. CONCLUSIONS: In this study, we showed that adenoviral vector expression of mutant p27kip1 protein inhibited degradation by the ubiquitin-proteasome system and strongly induced apoptosis and cell growth inhibition compared to wild type p27kip1. Thus recombinant adenovirus expressing mutant p27kip1 may be potentially useful for gene therapy against cholangiocarcinoma.

Adenovirus expressing mutant p27kip1 enhanced apoptosis and inhibited the growth of xenografted human breast cancer.

PURPOSE: To evaluate the anti-tumor effects of a novel adenovirus expressing mutant p27(kip1) (Adp27-mt), which consists of a mutation of Thr-187/Pro-188 to Met-187/Ile-188. METHODS: Using the human breast cancer cell lines, MDA-MB-231, ZR-75-1, and MCF-7, we tested Adp27-mt for cell cycle assay, growth inhibition assay, and TdT-mediated dUTP-biotin nick end labeling in a human breast cancer-grafted severe combined immunodeficiency (SCID) mouse model. RESULTS: The mutant p27(kip1) induced stronger apoptosis in the breast cancer cell lines than adenovirus expressing wild-type p27(kip1) (Adp27-wt). Adp27-mt inhibits cell growth significantly; being about 5- and 3.5-fold stronger for IC50 than Adp27-wt in the breast cancer cell lines, MDA-MD-231 and ZR-75-1, respectively. In the human breast cancer-grafted SCID mouse model, Adp27-mt induced tumor regression and antitumor effects significantly better than Adp27-wt. Furthermore, Adp27-mt mainly caused G2/M arrest in the cell cycle progression, whereas Adp27-wt mediated a G1/S arrest 48 h after infection. CONCLUSION: The mutant p27(kip1) protein induced apoptosis, and inhibited cell growth more efficiently with stronger anti-tumor effects than wild-type p27(kip1). Thus, the recombinant adenovirus expressing mutant p27(kip1) could be useful in gene therapy against breast cancer.