Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.

BACKGROUND: The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. METHODS: This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. RESULTS: A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). CONCLUSIONS: Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.

Association between social background and implementation of postoperative adjuvant chemotherapy for older patients undergoing curative resection of colorectal cancers, sub-analysis of the HiSCO-04 study.

PURPOSE: Adjuvant chemotherapy is recommended following colorectal cancer resection based on risk of recurrence. In older patients, treatment decisions should consider recurrence rates and tolerability, as well as functional prognosis, residual disease, and social factors. This study aims to investigate factors, including social background, influencing implementation of postoperative adjuvant chemotherapy in older patients undergoing curative resection for colorectal cancer. METHODS: This multi-institutional prospective cohort study included 15 institutions belonging to the Hiroshima Surgical study group for Clinical Oncology. We analyzed 159 older patients aged ≥ 80 years, who underwent curative resection for stage III colorectal cancer between December 2013 and June 2018, as sub-analysis of the HiSCO-04 study. RESULTS: In total, 62 (39.0%) patients underwent postoperative adjuvant chemotherapy. Four factors were significantly associated with its implementation: performance status < 2, Charlson Comorbidity Index < 2, prognostic nutritional index ≥ 40, and presence of a spouse or siblings as lifestyle supporters. No significant difference was found in the backgrounds between complete and incomplete postoperative adjuvant chemotherapy patients. CONCLUSION: Performance status, Charlson Comorbidity Index, nutritional status, and presence of a spouse or siblings as lifestyle supporters are possible factors influencing the implementation of postoperative adjuvant chemotherapy in older patients. To select appropriate treatment options, including postoperative adjuvant chemotherapy, it is essential to consider physical condition and comorbidities of older patients, thoroughly explain the situation to their families, and establish a support system to enhance understanding of the available treatment options.

Predictive factors associated with anastomotic leakage after resection of rectal cancer: a multicenter study with the Hiroshima Surgical study group of Clinical Oncology.

PURPOSE: Several factors have been reported as risk factors for anastomotic leakage after resection of rectal cancer. This study aimed to evaluate the risk factors for anastomotic leakage, including nutritional and immunological indices, following rectal cancer resection. METHODS: This study used a multicenter database of 803 patients from the Hiroshima Surgical study group of Clinical Oncology who underwent rectal resection with stapled anastomosis for rectal cancer between October 2016 and April 2020. RESULTS: In total, 64 patients (8.0%) developed postoperative anastomotic leakage. Five factors were significantly associated with the development of anastomotic leakage after rectal cancer resection with stapled anastomosis: male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection. The incidence of anastomotic leakage was correlated with the number of risk factors. The novel predictive formula based on odds ratios in the multivariate analysis was useful for identifying patients at high risk for anastomotic leakage. Diverting ileostomy reduced the ratio of anastomotic leakage ≥ grade III after rectal cancer resection. CONCLUSIONS: Male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection are possible risk factors for developing anastomotic leakage after rectal cancer resection with the stapled anastomosis. Patients at high risk of anastomotic leakage should be assessed for the potential benefits of diverting stoma.

A prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged ≥ 80 years after curative resection of colorectal cancer, the HiSCO-03 study.

PURPOSE: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥ 80 years. We conducted a prospective multi-institutional phase II study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. PATIENTS AND METHODS: Patients with stage III CRC aged ≥ 80 years who underwent curative resection were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1-28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. RESULTS: Sixty-nine patients were enrolled between 2013 and 2021. Of the 69 patients, 65 were included in the analysis. There were 32 males and 33 females with a median age of 82 years (range 80-88 years). In the primary endpoint, administration completion rate was 67.3% (95% confidence interval 54.9-77.6%), and the lower limit of the 95% confidence interval was below the threshold of 60%. 21 patients discontinued treatment because of adverse events (AEs) and refused treatment. The median relative dose intensities were 84% (range 4-100%) for UFT, and 100% (range 4-100%) for LV. Incidence of grade three or higher AEs were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). CONCLUSIONS: The indications for adjuvant UFT/LV therapy for elderly CRC aged ≥ 80 years were considered limited. It is necessary to clarify the background of patients in whom drug administration is discontinued and investigate their impact on long-term prognosis.

[A Case of Effective Chemoradiotherapy Using mFOLFOX6 for Locally Advanced Rectal Cancer].

We report a case of locally advanced rectal cancer, treated effectively with chemotherapy consisting of mFOLFOX6 combined with radiotherapy. A 63-year-old man was admitted to our hospital in March 2012 for diarrhea and anal and perineal pain. Advanced rectal cancer with invasion ofthe right perineum was diagnosed based on computer tomography(CT) findings. Surgery was performed; however, the rectal cancer was unresectable. A sigmoid colostomy was performed, and a central venous port was implanted. In April 2012, the patient was treated with chemotherapy using 3 courses ofmFOLFOX6 and concurrent radiotherapy. Radiotherapy at 2 Gy/day was administered 25 times(total dose, 50 Gy). After chemoradiotherapy, the patient underwent 3 courses ofmFOLFOX6 as an additional therapy. By June 2012, CT showed resolution ofthe tumor in the right perineum and a marked decrease in the size ofthe primary rectal cancer. Because the patient refused surgery, we started treatment with combination chemotherapy using oral S-1 and intravenous CPT-11 in August 2012. After 18 courses, the treatment was changed to oral administration ofS -1 alone, which was continued for 1 year. The patient remained well without recurrence for 54 months since the original diagnosis. Therefore, chemoradiotherapy with mFOLFOX6 is a possible option for the management of advanced rectal cancer.

possible role of soluble fibrin monomer complex after gastroenterological surgery.

AIM: To examine the role of soluble fibrin monomer complex (SFMC) in the prediction of hypercoagulable state after gastroenterological surgery. METHODS: We collected data on the clinical risk factors and fibrin-related makers from patients who underwent gastroenterological surgery at Hiroshima University Hospital between April 1, 2014 and March 31, 2015. We investigated the clinical significance of SFMC, which is known to reflect the early plasmatic activation of coagulation, in the view of these fibrin related markers. RESULTS: A total of 123 patients were included in the present study. There were no patients with symptomatic VTE. Thirty-five (28%) patients received postoperative anticoagulant therapy. In the multivariate analysis, a high SFMC level on POD 1 was independently associated with D-dimer elevation on POD 7 (OR = 4.31, 95%CI: 1.10-18.30, P = 0.03). The cutoff SFMC level was 3.8 µg/mL (AUC = 0.78, sensitivity, 63%, specificity, 89%). The D-dimer level on POD 7 was significantly reduced in high-SFMC patients who received anticoagulant therapy in comparison to high-SFMC patients who did not. CONCLUSION: The SFMC on POD 1 strongly predicted the hypercoagulable state after gastroenterological surgery than the clinical risk factors and the other fibrin related markers.

A multi-institutional feasibility study of S-1/oxaliplatin plus bevacizumab in patients with advanced/metastatic colorectal cancer: the HiSCO-02 prospective phase II study.

PURPOSE: FOLFOX is a standard combination chemotherapy regimen for metastatic colorectal cancer (CRC). 5-Fluorouracil (5-FU) is infused continuously through a pump for 46 h; therefore, replacement of infused 5-FU with oral S-1 would be more convenient for patients. We investigated the efficacy and safety of S-1/oxaliplatin (SOX) plus bevacizumab regimen in a community setting. METHODS: We conducted a phase II clinical study in Hiroshima, Japan. We enrolled individuals aged 20-80 years who had metastatic CRC, an Eastern Cooperative Oncology Group performance status of 0 or 1, assessable lesions, and not received previous chemotherapy. Eligible patients were administered SOX plus bevacizumab (S-1 80 mg/m2/day, day 1-14 orally; and oxaliplatin 130 mg/m2 day 1 i.v., bevacizumab 7.5 mg/kg, day 1 i.v. q3w). The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between May 2011 and January 2014, 55 patients (mean age 64 years) were enrolled at 12 institutions. Median follow up duration was 20.2 months (range 1.3-47.1 months). RR was 47.1 % [95 % confidence interval (CI) 33.7-60.6 %]. Median PFS and OS was 9.2 months (95 % CI 7.6-10.8) and 22.5 months (95 % CI 19.4-25.9), respectively. Major adverse events (grade 3/4) were neutropenia (9.3 %), thrombocytopenia (5.6 %), anorexia (18.5 %), and sensory neuropathy (16.7 %). CONCLUSION: These data suggested that SOX plus bevacizumab is effective and capable of being managed in metastatic CRC patients in our community clinical practice.

Total colectomy for multiple metachronous colon cancers in a patient with Lynch syndrome.

Lynch syndrome (LS) is a disorder caused by mismatch repair gene mutations, which have been recognized to be associated with an increased frequency of colorectal and extracolorectal tumors. However, it remains controversial as to whether total or segmental colectomy should be performed to treat colorectal cancer in patients with LS. A 58-year-old male underwent total colectomy with ileostomy for advanced transverse colon cancer. He was also found to have LS based on his characteristic family history and the findings of a preoperative examination, including a microsatellite instability analysis of past multiple metachronous cancers. The postoperative histological findings showed mucinous adenocarcinoma without lymph node metastasis, and the loss of the MSH2 protein expression was confirmed on an immunohistochemical examination. The present case provided important information on the clinical management of multiple developing metachronous colorectal cancers in patients with LS.

Up-front systemic chemotherapy is a feasible option compared to primary tumor resection followed by chemotherapy for colorectal cancer with unresectable synchronous metastases.

BACKGROUND: In stage IV colorectal cancer (CRC) with unresectable metastases, whether or not resection of the primary tumor should be indicated remains controversial. We aim to determine the impact of primary tumor resection on the survival of stage IV CRC patients with unresectable metastases. METHODS: We retrospectively investigated 103 CRC patients with stage IV colorectal cancer with metastases, treated at Hiroshima University Hospital between 2007 and 2013. Of these, those who had resectable primary tumor but unresectable metastases and received any chemotherapy were included in the study. We analyzed the overall survival (OS) and short-term outcomes between the patients who received up-front systemic chemotherapy (USC group) and those who received primary tumor resection followed by chemotherapy (PTR group). RESULTS: Of the 57 included patients, 15 underwent USC and 42 PTR. The median survival times were 13.4 and 23.9 months in the USC and PTR groups, respectively (P = 0.093), but multivariate analysis for the overall survival showed no significant difference between the two groups (hazard ratio, 1.30; 95% confidence interval (CI), 0.60 to 2.73, P = 0.495). In the USC group, the disease control rate of primary tumor was observed in 12 patients (80.0%), but emergency laparotomy was required for 1 patient. Morbidity in the PTR group was observed in 18 cases (42.9%). CONCLUSIONS: The overall survival did not differ significantly between the USC and PTR groups. USC may help avoid unnecessary resection and consequently the high morbidity rate associated with primary tumor resection for stage IV CRC with unresectable metastases.

Combined immunohistochemistry of beta-catenin, cytokeratin 7, and cytokeratin 20 is useful in discriminating primary lung adenocarcinomas from metastatic colorectal cancer.

BACKGROUND: It is important to discriminate between primary and secondary lung cancer. However, often, the discriminating diagnosis of primary lung acinar adenocarcinoma and lung metastasis of colorectal cancer based on morphological and pathological findings is difficult. The purpose of this study was to evaluate the clinical usefulness of immunohistochemistry of beta-catenin, cytokeratin (CK) 7, and CK20 for the discriminating diagnosis of lung cancer. METHODS: We performed immunohistochemistry of beta-catenin, CK7, and CK20 in 19 lung metastasis of colorectal cancer samples, 10 corresponding primary colorectal cancer samples and 11 primary lung acinar adenocarcinoma samples and compared the levels of accuracy of the discriminating diagnosis by using antibodies against these antigens. RESULTS: Positive staining of beta-catenin was observed in all the lung metastasis of colorectal cancer samples as well as in the primary colorectal cancer samples but in none of the primary lung acinar adenocarcinoma samples. Positive staining of CK7 was observed in 90.9% of the primary lung acinar adenocarcinoma samples and in 5.3% of the lung metastasis of colorectal cancer samples, but in none of the primary colorectal cancer samples. Positive staining of CK20 was observed in all the primary colorectal cancer samples and in 84.2% of the lung metastasis of colorectal cancer samples, but in none of the primary lung acinar adenocarcinoma samples. CONCLUSION: Combined immunohistochemistry of beta-catenin, CK7, and CK20 is useful for making a discriminating diagnosis between lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma. This method will enable accurate diagnosis of a lung tumor and will be useful for selecting appropriate therapeutic strategies, including chemotherapeutic agents and operation methods.

Alterations and correlations of the components in the Wnt signaling pathway and its target genes in breast cancer.

Both cyclin D1 and c-myc are key molecules in breast cancer carcinogenesis, and their transcriptional level and stability are regulated through several signaling pathways, including the Wnt signaling pathway. We performed immunohistochemical and mutational analyses of Wnt signaling components to investigate the association of Wnt signaling alterations with breast cancer carcinogenesis using 49 surgically resected primary breast cancer samples. Positive staining of cyclin D1 and c-myc was observed in 55.1% and 30.6% of the 49 breast cancer samples, respectively. Aberrant cytoplasmic expression of beta-catenin, which indicates the existence of alterations in the Wnt signaling pathway, was observed in 38.8% of breast cancer samples, though no mutation was found in the beta-catenin and Axin 1 genes. Reduced expression of APC was observed in 34.7% of samples. Statistical analysis revealed strong correlations between overexpression of beta-catenin and that of cyclin D1 and c-myc (p=0.0001 and 0.0117, respectively). Furthermore, overexpression of beta-catenin was significantly correlated with reduced expression of APC (p=0.0127). Wnt signaling alterations were frequently observed in breast cancer from the results of beta-catenin immunohistochemistry, although no mutation in the components of the Wnt signaling pathway was found in the present study. Based on the statistical analyses, we speculated that reduced expression of APC leads to overexpression of beta-catenin, and aberrant expression of cyclin D1 and c-myc mainly depends on alterations in the Wnt signaling pathway in breast cancer.

Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas.

The mechanisms of carcinogenesis in intrahepatic cholangiocarcinoma (ICC) are not well characterized although alterations in several oncogenes and onco-suppressor genes have been reported to occur in ICC. In the present study, we focused on alterations in the Wnt signaling components and target genes by analyzing 24 surgically resected samples of ICC. Immunohistochemical analysis of beta-catenin showed positive staining in cytoplasm and/or nucleus in 58.3% of the samples, indicating the presence of alterations in the Wnt signaling pathway in these samples. In sequencing analyses, mutations in the beta-catenin, adenomatous polyposis coli and Axin 1 genes were observed in 8.3, 12.5 and 41.7%, respectively, of the 24 ICC samples; however, the functional significance of these mutated genes is controversial. Furthermore, cyclin D1, c-myc and urinary-type plasminogen activator receptor, which are the downstream target genes in the Wnt signaling pathway, were overexpressed in 41.7, 41.7 and 58.3%, respectively, of the 24 ICC samples. The overexpression of cyclin D1 was statistically correlated with that of beta-catenin. Based on these results, we speculated that the Wnt signaling pathway plays an important role in carcinogenesis in ICC through overexpression of its target genes, particularly cyclin D1.

Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas.

Several lines of evidence show that the development of hepatocellular carcinoma (HCC) requires an accumulation of genetic alterations. However, molecular mechanism in HCC carcinogenesis remains unsolved. A total of 89 HCC samples were analyzed in this study to determine how alterations in the Wnt signaling pathway associate with the carcinogenesis of HCC. beta-catenin immunohistochemistry showed positive nuclear staining in 24 (27.0%) of the 89 HCC samples, indicating the existence of alterations in the Wnt signaling pathway in those 24 HCC samples. Mutations in the beta-catenin, Axin1 and Axin2 genes were detected in 10 (41.7%), 13 (54.2%) and 9 (37.5%) of the 24 beta-catenin-positive samples, respectively, but no mutation was detected in the APC gene. In conclusion, in addition to mutations in the beta-catenin gene, mutations in the Axin1 and Axin2 genes may alter the Wnt signaling pathway, resulting in accumulation of beta-catenin.

Immunohistochemical and sequencing analyses of the Wnt signaling components in Japanese anaplastic thyroid cancers.

We investigated the status of the components and target genes of the Wnt signaling pathway in Japanese anaplastic thyroid cancers (ATCs) in the present study. Nuclear and cytoplasmic positive staining of beta-catenin, which might indicate the existence of alterations in the Wnt signaling pathway, were found in 40.9% and 63.6% of the 22 ATC samples, respectively. The beta-catenin, adenomatous polyposis coli (APC) and Axin 1 gene mutations were observed in 4.5%, 9.0%, and 81.8% of the 22 ATC samples, respectively. Overexpression of cyclin D1 and c-myc, which are the target genes of the Wnt signaling pathway, was observed in 27.3% and 59.1% of the ATC samples, respectively. There was no significant correlation between nuclear or cytoplasmic positive staining of beta-catenin and nuclear positive staining of cyclin D1 or c-myc. Taken together, the results of beta-catenin immunohistochemistry suggest that alterations in the Wnt signaling pathway are associated with carcinogenesis of ATC, but the frequency of beta-catenin gene mutation in our series is lower than that previously reported. Furthermore, cyclin D1 and c-myc frequently accumulated in ATC, independently of dysfunction in the Wnt signaling pathway.

Immunohistochemical and mutational analyses of beta-catenin, Ki-ras, and p53 in two subtypes of colorectal mucinous carcinoma.

PURPOSE: The adenoma-carcinoma sequence theory is accepted in carcinogenesis of colorectal carcinoma. To elucidate the nature and genetic alterations in colorectal mucinous carcinoma (MC), we analyzed clinical and pathological characteristics of colorectal MC and nonmucinous carcinoma (NMC), and, furthermore, we compared the prognoses and the statuses of the Wnt signaling pathway, Ki-ras, and p53 in these two subtypes. EXPERIMENTAL DESIGN: Samples of colorectal MC obtained by surgical resections from 41 patients during the period from 1980 to 1999 were classified into fixed (FIX) type and floating (FLO) type (22 and 19 cases, respectively). The statuses of the Wnt signaling pathway and p53 protein were estimated by immunohistochemistry of beta-catenin and p53 proteins, respectively. The mutations in the Ki-ras gene were examined by direct sequencing. RESULTS: The prognosis of colorectal MC was poorer than that of NMC at both stage II and stage III (P = 0.0037 and <0.0001, respectively). The survival rate of patients with the FLO type of MC was lower than that of patients with the FIX type (P = 0.021). Although the results of immunohistochemistry of beta-catenin and mutational analysis of the Ki-ras gene in the two subtypes were not significantly different; the rate of positive nuclear staining of p53 was lower in the FLO type than in the FIX type (P = 0.04). CONCLUSIONS: Colorectal MC, particularly the FLO type, has a more aggressive nature than does colorectal NMC. The FLO type of colorectal MC may develop through different mechanisms from those through which NMC and the FIX type develop.

Immunohistochemistry of cyclin D1 and beta-catenin, and mutational analysis of exon 3 of beta-catenin gene in parathyroid adenomas.

Parathyroid adenomas are benign uniglandular tumors and are the most common cause of primary hyperparathyroidism. Several genetic changes in parathyroid tumors, including inactivation of tumor suppressor genes, activation of oncogenes and loss of heterozygosity at several chromosomal loci, have been reported. In this study, we analyzed the status of cyclin D1 and beta-catenin in 24 cases of parathyroid adenoma. Immunohistochemistry of cyclin D1 showed positive staining in 9 (37.5%) of the 24 parathyroid adenomas. The status of beta-catenin, which has recently been identified as a regulator of cyclin D1 transcription, was examined by direct sequencing of exon 3 of the beta-catenin gene and immunohistochemistry of beta-catenin protein, but neither mutation nor accumulation of beta-catenin was detected in any of the cases. These results indicate that cyclin D1 is frequently accumulated in parathyroid adenomas, independently of dysfunction in the Wnt signaling pathway.