Adjuvant chemotherapy is currently recommended for Stage IIIA colon cancers. This study aimed to elucidate the oncologic outcomes of Stage IIIA colon cancer according to the chemotherapeutic regimen based on a retrospective review.
From 1995 to 2008, Stage IIIA colon cancer patients were identified from a prospectively maintained database at a single institution. Exclusion criteria were as follows: rectal cancer, another malignancy other than colon cancer, no adjuvant chemotherapy and unknown chemotherapeutic regimen. One hundred thirty-one patients were enrolled in the study, and the clinicopathologic and the oncologic characteristics were analyzed. The number of males was 72, and the number of females was 59; the mean age was 59.5 years (range, 25 to 76 years), and the median follow-up period was 33 months (range, 2 to 127 months).
Of the 131 patients, fluorouracil/leucovorin (FL)/capecitabine chemotherapy was performed in 109 patients, and FOLFOX chemotherapy was performed in 22 patients. When the patients who received FL/capecitabine chemotherapy and the patients who received FOLFOX chemotherapy were compared, there was no significant difference in the clinicopathologic factors between the two groups. The 5-year overall survival and the 5-year disease-free survival were 97.2% and 94.5% in the FL/capecitabine patient group and 95.5% and 90.9% in the FOLFOX patient group, respectively, and no statistically significant differences were noted between the two groups.
Stage IIIA colon cancer showed good oncologic outcomes, and the chemotherapeutic regimen did not seem to affect the oncologic outcome.
Stage IIIA; Colon neoplasm; Chemotherapeutic agent; Prognosis
AIM: To evaluate the clinical parameters and identify a better method of predicting pathological complete response (pCR).
METHODS: We enrolled 249 patients from a database of 544 consecutive rectal cancer patients who underwent surgical resection after preoperative chemoradiation therapy (PCRT). A retrospective review of morphological characteristics was then performed to collect data regarding rectal examination findings. A scoring model to predict pCR was then created. To validate the ability of the scoring model to predict complete regression.
RESULTS: Seventy patients (12.9%) achieved a pCR. A multivariate analysis found that pre-CRT movability (P = 0.024), post-CRT size (P = 0.018), post-CRT morphology (P = 0.023), and gross change (P = 0.009) were independent predictors of pCR. The accuracy of the scoring model was 76.8% for predicting pCR with the threshold set at 4.5. In the validation set, the accuracy was 86.7%.
CONCLUSION: Gross changes and morphological findings are important predictors of pathological response. Accordingly, PCRT response is best predicted by a combination of clinical, laboratory and metabolic information.
Rectal cancer; Preoperative chemoradiotherapy; Downstaging; Tumor regression; Validation
Oral capecitabine has been used as adjuvant therapy for colorectal cancer patients since the 1990s. Patient-initiated cessation or reduced use of capecitabine occurs widely for various reasons, yet the consequences of these actions are unclear. The present study sought to clarify treatment outcomes in such patients.
The study included 173 patients who had been diagnosed with stage II or III colon cancer according to the pathologic report after radical surgery at Samsung Medical Center from May 2005 to June 2007 and who had received capecitabine as adjuvant therapy. The patients were divided into groups according to whether the dose was reduced (I, dose maintenance; II, dose reduction) or stopped (A, cycle completion; B, cycle cessation). Recurrence and disease-free survival rates between the two groups each were analyzed.
Of the 173 patients, 128 (74.6%) experienced complications, most frequently hand-foot syndrome (n = 114). Reduction (n = 35) or cessation (n = 18) of medication was most commonly due to complications. Concerning reduced dosage, both groups displayed no statistically significant differences in recurrence rate and 3-year disease-free survival rate. Concerning discontinued medication use, the cycle completion group showed an improved recurrence rate (P = 0.048) and 3-year disease-free survival rate (P = 0.028).
The results demonstrate that maintaining compliance with capecitabine as an adjuvant treatment for colon cancer to preventing complications positively affects patient prognosis.
Colon cancer; Capecitabine; Dose; Cycle; Disease-free survival
We report a case of fatal fungal peripheral suppurative thrombophlebitis, caused by Candida albicans, which was disseminated to the blood, lungs, eyes, and spine. Clinical suspicion and aggressive management are important in managing fungal peripheral suppurative thrombophlebitis. Early clinical suspicion is important in managing fungal peripheral suppurative thrombophlebitis, and radical excision of the affected veins, recognition of metastatic foci, and use of systemic antifungal agents are essential to avoid septic shock and death.
Candidemia; Shock, Septic; Thrombophlebitis
To determine the role of methylation in colorectal cancer patients with a family history, we enrolled 25 colorectal cancer patients with a family history of colorectal cancer but without a mutation in the hMLH1 and hMSH2 genes. Thirty patients with sporadic colorectal cancer were included as control. The methylation status of COX2, MGMT, hMLH1, TIMP3, p16, and MINT2 in normal mucosa and tumor were assessed using methylation-specific PCR. In patients with a family history, the methylation frequency ranged from 4.0% for TIMP3 to 44.4% for MGMT, whereas, in patients with sporadic colorectal cancer, it ranged from 6.7% for TIMP3 to 50.0% for p16. Nine of the 25 patients with family history (36.0%) were classified as methylation-prone, and nine of the 30 patients with sporadic cancers (30.0%) were as methylation-prone, making their methylation indices 0.19 and 0.16, respectively (p=0.522). As for the individual genes, the methylation rate of MGMT was higher in colorectal cancer patients with family history (44.0% vs. 13.0%, p=0.016), whereas the methylation rate of p16 was higher in sporadic colorectal cancers (50.0% vs. 8.7%, p=0.046). While CpG island methylation of tumor suppressor genes may play a role in colorectal carcinogenesis, the genes involved may be different between tumors of patients with and without a family history of colorectal cancer.
Colorectal Neoplasms; Familial; Carcinogenesis; Methylation; Microsatellite Instability
Granulocytic sarcoma is an extramedullary tumor composed of immature granulocytic cells. These tumors usually occur simultaneously with or follow after the onset of acute myeloid leukemia (AML) or other myeloproliferative disorders. Rarely, it is the first manifestation of AML which appears several months before the onset of leukemia. We report a case of a 48-year-old man presenting with symptoms of small bowel obstruction. Laparotomy and open biopsy were performed. Immunohistochemical studies showed that the neoplastic cells were of myeloid lineage positive for myeloperoxidase and leukocyte common antigen, but negative for CD3, 20, 56, 79a, and cytokeratin. Initially, there was no evidence of blood or bone marrow involvement suggesting acute leukemia or other myeloproliferative disorders. The findings were consistent with the diagnostic findings of solitary granulocytic sarcoma (preleukemic). However, one month later, bone marrow biopsy revealed 57% myeloblasts. Sequentially, the patient developed FAB M2 acute myeloid leukemia. Induction chemotherapy including cytarabine and idarubicine was done which led to complete remission. Allograft bone marrow transplantation was performed later, and there is no evidence of recurrence till present.
Granulocytic sarcoma; Acute myeloid leukemia; Small bowel obstruction
Colonic hamartomas are rare polypoid lesions. We report an unusual case of multiple colonic hamartomatous polyps, including a giant hamartoma, unrelated to hereditary or familial polyposis syndromes, in a 48-year-old man. The diameter of the largest polyp was 9.5 cm, and endoscopy revealed that the lesion caused colonic obstruction. The clinical, endoscopic and histological aspects of this case are discussed.
Hamartoma; giant hamartoma
Serum carcinoembryonic antigen (s-CEA) is used to detect recurrence and predict prognosis in colorectal cancer. However, the cutoff values of s-CEA for prognosis have not been determined. We therefore tried to determine the preoperative s-CEA levels predictive of survivals in colorectal cancer patients. We retrospectively analyzed the medical records of 989 patients who underwent curative resection for colorectal cancer between July 1990 and December 1997, with a mean follow-up of 46 months (range, 3-129 months). When patients were divided into four subgroups with the cutoff values of s-CEA at 3,6, and 17 ng/mL, their 5-yr disease-free survival rates were 85.3% (<3.0 ng/mL), 70.0% (3-6 ng/mL), 64.2% (6-17 ng/mL), and 55.2% (>17 ng/mL) (p<0.001). Multivariate analysis showed that factors predictive of survival included age (p=0.028), tumor stage (p<0.001), cell differentiation (p=0.016), and gross type (p=0.007), location (p=0.003) and preoperative s-CEA (p<0.001). Using the above-described cutoff levels, a significant difference in survival was observed only in patients with stage III tumors (p=0.007) when analyses were performed by stage. We can suggest the new cutoff values of s-CEA used in the present study.
Carcinoembryonic Antigen; Prognosis; Colonic Neoplasm
The aberrant methylation of CpG islands in the promoter is associated with colorectal cancer (CRC) carcinogenesis. In our previous study, the promoter of alcohol dehydrogenase, iron containing, 1 (ADHFE1) was most highly methylated in CRC compared to normal colorectal mucosa. In this study, we examined the expression and function of the ADHFE1 in CRC.
We examined the promoter methylation and mRNA expression of ADHFE1 with 5-aza-2′-deoxycytidine (5-Aza-2-dC) in 12 CRC cell lines, 124 paired CRC and adjacent normal mucosa, and 59 advanced adenomas. To confirm methylation of ADHFE1, we performed bisulfite genomic sequencing in 3 CRC cell lines, 6 paired CRC and adjacent normal mucosa. ADHFE1 protein expression was studied using western blot and immunohistochemistry, respectively in the 36 and 243 paired CRC and adjacent normal tissue. We transfected the DLD-1 with pcDNA3.1 vector containing ADHFE1 and examined the expression of differentiation marker, such as ALP, CEA and Cdx2. We examined the ADHFE1 expression at distinct developmental stages in mouse embryos.
The ADHFE1 promoter was hypermethylated in all CRC cell lines, 81.8% in CRCs, and 84.7% in advanced adenomas, with reciprocal change by 5-Aza-2-dC. The expression of ADHFE1 mRNA was down-regulated in all CRC cell lines and 96.3% in CRC tissues. The expression of ADHFE1 protein was down-regulated in 91.7% of CRC tissues. In the immunohistochemistry, normal epithelial cells at the crypt top showed very strong ADHFE1 expression, whereas they were much weaker at the crypt base. In CRC, the good differentiation was significantly associated with high ADHFE1 expression. The activity of differentiation marker, such as ALP and CEA, was higher in pcDNA3.1-ADHFE1 transfected CRC cells with consistent correlation with ADHFE1 protein than control. In mouse embryos, ADHFE1 in the large intestine was the first detected at E15.5. At E18.5, ADHFE1 was predominantly expressed in the top of the mature crypt epithelium.
It showed that the hypermethylation of ADHFE1 promoter in CRC is concordance with down-regulation of ADHFE1 mRNA and ADHFE1 protein. ADHFE1 has an important role of differentiation in CRC, as well as normal colorectal mucosa and embryonic developmental processes.
ADHFE1; Promoter methylation; Colorectal cancer; Differentiation
We evaluated the risk factors for late complications and functional outcome after total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC).
Pre- and postoperative clinical status and follow-up data were obtained for 55 patients who underwent TPC with IPAA between 1999 and 2010. The median follow-up duration was 4.17 years. Late complications were defined as those that appeared at least one month after surgery. For a functional assessment, telephone interviews were conducted using the Global Assessment of Functioning Scale. Twenty-eight patients completed the interview.
Late complications were found in 20 cases (36.3%), comprising pouchitis (n = 8), bowel obstruction (n = 5), ileitis (n = 3), pouch associated fistula (n = 2), and intra-abdominal infection (n = 2). The preoperative serum albumin level for patients with late complications was lower than for patients without (2.4 ± 0.5 vs. 2.9 ± 0.7, P = 0.04). Functional outcomes were not significantly associated with clinical characteristics, follow-up duration, operation indication, or late complications.
This study demonstrated that a low preoperative albumin level could be a risk factor for late complications of TPC with IPAA. Preoperative nutritional support, especially albumin, could reduce late complications. Functional outcomes are not related to late complications.
Ulcerative colitis; Proctocolectomy; Complications
Recently, an increase in well-differentiated rectal neuroendocrine tumors (WRNETs) has been noted. We aimed to evaluate transanal endoscopic microsurgery (TEM) for the treatment of WRNETs.
Between December 1995 and August 2009, 109 patients with WRNETs underwent TEM. TEM was performed for patients with tumors sizes of up to 20 mm and without a lymphadenopathy. These patients had been referred from other clinics after having been diagnosed with WRNETs by using a colonoscopic biopsy; they had undergone a failed endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) and exhibited an involved resection margin and remaining tumor after ESD or EMR, regardless of the distance from the anal verge. This study included 38 patients that had more than three years of follow-up.
The mean age of the patients was 51.3 ± 11.9 years, the mean tumor size was 8.0 ± 3.9 mm, and no morbidity occurred. Thirty-five patients were asymptomatic. TEM was performed after a colonoscopic resection in 13 cases because of a positive resection margin, a residual tumor or a non-lifting lesion. Complete resections were performed in 37 patients; one patient with a positive margin was considered surgically complete. In one patient, liver metastasis and a recurrent mesorectal node occurred after five and 10 years, respectively.
TEM might provide an accessible and effective treatment either as an initial or as an adjunct after a colonoscopic resection for a WRNET.
Well-differentiated rectal neuroendocrine tumors; Transanal endoscopic microsurgery; Colonoscopic resection; Treatment
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis.
To investigate differential gene expression signatures of metastatic vs non-metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation.
We first delineated six candidate genes for metastasis including ATM, CCND2, RBL2, CDKN3, CCNB1, and GTSE1. ATM was negatively correlated with metastatic NETs (p<0.001) with more than 2-fold change compared to non-metastatic NETs. Overexpression of ATM protein by IHC was strongly correlated with high ATM mRNA levels and low Ki-67 labeling index. Patients with ATM-negativity by IHC showed significantly decreased overall survival than patients with ATM-positivity (median OS, metastatic vs non-metastatic NETs; 2.7 years vs not reached; p = 0.003) and 85.7% of metastatic NETs were ATM-negative. In another validation set of GEP-NETs, decreased mRNA of ATM gene was associated with metastasis and remained significant (p = 0.023).
ATM down-regulation was strongly associated with metastatic NETs when compared with non-metastatic NETs and ATM may be a potential predictive marker for metastasis as well as a novel target in metastatic GEP-NETs.
Tubular colonic duplication presenting in adults is rare and difficult to diagnose preoperatively. Only a few cases have been reported in the literature. We report a case of a 29-year-old lady presenting with a long history of chronic constipation, abdominal mass and repeated episodes of abdominal pain. The abdominal-pelvic computed tomography scan showed segmental bowel wall thickening thought to be small bowel, and dilatation with stasis of intraluminal content. The provisional diagnosis was small bowel duplication. She was scheduled for single port laparoscopic resection. However, a T-shaped tubular colonic duplication at sigmoid colon was found intraoperatively. Resection of the large T-shaped tubular colonic duplication containing multiple impacted large fecaloma and primary anastomosis was performed. There was no perioperative complication. We report, herein, the case of a T-shaped tubular colonic duplication at sigmoid colon in an adult who was successfully treated through mini-laparotomy assisted by single port laparoscopic surgery.
Colonic duplication; Congenital abnormalities; Adult; Laparoscopy
Serous cystic neoplasms of the pancreas are almost always benign lesions. However, there are some case reports of malignant serous neoplasms of the pancreas. It is very difficult to distinguish malignant and benign tumors. Indeed, only clinicopathologic findings of locoregional invasion and metastasis represent a malignancy. We report a serous cystadenocarcinoma of the pancreas that was initially considered to be colon cancer. Post-operatively, the tumor was confirmed to be a malignant serous cystic tumor of the pancreas. One year later, the patient remains disease-free.
Pancreas; Cystadenocarcinoma; Colon; Spleen
The aim of this study was to investigate the relationship between heart rate variability (HRV), the Framingham risk score (FRS), and the 10-year risk of coronary heart disease (CHD) development among Korean adults.
The subjects were 85 healthy Korean adults recruited from a health check-up center. The FRS and 10-year risk of CHD development were calculated.
The FRS in men was inversely correlated with the standard deviation of all normal to normal RR-intervals (SDNN); the root mean square successive difference (RMSSD); the percentage of successive normal cardiac inter-beat intervals greater than 20 ms, 30 ms, and 50 ms (pNN20, pNN30, pNN50); the low frequency (LF); and the high frequency (HF) (P < 0.05). There was no significant relationship between the FRS and HRV in women. Overall, in the receiver operating characteristic (ROC) analysis, the RMSSD, HF, SDNN, LF, LF/HF ratio, and pNN30 predicted an increased 10-year CHD risk. After adjusting for sex and body mass index, those with greater than one standard deviation in the RMSSD, HF, and LF had a 52-59% reduction in their 10-year risk of CHD development ≥ 10%.
This study therefore indicates that the HRV indices, particularly SDNN, RMSSD, pNN30, LF, and HF may be useful parameters for the assessment of CHD risk. Most notably, the usefulness of these HRV measures as indicators for CHD risk evaluation may be greater among men than among women.
Heart Rate; Risk Assessment; Electrocardiography
The aim of this study was to assess the role of pre-operative chest computed tomography (CT) compared with abdominopelvic CT (AP-CT) and chest radiography (CXR) for detecting pulmonary metastasis in patients with primary colorectal cancer (CRC).
We retrospectively analyzed the data of 619 patients with primary CRC who simultaneously received a preoperative chest CT (chest CT group), AP-CT with hilar extension, and CXR (CXR group).
In the chest CT group, there were 297 (48.0%) normal, 198 (32%) benign, 96 (15.5%) indeterminate, 26 (4.2%) metastasis, and two lung cancers. Eighteen patients (2.9%) in the CXR group who had no pulmonary metastasis were diagnosed with pulmonary metastasis on a chest CT. The sensitivity and accuracy were 83.9% and 99.0% in the chest CT group, respectively, and 29.0% and 91.5% in the CXR group, respectively (P < 0.0001 and P = 0.0003).
Chest CT appears to improve the accuracy of pre-operative staging in patients with CRC and is useful for the early detection of pulmonary metastasis as a baseline study for abnormal lung nodules.
Colorectal neoplasm; Metastases; Computed tomography; Chest X-ray
We wanted to evaluate the usefulness of the computer-aided detection (CAD) system for detecting pulmonary nodules in real clinical practice by using the CT images.
Materials and Methods
Our Institutional Review Board approved our retrospective study with a waiver of informed consent. This study included 166 CT examinations that were performed for the evaluation of pulmonary metastasis in 166 patients with colorectal cancer. All the CT examinations were interpreted by radiologists and they were also evaluated by the CAD system. All the nodules detected by the CAD system were evaluated with regard to whether or not they were true nodules, and they were classified into micronodules (MN, diameter < 4 mm) and significant nodules (SN, 4 ≤ diameter ≤ 10 mm). The radiologic reports and CAD results were compared.
The CAD system helped detect 426 nodules; 115 (27%) of the 426 nodules were classified as true nodules and 35 (30%) of the 115 nodules were SNs, and 83 (72%) of the 115 were not mentioned in the radiologists' reports and three (4%) of the 83 nodules were non-calcified SNs. One of three non-calcified SNs was confirmed as a metastatic nodule. According to the radiologists' reports, 60 true nodules were detected, and 28 of the 60 were not detected by the CAD system.
Although the CAD system missed many SNs that are detected by radiologists, it helps detect additional nodules that are missed by the radiologists in real clinical practice. Therefore, the CAD system can be useful to support a radiologist's detection performance.
Computer-aided detection; Computed tomography (CT); Lung; Nodule
An anorectal melanoma (AM) is a very rare tumor. However, sufficient data supporting effective surgical options for the disease do not exist. This retrospective review aimed to analyze treatment outcomes for an AM.
From June 1999 to December 2008, we retrospectively reviewed a prospectively collected consecutive series of 19 patients who had undergone a surgical resection for an AM at a single institute. Surgical method and clinicopathological factors were analyzed.
The median age was 61.4 years (range, 46 to79 years). Main symptoms were an anal mass, hematochezia, perianal pain, tenesmus, fecal incontinence, and bowel habit change. The average duration of symptoms before diagnosis was 7.8 months (range, 1 to 36 months). S-100 and HMB-45 were positive in all patients, even in non-melanin pigmentation. There were 12 abdominoperineal resections (APRs) and 7 wide local excisions (WEs). The APR showed longer overall survival when compared with the WE (64.1 months vs. 10.9 months, P < 0.001). No patients who underwent a WE survived more than 13 months.
A high index of suspicion is necessary to establish the diagnosis for an AM in patients with anal symptoms, and S-100 and HMB-45 can be useful markers for an AM. Even with the small number of cases and the short follow-up, our data suggest that an APR for an AM may provide longer survival than a WE.
Anorectal melanoma; Wide excision; Abdominoperineal resection; Immunohistochemical markers
To determine whether family history of cancer may be a risk factor for the mutator phenotype in colorectal cancer, we recruited 143 consecutive colorectal cancer patients with a family history of accompanying cancers not meeting the Amsterdam criteria. Microsatellite instability (MSI) at 5 markers, hMLH1-promoter methylation, and expression of mismatch repair (MMR) proteins (hMLH1, hMSH2, hMSH6, hMPS1, and hPMS2) were determined. Among the relatives of familial colorectal cancer patients, colorectal cancer was the most common tumor type. Of the proband colorectal cancers, 26 (18.2%) showed high-level MSI (MSI-H); 47 additional tumors with mutator phenotype (32.9%) were identified by hMLH1-promoter methylation and/or loss of MMR protein expression. Mutator phenotype was associated with right-sided colon cancer and the type of accompanying cancer. Family history, which was differentially quantified according to the degree of relatives and the type of accompanying cancers, effectively discriminated MSI-H from microsatellite stable (MSS) and low-level microsatellite instability (MSI-L) and mutator phenotypes. Our findings indicate that familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers and that family history could be correlated with microsatellite instability.
Familial Colorectal Cancer; Family History; Mutator Phenotype; Ncrosatellite Instability
Capecitabine is an oral fluoropyrimidine carbamate and it is known as an effective radiosensitizer. Capecitabine and its metabolite reach their peak concentration in the plasma at 1~2 hours after a single oral administration of capecitabine and the levels fall rapidly thereafter. To verify the radiosensitizing effect of capecitabine that is based on such pharmacokinetic characteristics, we performed a retrospective analysis on the optimal timing of capecitabine administration with performing preoperative chemoradiation for locally advanced rectal cancer.
Materials and Methods
Among 171 patients who were treated with preoperative radiotherapy and concurrent capecitabine administration for rectal cancer, 56 patients were administered capecitabine at 1~2 hours before radiotherapy (group A), and at other time in the other 115 patients (group B). Total mesorectal excision was done at 4 to 6 weeks after the completion of chemoradiation. The radiosensitizing effect of capecitabine was evaluated on the basis of the pathological response.
Complete pathological regression of the primary tumor was observed in 12 patients (21.4%) for group A and in 11 patients (9.6%) for group B (p=0.031). Residual disease less than 0.5 cm (a good response) was observed in 19 patients (33.9%) for group A and in 23 patients (20.0%) for group B (p=0.038). On multivariate analysis, the capecitabine ingestion time showed marginal significance.
When performing preoperative chemoradiation for locally advanced rectal cancer, the radiosensitizing effect of capecitabine was enhanced when it was administered 1 hour before radiotherapy.
Rectal neoplasms; Combined modality therapy; Capecitabine
Lymph node involvement is the most important prognostic factor of rectal cancer. Cancer originating from sites other than the rectum rarely metastasizes to the mesorectal lymph node. We report a rectal cancer patient with a synchronous metastatic prostatic carcinoma to the mesorectal lymph node.
Mesorectal; Lymph node; Prostatic carcinoma
The aim of this study was to evaluate the responsiveness to CPT-11 with respect to hMLH1 and hMSH2 protein expressions in primary colorectal tumors.
Materials and Methods
91 patients with colorectal cancer treated having undergone surgery and postoperative CPT-11-based adjuvant chemotherapy, between 1997 and 2002, were prospectively recruited. Tumor samples were immunohistochemically analyzed for the expressions of hMLH1, hMSH2, p53 and CEA proteins.
Of the 91 tumors, 6 (6.6%) and 4 (4.4%) showed loss of hMLH1 and hMSH2 protein expressions, respectively. The response rate of patients with tumors not expressing either hMLH1 or hMSH2 was higher than that of those expressing either of these proteins (p=0.026). Patients with tumors not expressing hMLH1 showed a significantly better response to CPT-11 (p=0.04). The responsiveness was not associated with the expressions of hMSH2, p53 or CEA. There were no correlations between drug toxicity and the expressions of hMLH1, hMSH2 or p53. The overall survival was better in patients responsive to CPT-11-based chemotherapy compared to non-responders.
The immunohistochemical determination of loss of hMLH1 and hMSH2 expressions may be used in determining the responsiveness to CPT-11-based chemotherapy. Our results suggest that hMLH1 protein expression may be a predictor for CPT-11 responsiveness in patients with colorectal cancer.
Colorectal neoplasm; CPT-11; Response; hMLH1; hMSH2
Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer.
Materials and Methods
A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation.
Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed.
Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
Rectal cancer; Preoperative; Chemoradiotherapy; Capecitabine
Isolated diaphragmatic metastasis arising from colorectal cancer has been reported only one case in the literature presently. Here, we presented a new case and discussed the possible pathogenesis and the treatment options. A 42-year-old male patient had received anterior resection for sigmoid colon cancer. Although the increased serum CEA level was detected 20 months after the surgery, metastatic lesion could not be detected by repeated colonoscopy, CT scan, bone scan or PET scan for 35 months. We could detect a suspicious metastatic lesion on the liver by CT scan at 56 month after the surgery. During a second-look operation, we found a solitary metastasis on the diaphragm and removed it along with the 1 cm tumor-free resection margin. Although the prognosis associated with skeletal metastasis is poor, the complete resection of isolated diaphragmatic metastasis and subsequent appropriate adjuvant chemotherapy may achieve a cure the disease provided that other metastatic lesions are absent.
Colorectal neoplasm; Metastasis; Diaphragm; Carcinoembryonic antigen
The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.