[Correlation between mismatch repair proteins status and clinicopathological characteristics in sporadic colorectal cancer patients].

Objective: To explore the expression of mismatch repair (MMR) proteins in sporadic colorectal cancer (SCRC) patients, and its association with clinicopathological characteristics of SCRC. Methods: Patients with histologically confirmed colorectal cancer were consecutively recruited between December 2011 and June 2015 at Sun Yat-sen University Cancer Center. The exclusion criteria included multiple primary colorectal tumors, hereditary colorectal cancer (including Lynch syndrome, familial adenomatous polyposis), and the patients without the MMR proteins status tested. A total of 2 684 patients were included. Correlations of MMR proteins status and patients' demographics (including gender, age), tumor characteristics (site and differentiation) and TNM staging (excluding 315 SCRC patients receiving neoadjuvant therapy) were investigated. Results: The percentage of deficient MMR (dMMR) in these SCRC patients was 10.2%, and that of proficient MMR (pMMR) was 89.8%. The dMMR was more likely to be detected in younger (≤59 old years) SCRC patients compared to the elderly (>59 years) [12.7%(179/1 406)vs 7.5%(96/1 278), P<0.001]. The dMMR rate in right colon cancer was significantly higher than that in left colon cancer and rectal cancer [22.7%(151/664)vs 7.2%(69/956)vs 5.2%(55/1 064), P<0.001]. Among the various pathological types of SCRC, mucinous adenocarcinoma showed the highest rate of dMMR (24.4%), and neuroendocrine carcinoma the lowest rate of dMMR (0) (P<0.001). In addition, the proportions of dMMR in stage Ⅰ, stage Ⅱ, stage Ⅲ and stage Ⅳ SCRC were 9.7%, 16.5%, 8.5%, and 3.9%, respectively (P<0.001). There is no significant difference in the proportion of dMMR between male and female (11.0% vs 9.1%, P=0.114). Conclusion: dMMR status may be most likely to exist in younger (≤59 years) patients with stage Ⅱ right colon mucinous adenocarcinoma among SCRC.

Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer.

BACKGROUND: Conventional neoadjuvant chemoradiotherapy (CRT) is suboptimal for systemic control in locally advanced rectal cancer (LARC). To improve systemic control, we developed an alternative approach in which an intensified oxaliplatin and capecitabine (XELOX) chemotherapy regimen was administered concomitantly with radiation and extended to the resting period (consolidation chemotherapy) for high-risk LARC. The aim of the current study was to evaluate the short-term efficacy and toxicity of this strategy. METHODS: Patients with high-risk LARC were treated with CRT. Two cycles of XELOX were administered concomitantly with radiation. Thereafter, an additional cycle of the same regimen was administered during the resting period after completion of CRT. Tumor response, toxicities and surgical complications were recorded. RESULTS: This study includes 36 patients treated with the above strategy. All patients completed the planned concurrent CRT. Because of grade 3 toxicities, 2 patients were unable to complete the additional chemotherapy. Grade 3 toxicities were leucopenia (2.8 %), diarrhea (2.8 %) and radiodermatitis (2.8 %). All patients underwent optimal surgery with total mesorectal excision (TME) and a sphincter-saving procedure was performed in 27 patients (75 %). There was no perioperative mortality. Postoperative complications developed in 7 patients (19.4 %). Pathologic complete regression (pCR),"nearly pCR" (major regression), and moderate or minimal regression were achieved in 13 (36.1 %), 16 (44.4 %), and 7 patients (19.5 %), respectively. CONCLUSION: The preliminary results suggest that a XELOX regimen initially administered concomitantly with radiotherapy and then extended to the resting period in high-risk LARC patients is well tolerated. The strategy is highly effective in terms of pCR and nearly pCR rates, and thus warrants further investigation.

Prognostic factors in surgically managed gastrointestinal stromal tumours.

OBJECTIVE: To determine prognostic factors associated with survival in patients with surgically managed gastrointestinal stromal tumours (GISTs). METHODS: This retrospective study included 374 patients with pathologically confirmed GISTs. Medical records were reviewed and prognostic factors associated with adverse outcomes were determined. RESULTS: A total of 337 patients underwent complete resection with curative intent; 37 underwent incomplete resection. Overall mean survival time was 127.3 months; 5-year survival rate was 70.4%. Multivariate analyses determined that tumour size, risk status (of recurrence or metastasis) and surgical procedure were significant predictive factors for survival. There was a significant difference in the 5-year survival rate between patients who received adjuvant imatinib compared with those who did not (75.1% versus 13.8%). CONCLUSIONS: Patients with GISTs managed by surgical resection combined with targeted chemotherapy had a good prognosis. Clinical factors predictive of survival included tumour size, risk status and surgical procedure.

Neuroprotective effect of neurotropin on chronic oxaliplatin-induced neurotoxicity in stage II and stage III colorectal cancer patients: results from a prospective, randomised, single-centre, pilot clinical trial.

BACKGROUND: Oxaliplatin is effective in adjuvant and first-line colorectal cancer chemotherapy. Oxaliplatin-induced severe chronic neurotoxicity is the main dose-limiting adverse event. No standard treatment for oxaliplatin-induced chronic neurotoxicity has been identified. MATERIALS AND METHODS: We conducted a prospective pilot clinical trial to explore whether neurotropin has neuroprotective effects on chronic neurotoxicity. From May 1, 2010 to May 1, 2011, 80 stage II and III colorectal cancer patients who were eligible to receive oxaliplatin-based chemotherapy voluntarily enrolled in the trial. The patients were randomly divided into two groups, one of which received neurotropin treatment. RESULTS: The patients in the control group experienced significantly ≥ grade 2 and ≥ grade 3 neurotoxicity (by NCI CTCAE grading) than those in the neurotropin group (60.9 vs. 21.1 %, for at least grade 2 neurotoxicity, P = 0.001; 39 vs. 2.7 %, for at least grade 3 neurotoxicity, P < 0.001). If neurotoxicity was assessed by oxaliplatin-specific neurotoxicity grading, the patients in the control group also experienced significantly more ≥ grade 2 neurotoxicity (51.2 vs. 12.5 %, P = 0.001). Neurotropin was the only factor that affected the incidence of ≥ grade 2 neurotoxicity in the multivariate Cox proportional hazards regression analysis. CONCLUSION: Neurotropin combined with oxaliplatin decreases chronic neurotoxicity effectively and safely.

Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial.

BACKGROUND: Hand-foot syndrome (HFS) is the most common adverse event induced by capecitabine. Some clinicians think that HFS is a type of inflammation limited to the hands and feet and can be prevented with a COX-2 inhibitor (celecoxib). METHODS: We designed a single-center, prospective randomized clinical trial to test the hypothesis. From August 2008 to December 2010, stage II and III colorectal cancer patients receiving capecitabine-based chemotherapy enrolled in the trial voluntarily. All patients were divided randomly into two groups treated with or without celecoxib. All adverse events were recorded. RESULTS: Grade 1 and grade 2 HFS were more common in the capecitabine group than in the capecitabine/celecoxib group (74.6% versus 57.4%, P = 0.034, 29.6% versus 14.7% P = 0.035). The use of celecoxib (P < 0.001, P = 0.003) and the level of dihydropyrimidine dehydrogenase (P = 0.048, P = 0.014) affected the incidence of grade 1 and 2 HFS, as determined by log-rank analysis. Multivariate Cox proportional hazards regression analysis indicated that the use of celecoxib was the only factor that affected the incidence of ≥ grade 1 HFS [Hazard Ratio (HR): 0.556, P = 0.001] and ≥ grade 2 HFS (HR: 0.414, P = 0.005). CONCLUSIONS: Celecoxib can be used effectively and safely to prevent capecitabine-related HFS.

Circulating antibodies to carcinoembryonic antigen related to improved recurrence-free survival of patients with colorectal carcinoma.

This prospective study evaluated the prognostic value of antibodies to carcinoembryonic antigen (anti-CEA), detected by indirect immunosorbent assay, in the serum of colorectal carcinoma patients. Serum carcinoembryonic antigen (CEA) concentrations, measured by electrochemiluminescence immunoassay, were elevated in 26 (37.7%) of 69 patients with colorectal cancer and could not be detected among the 28 patients with benign intestinal conditions or 37 healthy individuals who comprised the control groups. Anti-CEA immuno globulin (Ig)G or IgM was detected by immunonephelometry in 44 (63.8%) patients with colorectal cancer, three (10.7%) with benign intestinal conditions and four (10.8%) healthy blood donors. Differences in antibody detection frequencies between the cancer patient group and the control groups were statistically significant. Titres of anti-CEA correlated significantly with CEA levels and Dukes' cancer stage. Antibody titre was an independent, significant, favourable predictor for 5-year recurrence-free survival. It is concluded that measurement of serum anti-CEA combined with CEA might be useful as a tumour marker and to assess prognosis. These results need to be confirmed in large, well-controlled, randomized clinical trials.

Phase II study of pre-operative radiotherapy with capecitabine and oxaliplatin for rectal cancer and carcinoembryonic antigen as a predictor of pathological tumour response.

This study investigated the efficacy and tolerability of pre-operative radiotherapy with concurrent capecitabine and oxaliplatin in patients with rectal cancer. Forty-seven patients with rectal adenocarcinoma (stages T3 - T4; node-positive) were enrolled and received radiotherapy (46 Gy in 23 fractions) in combination with capecitabine (1000 mg/m(2) twice daily on days 1 - 14 and 22 - 35) and oxaliplatin (130 mg/m(2) on days 1 and 22) (XELOX regimen). The main endpoints were safety and efficacy, as assessed by pathological complete response (pCR). All patients received pre-operative chemoradiotherapy (CRT) as planned. The most common severe toxicity was diarrhoea (12.8%); post-operative complications were rare (9.8%). The pCR rate was 20.9% in all patients and 34.8% in patients with normal pre-CRT serum carcinoembryonic antigen (CEA < or = 5 ng/ml) level, compared with 5.0% in the patients with elevated CEA (> 5 ng/ml). In conclusion, pre-operative radiotherapy with concurrent XELOX regimen in rectal cancer patients is feasible and effective. Serum CEA may be a suitable predictor of pCR.

Elevated expressions of MMP7, TROP2, and survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer.

PURPOSE: Colorectal cancer is one of the most common cancers worldwide. We tested the hypothesis that differences in the expression of certain molecular markers of colon cancer may account for different clinical outcomes. METHODS: Tissue microarray technology was used to assay the expression of 17 biological markers [beta-catenin, CD44v7, c-myc, cyclin D1, estrogen receptor beta, mitogen-activated protein kinase/extracellular signal-regulated kinase, maspin, matrix metalloproteinase-7 (MMP7), p53, Pin1, peroxisome proliferators-activated receptor-gamma, survivin, T cell transcription factor 4 (TCF4), transforming growth factor beta receptor II (TGFbetaR II), TGFbeta, TROP2, and Wnt] by immunohistochemistry in 620 colon cancer patients. The Cox proportional hazards regression model was applied to analyze the lifetime data, including time to death, time to recurrence, and time to liver metastasis. RESULTS: All the markers were present at significantly higher expression levels in tumor specimens than in normal colonic specimens. Kaplan-Meier analysis showed that high expression of TROP2, MMP7, and survivin were related to decreased survival; TCF4 and TROP2 were related to disease recurrence; and CD44v7, cyclin D1, MMP7, p53, survivin, and TCF4 were related to liver metastasis. However, the results of the multivariate analysis only showed that expression of MMP7, survivin, and TROP2 were significant predictors of lower patient survival, while TROP2 and MMP7 were significantly related to disease recurrence and liver metastasis, respectively. CONCLUSIONS: We conclude that elevated survivin, MMP7, and TROP2 expression levels are related to decreased survival. In addition, elevated MMP7 and TROP2 expression levels are predictors of disease recurrence and liver metastasis, respectively.

Analysis of spherical aberration of a water immersion objective: application to specimens with refractive indices 1.33-1.40.

The method of using immersion medium to correct spherical aberration for water immersion objectives when the samples are not water is investigated. Spherical aberration is measured by an interferometer converted from a confocal microscope for samples with different refractive indices. When the proper refractive index of the immersion medium and thickness of cover slip are selected, the measured spherical aberration approaches zero. A theoretical model can be used for prediction of the immersion medium to correct spherical aberration for various samples. Using the thinnest available cover slip (100 microm), the zero spherical aberration condition can be applied to samples with refractive index as high as 1.40. Confocal images in the condition of almost no spherical aberration are included to demonstrate the improvement of axial resolution due to this correction.

The polymorphism of GSTM1, mutagen sensitivity in colon cancer and healthy control.

The aim of this article is to study the relationship between GSTM1 polymorphism and colon cancer and to compare the chromosomal breakage induced by mutagen in a colon cancer group and healthy controls. Using PCR to identify the GSTM1 genotype, we found the frequency of GSTM1- in colon cancer (n = 19) and control group (n = 23) was 36.8% and 26.1%, respectively (p > 0.05, chi 2-test). The bleomycin-induced chromosomal breakage (break/cell) in the patient group was 0.75 +/- 0.29, and in the control group 0.42 +/- (0.24) (p < 0.05, t-test). The percentage of mutagen sensitivity (b/c > 0.8) in the patient group (68%) was 4 times as high as that in the control group (20%). The mutagen hypersensitivity (b/c > 1.0) in the patient group (47%) was 5 times as high as that in the control group (12%). The odds radio was 6.6.

Application of a Shack cube as a beam splitter in interferometers with a local reference beam.

A different setup of the Mach-Zehnder interferometer for testing the convergent wave front is described. A Shack cube is used to replace a traditional recollimator and a parallel-plate beam splitter. An equivalent pupil model has been suggested that describes the point diffraction mechanism. The calibration procedures for the Mach-Zehnder interferometer are described. The Shack-cube beam splitter has the advantages of compactness and better reference-beam quality compared with the recollimator and the parallel-plate beam splitter.

[Primary retroperitoneal tumor--an analysis of 303 cases].

Primary retroperitoneal tumor (PRT) is of a heterogeneous group of neoplasms of mesenchymal origin. From April 1964 through April 1992, 303 PRT cases were treated. Of the 288 cases with histological confirmation, 197 suffered from malignant tumors and 91 were benign. Since the PRT patients were usually symptomless, diagnosis was made late in the majority of patients. It resulted in low radical resection rate in both the malignant (36.9%) and the benign (84.6%) PRT owing to invasion to adjacent organs. The tumor recurrence rate was also high, being 74.2% for the malignant and 11.7% for the benign tumors. The overall 2-, 5-, and 10-year survival rates in the patients with malignant tumors were 55.3%, 19.5%, and 9.8%, respectively. The results of treatment were dependent primarily on completeness of tumor resection. Adjuvant radiotherapy could improve the survival rates but adjuvant chemotherapy did not help. In patients with tumor recurrence, operation remained to be the treatment of choice. If complete resection was impossible, the alternative was debulking operation followed by radiotherapy.

Profile measurements of cylindrical surfaces.

We introduce an interferometric method for measuring the profiles of cylindrical surfaces. A Fizeau interferometer with a flat reference is used to test part of a cylindrical surface, and various parts of the surface can be tested by the rotation of the surface. The algorithm for linking separate measurements is described, and testing examples for measuring sagitta over 3 mm of a cylindrical surface with an elliptical cross section are included. Measurement results show that repeatability for the above test to the order of 1 microm, is feasible.

Making aspherical mirrors by thin-film deposition.

An aspherical mirror is made by a thin-film coating technique. A special mask is placed between the evaporation source and the substrate that is to be coated as an aspheric. The design principle of the mask is fully described. An ion-assisted deposition technique is used to relieve aluminum film stress and to increase surface reflectance. The final wave front is tested by conventional interferometric methods for aspherics. Less than one-fifth of a wave (632.8 nm) of spherical aberration is achieved without much trial and error.

Expression of c-erb B-2/neu proto-oncogene in human prostatic cancer tissues and cell lines.

Both amplification and overexpression of c-erb B-2/neu have been associated with the progression and possible prognosis of a number of human cancers. In this study, we demonstrated that c-erb B-2/neu may also play an important role in human prostate cancer. Our conclusion is based on the following observations: (1) A monoclonal antibody raised against a peptide sequence from the C-terminal domain of the human c-erb B-2/neu gene product reacted positively with 68.7% (11 of 16) of the human prostatic cancer tissue extracts analyzed by western blot procedure. These results were supported by the immunohistochemical staining of the prostatic cancer specimens; 80% (12 of 15) showed positive staining, primarily around the plasma membranes of the prostatic cancer cells. c-erb B-2/neu oncoprotein was not detectable in normal prostate tissues (five examined by immunohistochemical staining and three by western blotting) or in human benign prostatic hyperplasia (two examined by immunohistochemical staining and six by western blotting) and was expressed less abundantly with lower intensity in "normal" human prostate tissues adjacent to cancerous prostate tissue (5 of 12 examined by immunohistochemical staining). We observed no evidence of c-erb B-2/neu gene amplification in 10 fresh human prostatic cancer specimens examined by Southern blotting and in the cultured human prostatic cancer cell lines PC-3, DU-145, and LNCaP. (2) The c-erb B-2/neu protein was detected in both androgen-receptor-positive (LNCaP) and -negative (PC-3 and DU-145) human prostate cancer cell lines. Positive immunostaining of c-erb B-2/neu protein was found to be associated predominantly with the plasma membranes of PC-3 cells, but was also found to be widespread in the cytoplasmic region of the LNCaP cells and in the perinuclear region of the DU-145 cells. (3) Like prostate-specific antigen (PSA) expression, c-erb B-2/neu mRNA expression was also positively regulated by androgen in androgen-receptor-positive LNCaP cells in vitro and LNCaP tumors in vivo. When LNCaP tumors were grown in castrated male hosts, levels of c-erb B-2/neu and PSA mRNA expression decreased initially, but rebounded at 3 wk to levels comparable to those expressed by tumors maintained in intact adult male hosts.

Profile measurement of an aspheric cylindrical surface from retroreflection.

A new algorithm for measuring the profile of an aspheric cylindrical surface is developed in which directions of the surface normal and slopes at various locations are found with the aid of a retroreflected beam. The locations of retroreflection can be found with the simple algorithm developed in this paper, and the surface profile is integrated from the slope. The accuracy of the new algorithm is determined mostly by the algorithm's ability to find the true range of the surface being integrated. In the measurement of the surface sagitta over the range of 5000 microm, the accumulated error from the integration is less than 30microm.

Ronchi test and a new phase reduction algorithm.

To fully interpret the Ronchigram, a good automatic phase reduction algorithm is necessary. A new phase reduction algorithm, originally designed for interferometry test of large optics, is presented for the Ronchi test. Due to the common path property, only two Ronchigrams shifted by pi/2 are necessary for the reproducing phase. Accuracy can be better than one-thirtieth of the grating space. Methods are suggested for finding spherical aberration and astigmatism without integrating the phase using the Ronchi test. Tests of results using the new algorithm show good agreement with typical interferometry tests.

Mirror deflection on multiple axial supports.

A theoretical model based on thin plate theory is developed to calculate mirror deflection on multiple axial supports. Thickness variation due to mirror curvature, sandwich structure, and shear effects is included in this model. Comparison with the finite element analysis shows almost identical results for a three-point support. Surface deflections due to more complicated support patterns (forty-eight- and eighty-four-point support) are also included. A tolerancing model of support forces is developed and applied to the case of eight-four-point support.

[Reevaluation of intraluminal fluorouracil chemotherapy as an adjuvant to radical resection of colorectal cancer--results of a randomized trial].

Eighty-two patients with colo-rectal cancers (29 colon and 53 rectum) were admitted and underwent radical resection from January 1982 to June 1984. There were 54 males and 28 females. The ages ranged from 25 to 74 years. According to Dukes's classification, there were 2 Stage A, 47 (57.3%) Stage B and 33 (40.2%) Stage C. Histologically, 70.7% were adenocarcinoma, 20.7% mucinous carcinoma and 8.6% others. All these patients were randomized into two groups: trial group and control group. In the trial group, there were 45 patients treated by radical resection plus adjuvant intraluminal 5-FU chemotherapy and intravenous 5-FU chemotherapy on the first and second days postoperatively. The intraluminal dose of 5-FU was 30 mg/kg injected into the bowel lumen of the isolated diseased segment between the tape ligatures. The intravenous dose was 10 mg/kg given on the first and second days after operation. In the control group, there were 37 patients treated by radical resection alone. The survival rates were calculated by the life-table method and the results showed that in patients with Dukes' C, the 5-year survival rate of the trial group was 61.8%, and that of the control group was 27.3% (P less than 0.05). In addition, hepatic metastasis in the trial group was less than that in the control group. The results of the randomized trial indicated that adjuvant intraluminal 5-FU chemotherapy may be an important approach to improve the results of radical resection for advanced colo-rectal cancer and to prevent hepatic metastases. Further clinical studies are recommended.

Comparative study of long-term effects of surgical excision and excision combined with radiotherapy or chemotherapy in breast cancer: an analysis of 192 cases.

Clinical data of 192 patients with breast cancer with a primary lesion of 2-5 cm (stage II according to the criteria recommended by the UICC) and with histopathologically confirmed positive axillary lymph nodes were analyzed. The patients were divided into three groups: 1) surgical excision alone; 2) surgery plus irradiation; and 3) surgery plus chemotherapy. It was shown that the 5-year survival rates for these groups were 40.5%, 61.0%, and 62.0%, respectively (P less than .05).