High preoperative serum carcinoembryonic antigen predicts metastatic recurrence in potentially curative colonic cancer: Results of a five-year study

INTRODUCTION: Serum carcinoembryonic antigen is used mainly for tumor follow-up to detect recurrence of colonic cancer. However, raised preoperative carcinoembryonic antigen levels may be helpful for the identification of understaged cases and of patients meriting more intensive preoperative and postoperative diagnostic workup. METHODS: From a prospectively collected database, the data on 261 patients who had curative colonic carcinoma with a minimal follow-up of five years and who had preoperative carcinoembryonic antigen levels assessed were retrieved and analyzed. Outcome parameters were local and/or distant recurrence and time to recurrence. These parameters were correlated with Dukes staging and preoperative carcinoembryonic antigen levels. RESULTS: The cumulative diseasefree survival of patients with a preoperative carcinoembryonic antigen level within the normal range was significantly better than that of those whose carcinoembryonic antigen was 5 ng/ml or more (P=0.001). No patient with carcinoembryonic antigen levels less than 1 ng/ml developed metastatic recurrence. Twenty-three percent of all patients with a raised carcinoembryonic antigen above 5 ng/ml compared with 2.1 percent of patients with carcinoembryonic antigen below 5 ng/ml developed a metastasis at two years. At five years, these figures were 37.2 percent and 7.5 percent, respectively. Dukes staging and carcinoembryonic antigen levels were found to be directly correlated (P<0.001) when all patients were included. Carcinoembryonic antigen of more of 15 ng/ml was found to be a significant adverse prognostic indicator for disease-free survival irrespective of Dukes staging (P<0.02). Raised carcinoembryonic antigen levels predicted distant metastatic recurrence (P<0.001) but did not predict local recurrence (P=0.72). CONCLUSIONS: High preoperative carcinoembryonic antigen levels above 15 ng/ml predicted an increased risk of metastatic recurrence in potentially curative colonic cancer and may indicate undetectable disseminated disease. Preoperative carcinoembryonic antigen levels predict understaging and the possibility of distant recurrence. Such patients may therefore be selected for adjuvant therapy where indicated. Therefore, carcinoembryonic antigen is complementary to conventional Dukes staging for the prediction of recurrence and survival.     

Risk prediction models of breast cancer: a systematic review of model performances

The number of risk prediction models has been increasingly developed, for estimating about breast cancer in individual women. However, those model performances are questionable. We therefore have conducted a study with the aim to systematically review previous risk prediction models. The results from this review help to identify the most reliable model and indicate the strengths and weaknesses of each model for guiding future model development. We searched MEDLINE (PubMed) from 1949 and EMBASE (Ovid) from 1974 until October 2010. Observational studies which constructed models using regression methods were selected. Information about model development and performance were extracted. Twenty-five out of 453 studies were eligible. Of these, 18 developed prediction models and 7 validated existing prediction models. Up to 13 variables were included in the models and sample sizes for each study ranged from 550 to 2,404,636. Internal validation was performed in four models, while five models had external validation. Gail and Rosner and Colditz models were the significant models which were subsequently modified by other scholars. Calibration performance of most models was fair to good (expected/observe ratio: 0.87–1.12), but discriminatory accuracy was poor to fair both in internal validation (concordance statistics: 0.53–0.66) and in external validation (concordance statistics: 0.56–0.63). Most models yielded relatively poor discrimination in both internal and external validation. This poor discriminatory accuracy of existing models might be because of a lack of knowledge about risk factors, heterogeneous subtypes of breast cancer, and different distributions of risk factors across populations. In addition the concordance statistic itself is insensitive to measure the improvement of discrimination. Therefore, the new method such as net reclassification index should be considered to evaluate the improvement of the performance of a new develop model.     

Stratifying risk factors for follow-up

INTRODUCTION: The selection of patients for individualized follow-up and adjuvant therapy after curative resection of colorectal carcinoma depends on finding reliable prognostic criteria for recurrence. However, such criteria are not universally accepted, and follow-up is often standardized for all patients without regard for each individual's level of risk of recurrence. Such a system of follow-up is not cost-effective. METHODS: A comparison of operative findings, pathologic features, and follow-up data of 1,731 cases of nonrecurrent colorectal cancer (821 colon, 910 rectum) with 357 cases of recurrent colorectal cancer (164 colon, 193 rectum) following potentially curative surgery was made, and results were analyzed to ascertain criteria for stratifying follow-up according to risk factors. RESULTS: Single-factor analysis showed that Dukes staging and tumor invasion were significantly associated with recurrence in both rectal and colon carcinoma. Tumor fixation and grading were additional significant factors in rectal cancer. Recurrence rates, time to recurrence, site of recurrence (locoregionalvs. distant), and pattern of metastatic spread were not significantly affected by original tumor site. Recurrence was not significantly affected by patient age and gender. Individual surgeon performance in this series had also no significant effects on tumor recurrence. With multivariate analysis only, Dukes staging and tumor invasion into adjacent tissues were found to be independent adverse prognostic factors for recurrence. CONCLUSIONS: Dukes staging and tumor penetration into adjacent tissues are the only significant adverse prognostic factors for tumor recurrence of colonic and rectal carcinoma. Tumor grade and tumor fixation are additional adverse prognostic factors in rectal cancer. Guidelines for follow-up may be based on these factors and follow-up thus stratified according to risk of developing recurrence.     

Factors associated with upstaging of ductal carcinoma in situ diagnosed by core needle biopsy using imaging guidance

Purpose  

The aim of this study was to estimate the upstaging rate of ductal carcinoma in situ (DCIS) diagnosed by core needle biopsy (CNB) under imaging guidance and to identify factors related to upstaging.     

Fibroadenoma versus phyllodes tumor: distinguishing factors in patients diagnosed with fibroepithelial lesions after a core needle biopsy

PURPOSE

We aimed to identify factors that might help differentiate phyllodes tumors from fibroadenomas among cases in which a fibroepithelial breast lesion was diagnosed from core needle biopsy (CNB) under imaging guidance.

MATERIALS AND METHODS

A retrospective review was performed on 213 lesions in 200 patients who had undergone both CNB and excisional biopsy during a four-year period between 2008 and 2011. The final pathology revealed 173 fibroadenomas and 40 phyllodes tumors. The data, including patient characteristics, clinical presentation, and mammography, ultrasonography (US), and pathology findings were analyzed.

RESULTS

Upon univariable analysis, the factors that significantly helped to identify phyllodes tumors consisted of the presenting symptoms (palpable mass or breast pain), increased size on clinical examination, hyperdense mass on mammogram, and the following three US features: heterogeneous echo, presence of round cysts within the mass, and presence of clefts within the mass. The pathologist’s suggestion of a phyllodes tumor was also helpful. The factors that remained statistically significant upon multivariable analysis consisted of symptoms of breast pain, the presence of clefts on US, the presence of round cysts on US and the pathologist’s favoring of phyllodes tumors from a CNB specimen.

CONCLUSION

A multidisciplinary approach was needed to distinguish phyllodes tumors from fibroadenomas in patients who had undergone CNB. US findings (clefts and round cysts), suggestive pathological diagnoses, and clinical symptoms were all useful for the decision to surgically remove the fibroepithelial lesions diagnosed from CNB.Core needle biopsy (CNB) under imaging guidance is an accepted standard of care for the diagnosis of breast lesions, particularly those that are nonpalpable (1–4). This procedure is safe, cost-effective and minimally invasive compared with surgical excision (1).In general, CNB allows for appropriate decision-making. Surgery could be obviated by a benign CNB pathology result. At times, however, CNB may provide only an inconclusive histopathology or may yield results associated with a potentially more worrisome pathology. Surgical excision may be needed in such circumstances.Fibroadenoma is the most common lesion in the breast, occurring in 25% of asymptomatic women (5), and it is usually readily diagnosed via CNB. In the presence of increased stromal cellularity, however, it is less likely to be distinguishable from a phyllodes tumor (1–4). In such cases, the term “fibroepithelial lesion” is used (1–5).The distinction between fibroadenomas and phyllodes tumors is clinically important. Fibroadenomas may be safely followed without further investigation. Even if an excisional biopsy is needed, the simple enucleation of a fibroadenoma is appropriate (1). In contrast, phyllodes tumors should not be managed by nonoperative means because they commonly and progressively enlarge. Moreover, wide excision of phyllodes tumors with adequate margins is essential to the prevention of local recurrence and to provide an accurate diagnosis as to whether it is benign, borderline or malignant (1–5). A CNB-diagnosed fibroepithelial lesion, therefore, provides the surgeon with the dilemma of whether to operate. Usually, surgical excision is chosen, and a considerable amount of normal breast tissue is sacrificed.The purpose of the present study was to determine factors that might help differentiate phyllodes tumors from fibroadenomas among cases in which a fibroepithelial lesion was diagnosed from CNB under imaging guidance.     

Personalized Tacrolimus Doses Determined by CYP3A5 Genotype for Induction and Maintenance Phases of Kidney Transplantation

Background

Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy.

Objectives

This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients.

Methods

Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method.

Results

The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus required for the induction and maintenance phases and MDR1 polymorphism.

Conclusion

Determination of the CYP3A5 genotype would be helpful in the design of adequate immunosuppressive treatment and in lowering toxicity by predicting the doses of tacrolimus required for the induction and maintenance phases in individual kidney transplant recipients.     

Impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand

Background: Thiopurine S-methyltransferase (TPMT) is a polymorphic enzyme associated with detoxification of azathioprine, an immunosuppressant used after renal transplantation in several Asian countries. Patients with variations of the TPMT gene may be at risk for myelosuppression after they receive a standard dosage of the drug. The frequency of TPMT*3C has been reported to be higher in the Thai population than in other Asian populations, possibly putting the Thais at higher risk for myelosuppression.Objective: The aim of this study was to assess the impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand.Methods: This study was conducted at Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand, and Chulalongkorn Hospital, Chulalongkorn University, Bangkok, Thailand. Eligible patients underwent kidney transplantation from deceased or living-related donors from 1984 to 2007. Electronic medical records were assessed retrospectively for the 6-month period after initiation of azathioprine treatment. TPMT genotyping and phenotyping were studied prospectively using real-time polymerase chain reaction and biochemical assay, respectively. The odds ratios (ORs), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined.Results: A total of 139 patients were enrolled (89 men, 50 women; median age, 42 years [range, 17–70 years]; mean weight, 58 kg [range, 37–87 kg]). The heterozygous TPMT*1/*3C genotype was found in 9 of the 139 patients (6.47%) (95% CI, 3.00–11.94). The TPMT activity of those patients was significantly lower than that of patients with the homozygous wild-type genotype (median, 21.37 vs 37.12 nmol 6-methylthioguanine/g · Hb/h, respectively; P < 0.001). The risk for azathioprine-induced myelosuppression in the patients with the heterozygous TPMT*1/*3C genotype was significantly higher than that in patients with the wild-type genotype (adjusted OR, 14.18 [95% CI, 3.07–65.40]; P < 0.005). The sensitivity and specificity of TPMT*3C genotyping for the prediction of azathioprine-induced myelosuppression in these kidney transplant recipients were 27% and 97%, respectively. Assuming a prevalence of azathioprine-induced myelotoxicity of 7% according to previously published data, the PPV and NPV were estimated to be 50% and 95%, respectively.Conclusion: In these kidney transplant recipients, patients who carried the TPMT*3C allele were at a higher risk for azathioprine-induced myelosuppres-sion than noncarriers.