Dynamic and subtype-specific interactions between tumour burden and prognosis in breast cancer.

We investigated the relationship between the prognostic importance of anatomic tumour burden and subtypes of breast cancer using data from the Korean Breast Cancer Registry Database. In HR+/HER2+ and HR-/HER2-tumours, an increase in T stage profoundly increased the hazard of death, while the presence of lymph node metastasis was more important in HR+/HER2+ and HR-/HER2+ tumours among 131,178 patients with stage I-III breast cancer. The patterns of increasing mortality risk and tumour growth (per centimetre) and metastatic nodes (per node) were examined in 67,038 patients with a tumour diameter ≤ 7 cm and < 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumours showed a persistent increase in mortality risk with an increase in tumour diameter, while the effect was modest in HER2+ tumours. Conversely, an increased number of metastatic nodes was accompanied by a persistently increased risk in HR-/HER2+ tumours, while the effect was minimal for HR-/HER2- tumours with > 3 or 4 nodes. The interactions between the prognostic significance of anatomic tumour burden and subtypes were significant. The prognostic relevance of the anatomic tumour burden was non-linear and highly dependent on the subtypes of breast cancer.

Influence of complications following total mastectomy and immediate reconstruction on breast cancer recurrence.

BACKGROUND: Immediate breast reconstruction is safe from an oncological perspective, but the relatively high rate of postoperative complications raises oncological concerns. The present study aimed to evaluate the potential influence of postoperative complications after immediate breast reconstruction on breast cancer recurrence and survival. METHODS: Patients with breast cancer who had total mastectomy and immediate reconstruction between 2008 and 2013 were followed for at least 5 years. The impact of postoperative complications on oncological outcomes was assessed using multivariable Cox regression analyses. RESULTS: In total, 438 patients with a median follow-up of 82 months were analysed. Five-year local recurrence-free, disease-free and overall survival rates were 95·4, 93·1 and 98·4 per cent respectively. Postoperative complications developed in the operated breast in 120 patients (27·4 per cent) and at other sites (flap donor) in 30 patients (6·8 per cent). Development of breast complications was associated with significantly increased rate of recurrence compared with no complications (16·7 versus 5·9 per cent; P = 0·002). In multivariable analysis, patients with breast complications had significantly worse disease-free survival than those with no complications (hazard ratio (HR) 2·25; P = 0·015). This remained significant in patients who received adjuvant therapy without delay (8 weeks or less after surgery) (HR 2·45; P = 0·034). CONCLUSION: Development of postoperative complications in the breast can have a negative impact on survival and recurrence after immediate reconstruction.

ANTECEDENTES: La reconstrucción mamaria inmediata es una técnica segura desde el punto de vista oncológico, pero con una tasa relativamente alta de complicaciones postoperatorias, lo que preocupa por si puede afectar a los resultados. Este estudio tuvo como objetivo evaluar la influencia potencial de las complicaciones postoperatorias tras la reconstrucción mamaria inmediata en la recidiva y la supervivencia del cáncer de mama. MÉTODOS: Se hizo un seguimiento de al menos 5 años de las pacientes a las que se realizó una mastectomía total por cáncer de mama y una reconstrucción mamaria inmediata entre 2008 y 2013. Se evaluó el impacto de las complicaciones postoperatorias en los resultados oncológicos mediante un análisis multivariables de regresión de Cox. RESULTADOS: Se analizaron 438 pacientes con una mediana de seguimiento de 82 meses. La supervivencia libre de recidiva local a 5 años, la supervivencia libre de enfermedad y la supervivencia global fueron del 95,4%, 93,1% y 98,4%, respectivamente. Hubo complicaciones postoperatorias en la mama en 120 (31,8%) pacientes y en otros lugares (zona donante de colgajo) en 30 (6,8%). La presentación de complicaciones mamarias se asoció con una tasa de recidiva significativamente mayor en comparación con el grupo de pacientes sin complicaciones (16,7% versus 5,9%, P < 0,01). En el análisis multivariable, las pacientes con complicaciones mamarias mostraron una supervivencia libre de enfermedad significativamente menor que aquellas que no padecieron complicaciones (cociente de riesgos instantáneos, hazard ratio, HR 2,25; P = 0,02). También fue significativo el porcentaje de pacientes que recibieron tratamiento adyuvantes sin demora (≤ 8 semanas después de la operación) (HR 2,45; P = 0,03). CONCLUSIÓN: El desarrollo de complicaciones postoperatorias en la mama puede impactar negativamente en la supervivencia y en la recidiva después de la reconstrucción inmediata.

High-flow haemangiomas versus hypervascular hepatocellular carcinoma showing "pseudo-washout" on gadoxetic acid-enhanced hepatic MRI: value of diffusion-weighted imaging in the differential diagnosis of small lesions.

AIM: To validate the usefulness of diffusion-weighted imaging (DWI) in the differentiation of high-flow haemangiomas showing pseudo-washout appearance on gadoxetic acid-enhanced hepatic MRI from small hypervascular hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: DWI (b=50, 800 s/mm2) with apparent diffusion coefficient (ADC) maps for 50 haemangiomas (6.4±2.9 mm) showing intense enhancement on arterial dominant phase imaging and hypointensity on transitional and/or hepatobiliary phase imaging during gadoxetic acid-enhanced MRI were retrospectively analysed and compared with that of 113 hypervascular HCCs (12.8±3.7 mm). In addition to measurement of mean ADC values on DWI and contrast-to-noise ratio (CNR) on corresponding T2-weighted imaging, qualitative analysis of DWI was performed for each lesion by two independent observers using a five-point scale. RESULTS: Both of mean ADC value (1.902 versus 0.997×10-3 mm2/s) and mean CNR (119.2 versus 36.9) for haemangioma were significantly larger than for HCC (p<0.001). On receiver operating characteristic (ROC) analysis, an area under the curve (AUC) of 0.995 for ADC values was significantly larger than 0.915 for CNRs (p=0.002). When the ADC value of 1.327×10-3 mm2/s was used as the threshold for the diagnosis of haemangioma, the sensitivity and specificity were 98% and 97.3%, respectively. The mean sensitivity and specificity of qualitative analysis for the differentiation of haemangioma from HCC were 92% and 99.1%, respectively. CONCLUSION: For high-flow small haemangiomas showing pseudo-washout appearance during gadoxetic acid-enhanced hepatic MRI, high b-factor DWI including an ADC map may provide additional information to enhance the confidence to exclude small hypervascular HCCs.

Induction of fibronectin by HER2 overexpression triggers adhesion and invasion of breast cancer cells.

Fibronectin (FN), an extracellular matrix ligand, plays a pivotal role in cell adhesion, migration, and oncogenic transformation. Aberrant FN expression is associated with poor prognoses in various types of cancer, including breast cancer. In the current study, we investigated the relationship between FN induction and HER2 expression in breast cancer cells. Our results showed that the level of FN expression increased in response to HER family ligands, EGF and TGF-α in a time- and dose-dependent manner. On the other hand, EGF-induced FN expression decreased in response to trastuzumab, which is a HER2-targeted monoclonal antibody. However, EGF-induced FN expression was not affected by trastuzumab in JIMT-1 breast cancer cells, which are trastuzumab insensitive cells. Next, we introduced the HER2 gene into MDA-MB231 cells to verify the relationship between FN and HER2. The level of FN expression significantly increased in HER2-overexpressed MDA-MB231 cells. In contrast, the induction of FN by HER2 was significantly decreased in response to trastuzumab treatment. In addition, the induction of FN by HER2 was down-regulated by the MEK 1/2 specific inhibitor, U0126. Using conditioned culture media of vec- and HER2-overexpressed MDA-MB231 cells, we observed the cell morphology, adhesion, and invasion of MDA-MB231 cells. Interestingly, in conditioned culture media of HER2-overexpressed MDA-MB231 cells, the cell morphology was altered, and adhesion and invasion of MDA-MB231 cells significantly increased. In addition, our results showed that recombinant human FN augmented cell adhesion and invasion of MDA-MB231 cells while these inductions decreased in response to an FN inhibitor. Therefore, we demonstrated that the induction of FN by HER2 triggers cell adhesion and invasion capacities.

Development and validation of Chemotherapy-induced Alopecia Distress Scale (CADS) for breast cancer patients.

BACKGROUND: A psychometric scale for assessing the distress that breast cancer patients experience due to the chemotherapy-induced alopecia was developed and validated. PATIENTS AND METHODS: Twenty-five items for chemotherapy-induced alopecia distress were developed based on a qualitative study, and a cross-sectional survey was conducted with 305 Korean women with breast cancer. To extract factor structure and evaluate construct validity, exploratory and confirmatory factor analysis (CFA) was carried out. Concurrent and discriminant validity were tested by correlations with the psychosocial factors. In addition, external validity analysis was conducted using data from another prospective study of 428 breast cancer patients. RESULTS: Exploratory factor analysis and CFA yielded 17 items in four domains and the model fit was good (CFI=0.925). Coefficient alphas ranged from 0.77 to 0.95 for subdomains and 0.95 for total, and it was similar with the validation dataset confirming its external validity. The total Chemotherapy-Induced Alopecia Distress Scale (CADS) was moderately correlated with the body image (r=-0.47, P<0.001), more weakly correlated with the patients' overall quality of life (QOL, r=-0.28, P<0.001), but did not correlate with self-esteem (r=-0.07, P=0.23). CONCLUSIONS: Our study confirmed that the CADS is a reliable and valid tool for measuring distress of chemotherapy-induced alopecia.

Nomogram for predicting invasion in patients with a preoperative diagnosis of ductal carcinoma in situ of the breast.

BACKGROUND: The aim of this study was to identify risk factors for invasive breast cancer in patients diagnosed with ductal carcinoma in situ (DCIS) on a preoperative biopsy. These factors were used to develop a nomogram for predicting the risk of invasion in the preoperative setting. METHODS: This was a retrospective analysis of patients who underwent surgical treatment for DCIS diagnosed before surgery between 1997 and 2009. Multivariable analysis was used to identify clinical, radiological and histopathological factors that may predict upstaging. A nomogram was developed to predict the probability of invasion using multiple logistic regression analysis. This nomogram was subsequently validated using another cohort of patients with a preoperative diagnosis of DCIS between 2010 and 2012. RESULTS: Upstaging to invasive cancer occurred in 123 (24.9 per cent) of 493 women treated between 1997 and 2009. A larger DCIS lesion (at least 15 mm), lack of hormone receptor expression, intermediate or high nuclear grade, diagnosis on core biopsy compared with vacuum-assisted biopsy, and non-cribriform subtype of DCIS were significantly associated with upstaging. A nomogram developed using these factors demonstrated good predictive performance (area under the receiver operating characteristic (ROC) curve (AUC) 0·823, 95 per cent confidence interval 0·787 to 0·860). The nomogram showed similar predictive performance in the validation data set, based on another 149 women (AUC 0·700, 0·613 to 0·786). CONCLUSION: Upstaging to invasive cancer in women with a preoperative diagnosis of DCIS is common. A nomogram based on the five most significant factors related to upstaging accurately predicted invasive cancer. This nomogram may be useful when deciding whether to pursue axillary staging with sentinel lymph node biopsy in patients with DCIS.

Clinical significance of CD151 overexpression in subtypes of invasive breast cancer.

BACKGROUND: CD151 is a member of the tetraspanin family, which interacts with laminin-binding integrins and other tetraspanins. This protein is implicated in motility, invasion, and metastasis of cancer cells, but the prevalence of CD151 expression in subtypes of breast cancers and its influence on clinical outcome remains to be evaluated. METHODS AND RESULTS: The immunohistochemistry-based tissue microarray analysis showed that 127 (14.3%) cases overexpressed CD151 among 886 breast cancer patients. CD151 overexpression was found to be significantly associated with larger tumour size, higher nodal stage, advanced stage, absence of oestrogen receptor and progesterone receptor, and human epidermal growth factor receptor 2 overexpression. CD151 overexpression resulted in poorer overall survival (OS) (P<0.001) and disease-free survival (P=0.02), and stage II and III patients with CD151 overexpression demonstrated substantially poorer OS (P=0.0474 and 0.0169). In the five subtypes analyses, CD151 overexpression retained its adverse impact on OS in the Luminal A (P=0.0105) and quintuple-negative breast cancer (QNBC) subtypes, one subgroup of triple-negative breast cancer (P=0.0170). Multivariate analysis that included stage, subtype, and adjuvant chemotherapy showed that CD151 overexpression was independently associated with poor OS in invasive breast cancer. CONCLUSION: CD151 overexpression may be a potential molecular therapeutic target for breast cancer, especially in QNBC subtype and more advanced stages of breast cancer.

Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

BACKGROUND: With the increasing incidence of breast cancer worldwide, in particular in southeast Asia (including Korea), and the common use of anthracyclines in the adjuvant and metastatic settings, the occurrence of Hepatitis B virus (HBV) reactivation may develop in this patient population. The use of prophylactic antiviral agents in cancer patients may result in a reduced HBV exacerbation. The purpose of the current study was to assess the efficacy of prophylactic lamivudine in reducing the incidence and severity of HBV reactivation in post-operative breast cancer patients undergoing adjuvant doxorubicin-containing chemotherapy. METHODS: The medical records of patients undergoing anthracycline-based adjuvant chemotherapy at Samsung Medical Center between January 2001 and September 2008 were reviewed. RESULTS: From the database, 1912 breast cancer patients who had received anthracycline-based adjuvant chemotherapy were identified. Of 131 patients who were HBV surface antigen positive, 55 and 76 did and did not receive prophylactic lamivudine, respectively. In all, 30 patients (23%) developed hepatitis during doxorubicin-containing adjuvant chemotherapy. Of the 30 patients, 5 (9%) were in the prophylactic lamivudine group and 25 (33%) in the control group (P=0.001). In the prophylactic lamivudine group, there was significantly less HBV reactivation (1 patient (2%) vs 20 patients (16%); P=0.002), less disruption of chemotherapy (7 vs 14%; P=0.04), and less severe hepatitis (0 vs 17%; P=0.002). CONCLUSION: Prophylactic lamivudine significantly reduced the incidence and severity of HBV reactivation in breast cancer patients undergoing anthracycline-based adjuvant chemotherapy.

Clinical relevance of TNM staging system according to breast cancer subtypes.

BACKGROUND: There has been reported that the association between nodal spread and tumor size was disrupted in triple-negative breast cancer (TNBC) and it showed characteristically early relapse. The TNM (tumor-node-metastasis) staging system might not be equally effective as a prognostic indicator for all subtypes. The aim of our study was to evaluate the usefulness of the staging according to subtypes. PATIENTS AND METHODS: We conducted a retrospective analysis of invasive breast cancer patients who received curative surgery at Samsung Medical Center from 2000 to 2004. Relapse-free survivals (RFS) by stage were analyzed. RESULTS: Thousand eight hundred and seventy-nine patients who were available clinicopathologic data were included. These patients were divided into three subtypes: hormone receptor (HR)+, human epidermal growth factor receptor 2+, and triple negative groups. As the stage became more advanced, the slope of each stage of the RFS curves of patients with HR+ and HER2+ steadily increased. In contrast, RFS curves intermingled and showed overlap from stage 1 to 3A in TNBC patients. There was only wide separation of RFS curves between stage 1-3A and 3B-3C in TNBC. CONCLUSIONS: The current TNM staging system might not be enough for encompassing the tumor biology and for predicting outcomes to make therapeutic decisions for all BCs, especially for TNBC patients.

The cardiac biomarker sodium-calcium exchanger (NCX-1) can differentiate between heart failure and renal failure: a comparative study of NCX-1 expression in dogs with chronic mitral valvular insufficiency and azotemia.

BACKGROUND: The sodium-calcium exchanger (NCX-1), an established cardiac biomarker, was postulated previously as differentiating between heart failure (HF) and renal failure (RF) in dogs. The effect of azotemia on NCX-1 expression has not been studied. HYPOTHESIS: In contrast to other cardiac biomarkers (eg, N-terminal-proBNP), we hypothesized that the expression level of NCX-1 is not influenced by either azotemia or decreased renal clearance. ANIMALS: Fifteen client-owned healthy control dogs, 14 dogs with chronic mitral valvular insufficiency (CMVI), classified based on severity of the disease by the established International Small Animal Cardiac Health Council classification system, and 15 dogs with RF, grouped according to the International Renal Interest Society stage classification. METHODS: A comparative study of the expression levels of NCX-1, evaluated in peripheral blood samples from dogs with HF, RF, and healthy controls by quantitative PCR. RESULTS: NCX-1 expression was significantly increased in moderate (2.99±0.61 [fold changes relative to normal group]) to severe (4.35±1.44) CMVI dogs (P<.01). In contrast, NCX-1 expression was not increased in the azotemic dogs. Furthermore, there was also no correlation between increased concentrations of creatinine and urea nitrogen in serum and NCX-1 expression in the RF group. CONCLUSIONS AND CLINICAL IMPORTANCE: Azotemia likely does not affect NCX-1 expression.

Sentinel lymph node biopsy in papillary thyroid cancer: comparison study of blue dye method and combined radioisotope and blue dye method in papillary thyroid cancer.

AIM: Occult lymph node metastasis is common in differentiated thyroid cancer (DTC). However, the role of lymph node dissection in the treatment of DTC remains controversial. The authors investigated the usefulness of methylene blue dye only method and combined radioisotope and methylene blue dye method for detecting SLN and compared the values of these two methods in patients with DTC. METHODS: From February to May 2008, 97 patients with DTC underwent sentinel lymph node biopsy (SLNB). The methylene blue dye method (dye only method) was used in 54 of the 97 patients, and radioisotope and methylene blue dye method (combined method) in 43 patients. RESULTS: The SLNs were identified in 89 patients, and the sensitivity and specificity of SLNB in the 97 patients were 85% and 100% respectively. For the dye only method, sensitivity, specificity, and the false negative rate (FNR) were 79%, 100%, and 21%; and for the combined method (43 patients) the corresponding figures were, 91%, 100%, and 9%, respectively. Six patients with SLN metastasis in the lateral neck underwent additional modified radical neck dissection (MRND). CONCLUSIONS: SLNB was found to be feasible, repeatable, and accurate in evaluating the lymph node status in patient with DTC. The present study indicates that the combined method could reduce false negative rate and increase detection rates of sentinel lymph node metastases, especially in lateral neck, compared to the dye only method.

Evaluation of ER and Ki-67 proliferation index as prognostic factors for survival following neoadjuvant chemotherapy with doxorubicin/docetaxel for locally advanced breast cancer.

BACKGROUND: The aim of the study was to identify reliable predictive biological markers for treatment outcome following neoadjuvant adriamycin/docetaxel (AT) chemotherapy in locally advanced breast cancer patients. MATERIALS AND METHODS: This study was a phase II study on AT neoadjuvant chemotherapy in locally advanced breast cancer patients. Patients received 50 mg/m(2) of doxorubicin intravenously (IV) over 15 min followed by docetaxel 75 mg/m(2) infused over 1 h, repeated every 3 weeks for three cycles. Surgery was performed within 3-4 weeks following the last cycle of chemotherapy. We analyzed the pre-treatment and post-treatment expression levels of ER, PgR, HER-2, Ki-67 proliferation index, and p53 and examined the correlation between the markers and clinical parameters with treatment response, overall survival and relapse-free survival following neoadjuvant treatment. RESULTS: From July 2001 to September 2004, 61 patients were enrolled. The meaningful parameters adversely influencing survival were post-treatment ER(-) status (P = 0.013) and post-treatment Ki-67 index above 1.0% (P = 0.013). At the multivariate level, the post-treatment Ki-67 proliferation index < or = 1.0 was the only meaningful prognostic factor for better survival (P = 0.033). Notably, tumors with Ki-67 index < or = 1.0 were more likely to express ER with statistical significance (P = 0.002). Tumors with ER(+) and Ki-67 index < or = 1.0 showed the highest survival rate, followed by ER(+) and Ki-67 index > 1.0%, ER(-) and Ki-67 < or = 1.0%, and ER(-) and Ki-67 > 1.0% with the worst survival (P = 0.033). CONCLUSION: Collectively, post-treatment ER status and Ki-67 proliferation index were prognostic of overall survival following neoadjuvant AT chemotherapy.

Health-related quality of life in disease-free survivors of breast cancer with the general population.

BACKGROUND: Although most of the literature about health-related quality of life (HRQoL) focuses on breast cancer patients, few studies compared the HRQoL in disease-free breast cancer survivors with that of the general population. MATERIALS AND METHODS: We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Quality of Life Questionnaire Breast Cancer Module, McGill Quality of Life Questionnaire, Beck Depression Inventory, and Brief Fatigue Inventory to 1933 disease-free survivors for over 1 year after being diagnosed with stage 0 to III breast cancer. We performed multivariate-adjusted analyses in all HRQoL comparisons. RESULTS: The scores for some health-related quality of life [corrected] HRQoL scales were comparable for both disease-free breast cancer survivors and the general female population, but [corrected] there was a [corrected] clinically significant difference between the two groups [corrected] in cognitive and social functioning, fatigue, insomnia, financial difficulties, body image, future perspective, breast symptoms, and arm symptoms. [corrected] CONCLUSIONS: Disease-free survivors of breast cancer had good HRQoL, which was less affected by the type of treatment than it was by demographic characteristics, time since surgery, comorbidity, fatigue, and depression.

Primary malignant retroperitoneal tumors: analysis of a single institutional experience.

AIMS: In order to achieve complete resection in the surgical management of retroperitoneal tumors, it is crucial to know the tumor's anatomical location relative to neighboring organs. METHODS: Forty-nine patients with primary malignant retroperitoneal tumors were divided by tumor location into two groups [upper abdomen (group 1) or lower abdomen (group 2)], and clinicopathological features, tumor recurrence, and patient survival were assessed. RESULTS: No significant differences in preoperative clinical characteristics existed between two groups, and liposarcoma was the most frequently observed tumor type. The difference in the rates of complete resection between the two groups was not statistically significant (75.9% for group 1 and 85% for group 2). En-bloc combined resection was performed in 52% and 30% of patients in groups 1 and 2, respectively. The local recurrence rate in group 2 (31.3%) was higher than that in group 1 (9.5%), despite the fact that the differences in rates of complete resection and distant recurrence rates (14.3% in group 1 and 12.5% in group 2) between the two groups were not statistically significant. The overall 5-year survival rates were 67.9% for group 1 and 43.2% for group 2 (p=0.038). The 5-year survival rate of patients with tumors smaller than 10 cm was 78.4%, while that of patients with tumors larger than 10 cm was 38.1% (p=0.017). The 5-year survival rate after complete excision was 61%, whereas that after incomplete resection or biopsy only was 40.0% (p<0.0001). CONCLUSIONS: An upper abdominal tumor location is a positive prognostic factor even if small tumor size (<10 cm) and complete resection of the tumor are still more important factors to improve outcome in patients with malignant primary retroperitoneal tumors. Because complete resection was shown to be the most important prognostic factor, an aggressive and careful surgical approach is recommended for the treatment of such tumors.

Foreign body granulomas of the breast presenting as bilateral spiculated masses.

In Asia, mammography following the injection of foreign materials into the breasts for cosmetic augmentation is frequently seen and diagnosis based on the typical radiologic findings is straightforward. We report the unusual radiologic findings in two patients with foreign body granulomas caused by injected foreign materials and discovered incidentally during screening work up. The mammographic findings were bilateral, hyperdense, spiculated masses, with occasional microcalcification, and at sonography, markedly hypoechoic, spiculated solid masses, located near the pectoralis muscle and partly extending into it, were observed. These radiologic findings mimicked malignancy.

Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Characterization of three infectious bronchitis virus isolates from China associated with proventriculus in vaccinated chickens.

Outbreaks of an avian disease in infectious bronchitis-vaccinated chickens in China have led to the characterization of coronaviral isolates Q1, J2, and T3, which were isolated from proventricular tissues of the affected young layer flocks. Serologic analysis revealed that they could induce high titers of infectious bronchitis virus (IBV) antibodies in inoculated specific-pathogen-free (SPF) chickens in indirect enzyme-linked immunosorbent assay but were not neutralized by antisera specific to the IBV serotype M41 and the Australian T strain. In a pathogenicity experiment, the clinical signs and related gross lesions resembling those of field outbreaks were reproduced in SPF chickens, and viruses were reisolated from the damaged tissues, including trachea, proventriculus, duodenum, and cecal tonsil. Sequence data demonstrated the complete S1 amino acid sequences of these isolates were almost identical despite recovery from geographically different areas in China and had 47.3%-82.3% similarity in comparison with the 47 published S1 sequences. On the basis of genotyping and limited serology, the three isolates, which were responsible for field outbreaks of the disease, might be a new IBV variant.

Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases.

BACKGROUND: Medullary thyroid carcinoma (MTC) is characterized by a high concentration of serum calcitonin. Routine measurement of serum calcitonin concentration has been advocated for detection of MTC among patients with nodular thyroid diseases. However, a minimal to moderate increase of serum calcitonin concentration has been frequently observed in diseases other than MTC. Fine-needle aspiration cytology (FNAC) is not a reliable method for detection of MTC. Therefore, we evaluated the usefulness of routine measurement of serum calcitonin concentration in patients with nodular thyroid diseases, and studied the validity of pentagastrin stimulation test and FNAC in these patients. SUBJECTS AND METHODS: We performed routine measurement of serum calcitonin concentrations in 1,448 patients (male, 285, female, 1,163) with nodular thyroid diseases. The average age was 46 years (range, 14-86 years). Initial examination included thyroid examination, thyroid scan or ultrasonography, measurements of serum free triiodothyronine) (T3), free thyroxine (T4), thyrotropin (TSH) levels, and antithyroid autoantibodies. FNAC was performed in all patients who had palpable or visible thyroid nodule by ultrasonography, and pentagastrin stimulation test was performed in 39 patients who consented. Serum calcitonin concentration was measured with a two-site immunoradiometric assay using commercial kits. We also measured the serum calcitonin concentration in 407 healthy subjects without thyroid or nonthyroid diseases. RESULTS: Serum calcitonin concentration was 10 pg/mL or less in 403 normal subjects (99.0 percentile), and 11-13 pg/mL in the remaining 4 subjects. We found that 56 (3.87%) of 1,448 patients with nodular thyroid diseases had serum calcitonin level above 10 pg/mL. Ten patients (0.69%) with histologically confirmed MTC were detected by the routine measurement of serum calcitonin. The prevalence of MTC was 5.2% in 194 patients with thyroid carcinoma. Five of 10 patients with MTC had basal serum calcitonin level above 100 pg/mL. The remaining 5 patients had minimal or moderate elevation of basal serum calcitonin (range, 12-86 pg/mL). Serum calcitonin concentration increased to more than 100 pg/mL by pentagastrin in all patients with MTC (2.4- to 37.7-fold increase). FNAC suggested MTC in only 2 patients (22.2%), and failed to diagnose MTC in 7 patients. FNAC was not performed in 1 patient with MTC, because he had no visible mass by ultrasonography. CONCLUSION: These results suggested that routine measurement of serum calcitonin is useful in the early detection of MTC among patients with nodular thyroid diseases. Pentagastrin stimulation test may also be a reliable way for evaluating thyroid nodular patients with mild or moderate elevation of serum calcitonin concentrations. However, FNAC was not sensitive in detecting MTC. We recommend routine measurement of serum calcitonin concentration in patients with nodular thyroid diseases.