Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.

BACKGROUND: RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival. METHODS: Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used. RESULTS: From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients. CONCLUSION: Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.

Three-dimensional power Doppler ultrasound in cervical carcinoma: monitoring treatment response to radiotherapy.

OBJECTIVES: To investigate, using three-dimensional power Doppler ultrasound (3D-PDU), alterations in cervical intratumoral vascularization during and after radiotherapy. METHODS: Between 2004 and 2009 we enrolled into the study 37 patients with FIGO Stages IB1-IIB cervical carcinoma who were undergoing radiotherapy. Serial 3D-PDU scans were performed during treatment, providing ultrasonographic measurement of tumor size, vascularization index, flow index and vascularization flow index, as well as monthly for 3 months post-treatment and tri-monthly thereafter, until vascularity was undetectable on two consecutive occasions. Physical examination, cervical cytology and serum marker evaluation were performed every 3-6 months for the first 5 years following treatment. Patients evaluated after a 2-year tumor-free interval and those with clinically assessed positive findings at follow-up underwent 3D-PDU to detect possible local disease. RESULTS: A total of 329 3D-PDU scans were performed in the 37 women. Cervical tumors and intratumoral vascularization disappeared within 3 months following radiotherapy, except in one patient with persistent disease. Nine patients had disease relapse, in four of whom the recurrence was local. In three of these four, there was recurrence of tumor and vascularization after a complete response. At follow-up, 3D-PDU detected local disease with 75.0% sensitivity and 98.5% specificity, while serum markers detected local disease among 34 patients with squamous cell carcinoma with 20.0% sensitivity and 77.3% specificity. CONCLUSIONS: Compared with serum markers in cervical squamous cell carcinoma, 3D-PDU has higher sensitivity and specificity for detecting local recurrence or persistence in cervical carcinoma. Thus, 3D-PDU combined with clinical assessment may be a new and safe method for monitoring radiotherapy treatment response and detecting local recurrence.

Influence of age on PPV of sonographic BI-RADS categories 3, 4, and 5.

PURPOSE: The purpose of this retrospective study was to calculate the positive predictive value (PPV) of sonographic Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 in different age groups to investigate whether age influences the PPV of the BI-RADS category in breast ultrasound. MATERIALS AND METHODS: From our sonography-guided core biopsy database of breasts between 2006 and 2008, we identified 2817 BI-RADS category 3, 4, and 5 lesions with known pathological diagnosis in 2587 women, all of whom underwent the earlier breast assessment via ultrasound with a sonographic BI-RADS lexicon and later sonography-guided core biopsy. All lesions were classified into three age groups (< 45, 45 - 59, and > 59 years). The age-related PPVs of each BI-RADS category among three age groups were calculated on the basis of pathological diagnoses and were compared using a χ(2)-test. RESULTS: The overall PPV of each BI-RADS category was 2.2 % in category 3, 6.5 % in category 4a, 35.2 % in category 4b, 79.6 % in category 4c, and 99.6 % in category 5. The age-related PPVs of category 3 varied significantly among the three age groups (0.9 % versus 3.9 % versus 2.0 % p = 0.048), and notably, the age-related PPV in group 2 was higher than the others. Additionally, there was a significant positive association between the age-related PPVs and increasing age in categories 4a and 4b (4a, p < 0.0001 and 4b, p = 0.0139), but not in categories 4c and 5 (4c, p = 0.1853 and 5, p = 0.2871). CONCLUSION: The incidence of female breast cancer differs not only in different sonographic BI-RADS categories, but also in different age groups. Therefore, more attention should be paid to the special age group that we found for sonographic BI-RADS categories 3, 4a, and 4b.

A progesterone-receptor-positive huge retroperitoneal tumour mimics metastasis in a breast cancer patient: sarcomatoid renal cell carcinoma.

We report a rare case of breast cancer concomitant with progesterone-receptor-positive renal cell carcinoma. A 48-year-old woman was diagnosed as having infiltrating ductal carcinoma of the breast and underwent modified radical mastectomy. A synchronous retroperitoneal tumour was detected by sonography of the abdomen in a routine cancer staging. Initially, the tumour was diagnosed as a synchronous retroperitoneal metastasis by needle biopsy; further tests revealed that it was progesterone receptor-positive. The retroperitoneal tumour showed poor response to full courses of adjuvant chemotherapy for breast cancer. Subsequently, the patient underwent a radical operation that included nephrectomy. The final pathology confirmed a sarcomatoid renal cell carcinoma. The post-operative course was uneventful. The patient had no recurrence at the 1-year follow-up. In this report, accurate diagnosis and adequate treatment were discussed. An intra-abdominal tumour with progesterone receptor- (PR) positive features is usually considered to be metastatic in breast cancer patients. For breast cancer patients with a PR-positive retroperitoneal tumour, renal cell carcinoma should be differentiated from a metastatic lesion of breast cancer, even if PR-expression is rare in renal cell carcinoma. To the best of our knowledge, this is the first case of PR-positive expression in breast cancer concomitant with renal carcinoma. In clinical settings, it is challenging for the surgeon to make an accurate diagnosis and to provide prompt treatment in such cases.

The relationship between acid-suppressing drugs and phytobezoar formation: a retrospective analysis and discussion of phytobezoar formation.

OBJECTIVES: Although phytobezoars are a rare cause of gastrointestinal obstruction, they are most commonly found in patients with previous gastric surgery. It is well known that predisposing factors of phytobezoar formation are ingestion of fruits containing soluble tannin, presence of dilute hydrochloric acid in the stomach, and gastric stasis or delayed emptying. We investigated whether intake of acid-suppressing drugs that neutralize gastric acidity or inhibit gastric acid secretion to constitute a hypo-acidic condition, increases the risk of phytobezoar formation. MATERIALS AND METHODS: Between September 1992 and October 2008, 32 patients (24 male and 8 female) with gastrointestinal phytobezoars were diagnosed either surgically or endoscopically at the Tri-Service General Hospital, Taipei, Republic of China. The data were collected from hospital records and analyzed retrospectively. RESULTS: Eighteen (56.25%) of all patients had previous gastric surgery and 6 (42.9%) of the 14 patients who had not undergone surgery had diabetes mellitus. The majority of admissions were during winter and spring (between October and March) (P < 0.01) and none of the patients had taken acid-suppressing drugs during the 6 months before detection of gastrointestinal phytobezoars. CONCLUSIONS: In our study, intake of acid-suppressing drugs did not increase the risk of phytobezoar formation in patients with normal gastric motility. Moreover, we believe that the major factor in phytobezoar formation is gastric stasis or delayed emptying, which sufficiently prolongs the retention period of materials in the stomach, while dilute hydrochloric acid is a minor factor.

Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma.

Cortactin, fascin, and survivin have been documented in several human cancers and play important roles in tumor progression. We collected 57 surgical specimens, including esophageal squamous cell carcinomas (SqCC; 7 well-differentiated, 15 moderately differentiated, and 24 poorly differentiated), 3 dysplasias, and 8 normal esophageal tissues. Tissue microarrays were constructed and the immunostaining scores for cortactin, fascin, and survivin were assessed. In 46 SqCC specimens, we examined the relationship between the expression of three biomarkers and tumor differentiation or clinical parameters. Higher immunostaining scores for cortactin, fascin, and survivin correlated positively with tumor differentiation of esophageal SqCC. Univariate survival analysis showed significantly worse prognosis in patients with high scores of cortactin (>or=290), fascin (>or=245), and survivin (score >or= 175), poor differentiation, T4 stage, positive for lymph node metastasis, and positive for distant metastasis. In multivariate survival analysis, high scores of survivin (>or=175) and poor differentiation were independent risk factors for worse prognosis. Our results demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of esophageal SqCC. Survivin may be a good biomarker to be applied in clinic to predict the prognosis of esophageal SqCC.

Extra-mammary Paget's disease of the scrotum and penis: a case report.

Extra-mammary Paget's disease is a rare disease mainly observed in elderly patients. It is an intra-epithelial adenocarcinoma that involves the area rich in apocrine glands. The most common affected lesions are the vulva and perianal region, followed by the axillae and inguinoscrotal area. Mostly, extra-mammary Paget's disease is restricted to the epidermis, but advanced invasion to the dermis is possible with a poor prognosis of disease. The associated occult malignancy is reported and often exists for more than 10 years without clinical manifestation. We report a case of a 66-year-old male with extra-mammary Paget's disease of the scrotum and penis. The diagnosis and treatment are discussed.

Clinical implications of insulin-like growth factor 1 system in early-stage cervical cancer.

This study was aimed to identify the expression and the correlation of insulin-like growth factor-1 (IGF-1) system and their prognostic impacts in cervical cancer. Seventy-two patients with early-stage cervical cancer were eligible. We obtained the serum levels of total IGF-1 and IGF binding protein-3 (IGFBP-3) by enzyme-linked immunosorbent assay and the expression of IGF-1 receptor (IGF-1R) in cancerous tissue by immuno-fluorescent (IF) stains. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.003 and P=0.01, respectively) among patients with high-grade expression of tissue IGF-1R, compared with those with low-grade expression. After adjustment for other factors, preoperative serum total IGF-1 or IGFBP-3 levels failed to predict cancer death and recurrence. High-grade expression of IGF-1R and elevated preoperative squamous cell carcinoma antigen level were independent predictors of both death and recurrence, and combination of both factors could further help identify the subgroup of patients at higher death risk. The IF staining indicates the colocalisation of IGF-1 and IGF-1R in the cancerous tissues, whereas the IGF-1R expression is not correlated with circulating levels of IGF-1 or IGFBP-3. In early-stage cervical cancer, IGF-1 system may have a paracrine or autocrine function and the adverse impacts on prognosis by IGF-1R overexpression are implicated.

Pseudo-Meigs' syndrome caused by uterine smooth muscle tumor of uncertain malignant potential with low vascular endothelial growth factor expression.

Smooth muscle tumor of uncertain malignant potential (STUMP) presenting as pseudo-Meigs' syndrome with low vascular endothelial growth factor (VEGF) expression has not been reported in previous literature. Here, we report a case of uterine STUMP associated with ascites and pleural effusion, which was resolved completely after hysterectomy. A 47-year-old woman presented to the clinic with a complaint of progressive abdominal distension for several months. A large movable, painless pelvic mass located upward above the umbilical level was palpated. Sonography and computed tomography showed a hypervascular solid pelvic mass measuring 20 x 17 x 15 cm in size associated with ascites and right pleural effusion. Laparotomy revealed a large uterine mass with ascites in the abdomen. Total hysterectomy and left-side salpingo-oophorectomy were performed. The final pathologic report revealed a STUMP tumor with low expression of VEGF by immunohistochemistry. A follow-up chest X-ray revealed that the pleural effusion was resolved completely 1 week postoperatively. The patient is doing well without recurrence in the following 2 years. Uterine STUMP tumor may cause pseudo-Meigs' syndrome. However, the ascites or the pleural effusion may not be induced by VEGF, known as vascular permeability factor, in our case.

Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen.

Antigen-specific cancer immunotherapy and antiangiogenesis have emerged as two attractive strategies for cancer treatment. An innovative approach that combines both mechanisms will likely generate the most potent antitumor effect. We tested this approach using calreticulin (CRT), which has demonstrated the ability to enhance MHC class I presentation and exhibit an antiangiogenic effect. We explored the linkage of CRT to a model tumor antigen, human papilloma virus type-16 (HPV-16) E7, for the development of a DNA vaccine. We found that C57BL/6 mice vaccinated intradermally with CRT/E7 DNA exhibited a dramatic increase in E7-specific CD8(+) T cell precursors and an impressive antitumor effect against E7-expressing tumors compared with mice vaccinated with wild-type E7 DNA or CRT DNA. Vaccination of CD4/CD8 double-depleted C57BL/6 mice and immunocompromised (BALB/c nu/nu) mice with CRT/E7 DNA or CRT DNA generated significant reduction of lung tumor nodules compared with wild-type E7 DNA, suggesting that antiangiogenesis may have contributed to the antitumor effect. Examination of microvessel density in lung tumor nodules and an in vivo angiogenesis assay further confirmed the antiangiogenic effect generated by CRT/E7 and CRT. Thus, cancer therapy using CRT linked to a tumor antigen holds promise for treating tumors by combining antigen-specific immunotherapy and antiangiogenesis.

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine.

DNA vaccine and dendritic cells (DCs)-based vaccine have emerged as promising strategies for cancer immunotherapy. Fms-like tyrosine kinase 3-ligand (Flt3L) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) have been exploited for the expansion of DC. It was reported previously that combination of plasmid encoding GM-CSF with HER2/neu DNA vaccine induced predominantly CD4(+) T-cell-mediated antitumor immune response. In this study, we investigated the modulation of immune responses by murine Flt3L and GM-CSF, which acted as genetic adjuvants in the forms of bicistronic (pFLAG) and monocistronic (pFL and pGM) plasmids for HER2/neu DNA vaccine (pN-neu). Coexpression of Flt3L and GM-CSF significantly enhanced maturation and antigen-presentation abilities of splenic DC. Increased numbers of infiltrating DC at the immunization site, higher interferon-gamma production, and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG. Importantly, a potent CD8(+) T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing HER2/neu was induced in the vaccinated mice. Collectively, our results indicate that murine Flt3L and GM-CSF genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for HER2/neu DNA vaccine.

New metal chalcogenides found in MnN-1(Gd2-xInx)SN+2 (N = 3, 4, 5): syntheses, structures, and magnetic properties.

Three new metal chalcogenides have been identified in MnN-1(Gd2-xInx)SN+2 with N = 3, 4, and 5 via a flux-growth synthesis. All compounds crystallize in the same space group of orthorhombic Cmcm with cell constants: Mn2GdInS5 (1), a = 3.789(1) Å, b = 12.411(1) Å, and c = 15.489(1) Å; Mn3Gd2S6 (2), a = 3.778(1) Å, b = 12.505(2) Å, and c = 19.114(2) Å; Mn4Gd2S7 (3), a = 3.769(1) Å, b = 12.466(2) Å, and c = 22.289(3) Å. Compounds 1-3 form a homologous series through the modulation of the MnS unit, whose structures represent a complete system of the corresponding lillianites (N1,N2L) of 3,3L, 4,4L and 5,5L. The gradually wider slabs formed in the series result in a monotonic increase along the c dimensions from 1 to 3. Crystal 3 is the first to achieve a predicted structure of 5,5L. Mn2GdInS5 (1) displays a weak antiferromagnetic (AFM) ordering at 10 K and the Weiss constant (θ) of -0.76 K. Mn2Gd1.5In0.5S5 (1a), an isostructure of 1, shifts the AFM transition temperature to 12 K and possesses a slightly larger θ constant of -6.06 K. Mn4Gd2S7 (3), featuring the thickest slabs in this series, shows a significant antiferromagnetic behavior beginning at a high temperature of 70 K and has a largest θ constant of -40.25 K. A small amount of impurity α-Gd2S3 with an AFM transition temperature around 4 K was characterized in sample 3, which does not interfere with the magnetic ordering of 3 at much higher temperatures. These magnetic chalcogenides display band gaps of 1.66 eV for 1, 1.75 eV for 1a, and 1.44 eV for 3.

Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand.

Recently, Flt3 (Fms-like tyrosine kinase 3)-ligand has been identified as an important cytokine for the generation of professional antigen-presenting cells (APCs), particularly dendritic cells (DCs). A recombinant chimera of the extracellular domain of Flt3-ligand (FL) linked to a model antigen may potentially target the antigen to DCs and their precursor cells. Using human papillomavirus-16 E7 as a model antigen, we evaluated the effect of linkage to FL on the potency of antigen-specific immunity generated by naked DNA vaccines administered intradermally via gene gun. We found that vaccines containing chimeric FL-E7 fusion genes significantly increased the frequency of E7-specific CD8+ T cells relative to vaccines containing the wild-type E7 gene. In vitro studies indicated that cells transfected with FL-E7 DNA presented E7 antigen through the MHC class I pathway more efficiently than wild-type E7 DNA. Furthermore, bone marrow-derived DCs pulsed with cell lysates containing FL-E7 fusion protein presented E7 antigen through the MHC class I pathway more efficiently than DCs pulsed with cell lysates containing wild-type E7 protein. More importantly, this fusion converted a less effective vaccine into one with significant potency against established E7-expressing metastatic tumors. The FL-E7 fusion vaccine mainly targeted CD8+ T cells, and antitumor effects were completely CD4 independent. These results indicate that fusion of a gene encoding the extracellular domain of FL to an antigen gene may greatly enhance the potency of DNA vaccines via CD8-dependent pathways.

Cancer immunotherapy using a DNA vaccine encoding the translocation domain of a bacterial toxin linked to a tumor antigen.

Certain domains of bacterial toxins have been shown to facilitate translocation from extracellular and vesicular compartments into the cytoplasm. This feature represents an opportunity to enhance class I presentation of exogenous antigen to CD8(+) T cells. We investigated this notion by creating a novel fusion of the translocation domain (domain II) of Pseudomonas aeruginosa exotoxin A (ETA(dII)) with a model tumor antigen, human papillomavirus type 16 E7, in the context of a DNA vaccine. Our in vitro studies indicated that cells transfected with ETA(dII)/E7 DNA or dendritic cells pulsed with lysates containing ETA(dII)/E7 protein exhibited enhanced MHC class I presentation of E7 antigen. Vaccination of mice with ETA(dII)/E7 DNA generated a dramatic increase in the number of E7-specific CD8(+) T cell precursors ( approximately 30-fold compared with wild-type E7 DNA) and converted a less effective DNA vaccine into one with significant potency against human papillomavirus type 16 E7-expressing murine tumors via a CD8-dependent pathway. These results indicate that fusion of the translocation domain of a bacterial toxin to an antigen may greatly enhance vaccine potency.