Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma.

Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-ß signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-ß receptor (TGFBR3) through TGF-ß-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.

Upregulated hPuf-A promotes breast cancer tumorigenesis.

hPuf-A is a member of RNA-binding PUF family that regulates mRNA translation. Redistribution of hPuf-A from the nucleolus to the nucleoplasm upon genotoxic stress modulates the poly(ADP-ribosyl)ation activity of PARP-1. Here, we report a novel function of hPuf-A involved in promoting breast cancer progression. Immunohistochemical studies showed higher expression levels of hPuf-A in stage I, II, III, and IV breast cancer specimens in contrast with those of hPuf-A in ductal carcinoma in situ. The presence of hPuf-A is highly associated with colony formation capacities in breast cancer T47D and MDA-MB-231 cells. Xenograft growth of hPuf-A-silenced and hPuf-A overexpressing MDA-MB-231 cells in nude mice was substantially in concert with colony formation capacities. This promoting effect of hPuf-A in tumorigenesis might be correlated with the regulation of its associated mRNAs, such as RbAp48 and DDX3. Collectively, hPuf-A may have diagnostic values in breast cancer progression.

Intraoperative Sentinel Lymph Node Imprint Cytology Diagnosis in Breast Cancer Patients by General Surgical Pathologists: A Single-Institution Experience of 4327 Cases.

Context: Sentinel lymph node (SLN) biopsy is the standard of care for breast cancer (BC) patient staging. The axillary node status can be evaluated by frozen section (FS) or imprint cytology (IC). Despite the major disadvantages of tissue loss and freezing artifact in FS, many pathologists consider SLN IC a more difficult task requiring special expertise and prefer FS to IC. Aims: To conduct a large cohort study to evaluate the results of intraoperative SLN IC, compare them with those of FS and permanent section (PS), and determine the best method for general pathologists. Settings and Design: A very large cohort study with many pathologists engaged was designed and the diagnostic results were compared. Materials and Methods: With 12 pathologists engaged, we conducted the largest patient cohort study of SLN IC to date, including 4,327 consecutive BC patients undergoing SLN biopsy during the past 15 years. The touch imprints were stained using three different methods and evaluated. The PS was used as the gold standard for evaluation. Statistical Analysis: The false positivity, false negativity, accuracy, sensitivity, and specificity of the IC and FS for each pathologist were evaluated and compared. Results: Our results showed an overall sensitivity of 82.7%, specificity of 99.3%, and an accuracy rate of 95.9% for SLN IC, which were comparable to those of FS. The accuracy rate did not correlate with the length of working experience and the staining method. Conclusions: Intraoperative hematoxylin and eosin (H&E)-stained IC preparation was found to be the best SLN examination method for general pathologists.

Recurrent sebaceous gland carcinoma of eyelid previously diagnosed as basal cell carcinoma: case report.

Sebaceous gland carcinoma (SGC) of the eyelid is a highly malignant neoplasm that arises from the meibomian glands, glands of Zeis, and sebaceous glands of the skin. The characteristics of this disease are high recurrence rate, significant metastatic potential, and notable mortality rate, which are quite different from basal cell carcinoma (BCC). We report the case of a 37-year-old woman with the history of left lower eyelid BCC (diagnosed 9 years ago), who had left parotid lymph nodes metastases and local recurrence twice. The chief complaint during visit was a left upper eyelid swelling mass noted for 3 months. She received salvage ablation surgery later. The final pathologic report is SGC. The diagnosis corresponds to the clinical presentation of this patient at last. The delay between initial examination and final diagnosis in this patient is about 9 years, but operation and concurrent chemotherapy and radiotherapy were performed after left parotid lymph nodes metastasis was noted. Although there was still local recurrence after concurrent chemotherapy and radiotherapy, the patient is still alive without distant metastasis. In this article, we would discuss the differences of the pathologic characters, treatment, and prognosis between SGC and BCC.

A Zigzag Flap for Correcting a Nail Deformity Caused by Subungual Schwannoma.

Subungual schwannoma is quite rare and often causes nail deformity and difficulty in wearing shoes. Complete tumor excision is the treatment of choice, and we advocate that restoring the nail appearance should be considered at the same time. We present the case of 43-year-old man with a big toe subungual schwannoma. We designed a zigzag incision method to excise the tumor and also corrected nail-bed deformity. The patient had a smooth recovery, and the nail plate regrew with a good appearance.

Characteristics of well-differentiated thyroid cancer associated with multinodular goiter.

BACKGROUND: The likelihood of thyroid cancer is similar in patients with one or more nodules, but tumor characteristics of thyroid cancer in glands with multinodular goiter are unclear. MATERIALS AND METHODS: This study consisted of 100 consecutive patients (ages 15-81 years; 84 women), who underwent thyroidectomy for papillary or follicular thyroid carcinoma between 2005 and 2006. Patient demographics, diagnostic tests, operations, and pathological findings were reviewed. RESULTS: In a univariate analysis, cancer diagnosed within multinodular goiter was different from solitary cancer nodule in age of diagnosis (48 vs 40 years, p = 0.002), tumor size (1.42 vs 2.20 cm, p = 0.024), and the presence of cervical lymph node metastases (p = 0.035). There was no difference in gender, extrathyroidal invasion, multifocality, and types of operation. Only age (odds ratio, 1.056) and tumor size (odds ratio, 0.730) revealed independent correlation in multivariate analysis. CONCLUSION: Thyroid cancer in glands with multiple nodules is associated with older age at diagnosis and smaller tumor size.

FANCA D1359Y mutation in a patient with gastric polyposis and cancer susceptibility: A case report and review of literature.

Gastric polyposis is a rare disease. Not all polyps progress to cancer. Monoallelic mutation in Fanconi anemia (FA) genes, unlike biallelic gene mutations that causes typical FA phenotype, can increase risks of cancers in a sporadic manner. Aberrations in the FA pathway were reported in all molecular subtypes of gastric cancer. We studied a patient with synchronous gastric cancer from gastric polyposis by conducting a 13-year long-term follow up. Via pathway-driven massive parallel genomic sequencing, a germline mutation at FANCA D1359Y was identified. We identified several recurrent mutations in DNA methylation (TET1, V873I), the ß-catenin pathway (CTNNB1, S45F) and RHO signaling pathway (PLEKHG5, R203C) by comparing the genetic events between benign and malignant gastric polyps. Furthermore, we revealed gastric polyposis susceptible genes and genetic events promoting malignant transformation using pathway-driven targeted gene sequencing.

Hyperdense appendix on unenhanced CT: a sign of acute appendicitis.

The purpose of this study was to evaluate the presence of the hyperdense appendix in acute appendicitis. The CT scans of 183 patients with pathologically proven acute appendicitis were reviewed to determine the prevalence of a hyperdense appendix, defined as a high-attenuated appendix when compared with the adjacent cecal wall on precontrast CT. A control group consisted of 100 patients with CT examinations performed in the emergency department were also randomly allocated to search for any hyperdense appendix in other disease conditions. The images were reviewed by two radiologists who reached a decision by consensus. A hyperdense appendix sign was found in 61 of 183 (33%) patients, including 92 men and 91 women ranging in age from 17 to 85 years (mean 37 years). On the other hand, the sign was seen in only two (2%) of the 88 patients in whom appendicitis was not diagnosed. The hyperdense appendix sign on unenhanced CT is seen in about 33% of patients with acute appendicitis. The false-positive rate is very low, rendering it a very useful sign for diagnosis of acute appendicitis.

Delayed hemopericardium with constrictive pericarditis after blunt trauma: a report of a surgical case.

Constrictive pericarditis (CP) following hemopericardium has been reported in the literature but its pathogenesis is open to question. Proposed mechanisms include trauma leading to damage of the mesothelial lining resulting in decreased fibrinolytic activity in the presence of blood. We present a patient who sustained blunt thoracoabdominal trauma in a car accident and subsequently developed delayed hemopericardium leading to constrictive pericarditis and impending cardiac tamponade. We performed a pericardiectomy to relieve the compression. Closely prolonged monitoring and emergent operation are suggested for such kinds of delayed complications.

Detection of mycobacteria in Crohn's disease by a broad spectrum polymerase chain reaction.

BACKGROUND: The role of mycobacterial infection, particularly related to Mycobacterium avium subsp paratuberculosis (Map), in Crohn's disease has long been debated. We developed primer pairs capable of detecting a broad spectrum of mycobacterium and employed them to investigate surgical specimens from patients with Crohn's disease. METHODS: Pan mycobacterium primers of the 65-kDa heat shock protein gene (Hsp65) were used in a polymerase chain reaction (PCR) to examine 12 surgically-resected, formalin-fixed, paraffin-embedded specimens from 11 patients with Crohn's disease. The DNA sequences of amplicons were aligned with those in GenBank. RESULTS: Mycobacterial DNA was found in specimens from three of 11 patients. M. mucogenicum was identified in a specimen from one patient and M. tuberculosis in two, but Map was not identified in any. CONCLUSION: Hsp65-based PCR can be employed to search for occult mycobacterial infection of the gastrointestinal tract in patients with a diagnosis or suspicion of Crohn's disease. This approach may have a therapeutic implication.

Esophagectomy for locally advanced esophageal cancer, followed by chemoradiotherapy and adjuvant chemotherapy.

AIM: To compare the efficacy and toxicity of a three-step combination therapy with post-operative radiation alone for locally advanced esophageal cancer. METHODS: Patients with T3-4 and N0-1 esophageal carcinoma from a number of institutions were non-randomly, prospectively enrolled in the study. All patients underwent single-stage curative en bloc esophagectomy. The patients were then assigned into one of two treatment groups based on treatment consisting of either post-operative concurrent chemoradiotherapy (CCRT) with weekly cisplatin 30 mg/m2 followed by systemic adjuvant chemotherapy (four monthly cycles of cisplatin 20 mg/m2 and 5-fluorouracil 1 000 mg/m2 for five consecutive days), or, post-operative radiation alone. The radiotherapy dose was 55-60 Gy for all patients. Primary end-point of this study was to assess the per-protocol patients' improvement of overall survival benefit. Secondary end-point was designed to evaluate both the per-protocol and intent-to-treat patients' outcome of survival. RESULTS: A total of 60 patients (n = 30 per group) were enrolled in this study. The two groups were generally comparable for demographic characteristics and hematological and non-hematological toxicities. The CCRT with weekly cisplatin was well tolerated, with significantly better overall survival (30.9 mo vs 20.7 mo; 95% CI, 27.5-36.4 vs 15.2-26.1) and 3-year survival (70.0% vs 33.7%; P = 0.003). Low histological grade of tumor (P<0.001) was associated with favorable survival in these locally advanced patients. CONCLUSION: For locally advanced esophageal cancer, the combination of esophagectomy, post-operative CCRT with weekly cisplatin and systemic adjuvant chemotherapy is well tolerated and effective. A large-scale, prospective randomized trial of this regimen is in progress.

Primary high-grade salivary-type duct carcinoma of the lung: a case report.

Primary salivary gland-type lung cancers are a rare group of tumors. When they do occur, the most common type is adenoid cystic carcinoma, followed by mucoepidermoid carcinoma. Primary high-grade salivary-type duct carcinoma (HGSDC) arising in the lung has not been described. We report a case of primary pulmonary HGSDC in a 55-year-old woman who was referred to our hospital for a suspicious lung tumor. The chest computed tomography revealed a solid mass in the left upper lobe. A lobectomy was performed afterward, and the mass was a primary lung HGSDC. To the best of our knowledge, HGSDC arising in the lung has not been reported previously.

Prognostic factors in desmoid-type fibromatosis: a clinicopathological and immunohistochemical analysis of 46 cases.

AIMS: To determine risk factors for recurrence of desmoid-type fibromatosis (aggressive fibromatosis). METHODS: Forty-six cases of desmoid-type fibromatosis in Taiwanese patients were analysed for an association between tumour recurrence and clinical features, pathology, and the presence of p53 protein and beta-catenin on immunohistochemical staining. RESULTS: Six (13%) of 46 patients developed recurrence after surgical resection. The only factor significantly associated with tumour recurrence was positive surgical margin (p = 0.035). CONCLUSIONS: A positive surgical margin is a risk factor for recurrence of desmoid-type fibromatosis.

Clinicopathologic significance of leptin and leptin receptor expressions in papillary thyroid carcinoma.

BACKGROUND: Epidemiologic studies have shown that obesity is associated with an increased risk of thyroid cancer. Leptin, an adipocyte-derived cytokine, can act as a growth factor on certain normal and transformed cells. Aberrant expression of leptin or leptin receptor has been detected in some types of cancer. The aim of this study is to determine immunohistochemical expression of leptin and leptin receptor in papillary thyroid cancer to investigate the relationship between their expression and clinicopathologic features. METHODS: The expression of leptin and leptin receptor was assessed in 49 primary neoplasms and 15 lymph node metastases using a semiquantitative immunohistochemical staining method. RESULTS: Leptin and leptin receptor were expressed in 37% and 51% of papillary thyroid cancer, respectively. They were not expressed in normal follicles. In the primary neoplasms and the metastatic nodes, expression of leptin correlated closely with leptin receptor (P < .001 for the primary neoplasms and P = .017 for nodal metastases). Expression of either protein was associated with greater neoplasm size (leptin expression, 32.0 +/- 10.7 vs 20.5 +/- 8.4 mm; P = .001; leptin receptor expression, 27.9 +/- 11.5 vs 21.4 +/- 9.0 mm; P = .032). Coexpression of leptin and leptin receptor in primary neoplasms had greater incidence of lymph node metastasis (P = .038). CONCLUSION: Expression of leptin and/or leptin receptor in papillary thyroid cancer is associated with neoplasm aggressiveness, including tumor size and lymph node metastasis.

Lafora disease and congenital generalized lipodystrophy: a case report.

We report a patient with congenital generalized lipodystrophy who had suffered from seizures, myoclonus, ataxia and cognitive decline since late childhood. Lafora disease was diagnosed based on skin biopsy results, which revealed pathognomonic Lafora bodies. The results of genetic analysis for mutations in EPM2A and EPM2B genes were negative. This is the first case report describing an association between congenital generalized lipodystrophy and Lafora disease. Further studies focusing on the relationship between these two diseases and the identification of a third locus for Lafora disease are needed.

Incidence of gastrointestinal stromal tumor: a retrospective study based on immunohistochemical and mutational analyses.

The aim of this study is to estimate the incidence of the gastrointestinal stromal tumor after the previous diagnoses were confirmed and/or revised by both immunohistochemical and mutational analyses. We reviewed 17,858 surgically excised gastrointestinal lesions in our hospital from 1998 to 2004. All mesenchymal tumors were examined for CD117 expression by immunohistochemistry, and every CD117-negative mesenchymal tumors were further subjected to mutational analysis for KIT and PDGFRA exons. The results showed that approximately 35% of gastrointestinal stromal tumors were misdiagnosed if immunohistochemical analysis of CD117 expression was not performed; and approximately 15% misdiagnosed if mutation analysis was not available. Because approximately 4.72% of patients with gastrointestinal malignancies in Taiwan were treated in our hospital and the average of newly diagnosed gastrointestinal stromal tumors in our hospital was 14.33 cases per year, the estimated annual incidents of gastrointestinal stromal tumor in Taiwan were 303.60. Therefore, the annual incidence of gastrointestinal stromal tumor is 13.74 per million Taiwanese.

Phyllodes tumor of the breast: the challenge persists.

INTRODUCTION: Phyllodes tumors of the breast are uncommon, and it is difficult to predict biologic behavior based on clinicopathologic features. Despite the wealth of data on the factors to predict recurrence, little is known about the impact of treatment refinements. This study seeks to define changes in patient characteristics, histopathologic parameters, and outcome between the two periods before and after the care of patients with breast diseases was centralized to a breast specialty. METHODS: The records of 182 patients with phyllodes tumors managed surgically were reviewed. Patients treated from 1985 to 1996 (n=81) were compared with those seen from 1997 to 2004 (n=101). RESULTS: The analysis of the two treatment periods revealed that there was a decrease in tumor size at diagnosis, from 7.7 cm during the earlier period to 4.6 cm during the recent period (P=0.003). The patients undergoing breast-conserving surgery were significantly increased during the recent period. In contrast, pathologic features and local recurrence rates remained unchanged during the study period. Multivariate analysis revealed that positive surgical margin was the only independent predictor of recurrence, with an increased hazard of 8.0. Overall, upgrading to the next grade was observed in 16% of recurrences. CONCLUSIONS: Breast-conserving surgery with clear margins is the current treatment of choice for phyllodes tumors, but this strategy does not further reduce local recurrence effectively. Optimal management continues to be a challenge.

Pseudomembranous tracheobronchitis caused by Aspergillus in immunocompromised patients.

We report 2 cases of Aspergillus pseudomembranous tracheobronchitis in patients with diabetes. The first patient succumbed to progressive obstructive respiratory failure despite mechanical ventilation and antifungal therapy. However, the second patient survived. Aspergillus tracheobronchitis should be considered in immuno-compromised patients presenting with cough, chest pain, fever, dyspnea and upper airway obstruction. Early bronchoscopy and histologic examination should be performed. Early, appropriate treatment may be life saving.