Enhanced liver autophagic activity improves survival of septic mice lacking surfactant proteins A and D.

Autophagy is a protective cellular mechanism in response to various stresses, including sepsis. Sepsis is defined as systemic inflammation by infection. Surfactant protein A and D (SP-A and SP-D) are involved in host defense, regulation of inflammation, and homeostasis, but their roles in the autophagic activity and relevant gene expression in sepsis are unclear. In this study, mice lacking SP-A and SP-D (SP-A/D KO mice) and background-matched wild-type (WT) C57BL/6 mice underwent either cecal ligation and puncture (CLP) or sham surgery. The results showed that SP-A/D KO mice had lower mortality than WT mice in CLP sepsis. Liver tissues showed marked pathological changes in both septic SP-A/D KO and WT mice 24 hrs after CLP treatment; and quantitative analysis of liver histopathology revealed significant difference between septic SP-A/D and septic WT mice. SP-A/D KO mice had higher basal and sepsis-induced level of autophagy than WT mice (p < 0.05), as judged by Western blot and electron microscopic analyses. The expression of 84 autophagy-related genes revealed differential basal and sepsis-induced gene expression between SP-A/D KO and WT mice. The expression increased in three genes and decreased in four genes in septic WT mice, as compared to septic SP-A/D KO mice (p < 0.05). Furthermore, differential responses to sepsis between SP-A/D KO and WT mice were found in six signaling pathways related to autophagy and apoptosis. Therefore, enhanced autophagic activity improves the survival of septic SP-A/D KO mice through the regulation of liver autophagy/apoptosis-related gene expression and signaling pathway activation.

Is Regional Lymph Node Metastasis of Head and Neck Paraganglioma a Sign of Aggressive Clinical Behavior: A Clinical/Pathologic Review.

BACKGROUND: Head and neck paraganglioma is a rare neoplasm of the paraganglia. It accounts for <1% of all head and neck tumors. It usually has benign clinical course; however, malignant paraganglioma can only be diagnosed by showing metastatic disease. We undertook a retrospective study to assess the clinical significance of regional lymph nodes metastases in head and neck paragangliomas. DESIGN: From 1993 to 2016, primary head and neck paragangliomas are identified. The patient clinical and histopathologic materials were reviewed. RESULTS: Sixty-five specimens from 62 patients (3 patients with more than 1 specimens) with head and neck paragangliomas were recorded (49 female and 13 males) with mean age of 54 (24-78 years). The locations of the tumors were as follows: carotid body: 30, glomus tympanicum: 11, glomus jugulare: 14, parapharyngeal space: 3, and 1 case each of larynx, skull base, paraglottic area, infratemporal fossa, mastoid, cerebellopontine (CP) angle, and pyriform sinus. On histopathology, we found 5 cases of sclerosing variant. Thirty-two (52%) of the 62 patients had regional lymph node biopsy. Four (12%) of the 32 show metastatic paraganglioma (3 females and 1 male with mean age = 35). Two of the 5 cases of sclerosing variant had positive lymph nodes. No evidence of local recurrence or distant metastasis in the patients with positive lymph nodes with a 6 to 11 years follow-up. One of the 28 patients with negative lymph nodes developed metastatic disease to lumbar spine in 5 years. CONCLUSION: Metastatic paraganglioma to regional lymph nodes may have indolent clinical behavior, with disease-free survival of up to 11 years. The incidence of metastatic disease in lymph nodes was 4 (12%) of 32. Forty percent (2/5) of the cases with sclerosing variant of paraganglioma had lymph node metastases indicating that this tumor may have a more aggressive histological behavior.

Should the Reporting of Bone Marrow Positivity for Amyloid Be Revised? A Critical Assessment Based On 66 Biopsies From a Single Institution.

CONTEXT.­: Amyloidoses are rare but heterogeneous disorders for which diagnosis is contingent upon the detection of deposits by Congo red stain and amyloid protein typing determines the treatment options. OBJECTIVE.­: To address the reporting of bone marrow (BM) involvement by amyloid in relation to the spatial distribution of deposits and to explore whether the location of deposits may have clinical relevance. DESIGN.­: We examined 66 BM biopsies positive for amyloid with regard to the location and type of amyloid, the percentage and clonality of plasma cells, other organ involvement, and relevant clinical information. RESULTS.­: In 21 cases, amyloid deposits involved BM stroma, whereas 45 cases were nonstromal. All cases of stromal involvement were typed as AL amyloidosis (or presumed AL), whereas nonstromal involvement was associated with at least 3 types of amyloidosis: AL, ATTR, and AA. The initial diagnosis of amyloidosis was made in a BM specimen in 21 of 66 cases (31.8%). Plasma cells ranged from 1% to 80% (mean, 13.4%; median, 8%; <10% in 44 of 66 specimens [66.6%]) and were monoclonal in 58 of 66 cases (87.8%), and in 54 of 66 cases (81.8%) amyloid deposits were documented in at least one other organ. CONCLUSIONS.­: This study demonstrates that there is significant heterogeneity in the spatial distribution of amyloid in BM biopsy specimens with medullary, extramedullary, purely vascular, or combined involvement. Whereas stromal deposits were associated exclusively with AL, nonstromal and purely vascular deposits were seen in at least 3 types of systemic amyloidosis (AL, AA, and ATTR). We discuss the reporting of BM biopsy tissue positivity for amyloid deposits.

Hypercalcemia in Metaplastic Squamous Cell Carcinoma of the Breast.

BACKGROUND Metaplastic breast carcinoma is a rare entity characterized by rapid growth and heterogeneous histological features. It comprises less than 1% of all breast cancers, and no definitive treatment has yet been identified. CASE REPORT We describe here a patient who presented with acute hypercalcemia and was found to have a large ulcerated breast mass. Once the patient's hypercalcemia was stabilized, she underwent complete surgical resection that revealed a large, cavitary, necrotic mass measuring over 11 cm. The final surgical pathology revealed metaplastic carcinoma with extensive squamous differentiation and ductal carcinoma in situ. At the request of her family, no additional treatment was pursued. CONCLUSIONS While there is not a significant body of data on the pathogenesis of metaplastic breast carcinoma, it is typically hormone receptor negative and has a variable response to chemotherapy. Surgical excision is the most commonly pursued treatment.

Role of fine-needle aspiration in post liver transplant patients: A clinical/cytological review.

BACKGROUND: Fine-needle aspiration (FNA) of superficial and deep-seated lesions has been used with high sensitivity and specificity in the diagnosis of neoplastic and nonneoplastic lesions. However, literature of FNA in posttransplant patients is sparse, especially in postliver transplant. We undertook a retrospective study to evaluate the utility of FNA in the clinical management of post liver transplant patients. METHODS: We searched our institution's surgical/cytologic databases (November1993-February2016) to identify liver transplant cases and FNA procedures performed on allograft liver recipients. Institutional IRB approval was obtained for this study. RESULTS: 886 liver allograft recipients were reviewed, 41(5%) of which were transplanted for hepatocellular carcinoma. 62/886(7%) underwent an FNA procedure. 39males and 23females included with mean age of 58years. Mean time between transplant and FNA was 34months. 21/62(34%) were malignant neoplasms, most common malignancy was adenocarcinoma: 8cases(3lung,3pancreas,1colon,1cholangiocarcinoma)and 8cases of transplanted hepatocellular carcinoma patients had recurrence, 6 in the allograft liver and 1case each of metastasis to the iliac bone and periportal lymph node. 3cases were squamous-cell carcinoma (2lung and 1scalp). 2cases were posttransplant lymphoproliferative disorders. 34/62(55%) cases were benign aspirates from various organs (8lung,6liver,5pancreas,4breast,3thyroid,3lymph-nodes and 1case each of salivary gland, bile-duct,intraabdominal,abdominal wall,and oral cavity) 0.6/62(10%) cases were inflammatory. 22cases had histologic correlation: 5true-positives,16true-negatives,1false-negative (a patient with parotid mucoepidermoid carcinoma whose FNA diagnosis was sialadenitis), and no false-positive. The sensitivity was 83% and the specificity was 100%. The positive predictive value was 100% and the negative predictive value was 94%. CONCLUSIONS: This review shows that 40/62(65%) of the aspirates were benign lesions, indicating that a conservative approach is recommended in the clinical management of these patients, especially since the interval between transplant and FNA was on average 34months. FNA is a safe, minimally invasive method to follow-up these patients.

Ectopic Thyroid Tissue: Immunohistochemistry and Molecular Analysis.

Ectopic thyroid tissue is rare and controversial. Some experts consider it to always be metastatic thyroid carcinoma, whereas others consider it benign as long as it is restricted to few follicles without cytoarchitectural features of papillary thyroid carcinoma. Immunohistochemistry (IHC) and molecular studies have not yet been performed to further characterize this entity. We retrospectively searched our pathology files for all ectopic thyroid inclusions and reviewed clinicopathologic characteristics and concurrent thyroid pathologic findings. We identified 8 cases from 7 patients. Ectopic thyroid tissue was present in the following locations: neck soft tissue: 3, thymus: 2, neck lymph nodes: 2, perihilar soft tissue: 1. All patients had histologically benign thyroid specimens. BRAFV600E (VE1) IHC, HBME-1 IHC, galectin-3 IHC, BRAFV600E allele-specific polymerase chain reaction (PCR) and NRAS/KRAS pyrosequencing were performed. To assess the sensitivity and specificity of BRAFV600E IHC compared with PCR; we tested 13 cases of primary and metastatic papillary and follicular thyroid carcinomas. All the ectopic cases were HBME-1, galectin-3, BRAFV600E (IHC, PCR), and NRAS/KRAS mutation negative (specificity=100%). Compared with PCR, BRAF IHC had 89% sensitivity and 100% specificity. Lack of common carcinoma-associated mutations supports benign nature of this entity. BRAF, HBME-1, and galectin-3 IHC are accurate and helpful when not enough tissue is available for molecular studies. IHC and molecular studies are more helpful than morphology alone in identifying benign thyroid rests.

Male Breast Carcinoma: A Clinical and Pathological Review.

Male breast carcinomas (MBCs) are rare neoplasms that account for 0.1% of all male cancers. Still, there are 2000 new cases of MCB diagnosed annually in the United States. Because of its rarity, data regarding the etiology, risk factors, diagnosis, management, and prognosis of MBC are limited. MBC shares some similarities with female breast carcinoma (FBC). This review will address the important clinical, histopathological, immunohistochemical and molecular features, genetics, management, and prognosis of MBC.

Prognostic Markers and Histologic Subtypes in Patients with Meningeal Carcinomatosis in Breast Cancer.

OBJECTIVE: Meningeal carcinomatosis (MC) is a rare complication in breast cancer patients. It is defined as a diffuse or multifocal leptomeningeal metastasis. STUDY DESIGN: From our institution database, we retrospectively studied 19 patients diagnosed with MC in the cerebrospinal fluid (CSF) in 1997-2015, in order to evaluate tumor prognostic markers, histologic subtypes, and clinical outcome. RESULTS: All patients were female, with a mean age of 53 years (range 36-75 years). The mean interval between diagnosis of breast carcinoma and MC was 28 months (range 6-62 months). The median survival from the time of diagnosis was 2 months (1-51 months). Sixteen cases (84%) were the ductal phenotype, 62% of which were of a high grade (grade 3), and 3 cases (16%) were lobular. Estrogen and progesterone receptors were positive on immunohistochemistry (IHC) in 53 and 33% of patients, respectively. HER2 IHC was positive (3+) in 20% of the cases; all were amplified by fluorescence in situ hybridization. The incidence of MC in triple-negative tumors was 40%. Twelve patients (63%) already had known metastasis at the time of diagnosis. CONCLUSIONS: Most cases of MC are high-grade ductal. MC is more common in triple-negative breast cancers. The outcome of these breast cancer patients with MC was poor. There was no survival difference according to age, histologic subtype, grade, or hormonal or HER2 status.

Clinicopathological and molecular characteristics of synchronous gastric adenocarcinoma and gastrointestinal stromal tumors.

Synchronous gastric tumors that consist of both gastrointestinal stromal tumor (GIST) and adenocarcinoma are rare. We studied the clinicopathological and molecular characteristics of six cases containing both gastric adenocarcinoma and GIST. By means of immunohistochemical analysis, all GIST cells expressed CD117, CD34 and Dog1 in all six synchronous gastric adenocarcinomas with GIST, and in GIST alone. Sequencing analysis demonstrated that exon 11 c-kit mutations were present in two of six synchronous tumors and four of five GISTs. One of the two exon 11 c-kit mutations in synchronous adenocarcinomas with GISTs was an uncommon mutation of CTT > CCA at amino acid 576, and the other was a GTT deletion at amino acid 560. The mutation was a homozygous A > G mutation in exon 12 (amino acid 567) of PDGFR-α. We concluded that the exon 11 mutations were the most important in both cases of synchronous gastric adenocarcinoma with GIST and GIST alone. The mutation rate was higher in GIST alone than in synchronous adenocarcinoma with GIST.

Matrilin-2 is a widely distributed extracellular matrix protein and a potential biomarker in the early stage of osteoarthritis in articular cartilage.

In this study, we first generated and characterized a polyclonal antibody against unique domain of matrlin-2 and then used this specific antibody to assess the expression pattern of matrilin-2 by immunohistochemistry. We found that marilin-2 is widely distributed in the connective tissues of many mouse tissues including heart, colon, penis, esophagus, lung, kidney, tracheal cartilage, developmental bone, and adult bone. The expression level of matrilin-2 was remarkably increased in the tissues of osteoarthritis developmental articular cartilage, compared to normal healthy tissues. Furthermore, we determined matrilin-2 expression in specific epithelial cells in stomach and ductal epithelial cells of salivary gland. In other tissues, the positive signals were mainly located around cardiac muscle cells and Purkinje fibers in the heart; corpus spongiosum in the penis; submucosa in the colon and esophagus; extracellular matrix of cartilage in the tracheal cartilage; and, glomerulus, the basement membrane of distal convoluted tubule and renal matrix in kidney. These observations indicated that the distribution pattern of matrilin-2 is heterogeneous in each tissue. Matrilin-2 may play an important role in the communication of matrix to matrix and matrix to cells and will be used as a potential biomarker in the early stage of osteoarthritis of articular cartilage.

Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats.

The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42-46°C and 50-55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50-55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.

Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases.

Pulmonary abnormalities, dysfunction or hyper-reactivity occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Emerging evidence suggests that subtle inflammation exists in the airways among IBD patients even in the absence of any bronchopulmonary symptoms, and with normal pulmonary functions. The pulmonary impairment is more pronounced in IBD patients with active disease than in those in remission. A growing number of case reports show that the IBD patients develop rapidly progressive respiratory symptoms after colectomy, with failure to isolate bacterial pathogens on repeated sputum culture, and often request oral corticosteroid therapy. All the above evidence indicates that the inflammatory changes in both the intestine and lung during IBD. Clinical or subclinical pulmonary inflammation accompanies the main inflammation of the bowel. Although there are clinical and epidemiological reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD, the detailed mechanisms of pulmonary-intestinal crosstalk remain unknown. The lung has no anatomical connection with the main inflammatory site of the bowel. Why does the inflammatory process shift from the gastrointestinal tract to the airways? The clinical and subclinical pulmonary abnormalities, dysfunction, or hyper-reactivity among IBD patients need further evaluation. Here, we give an overview of the concordance between chronic inflammatory reactions in the airways and the gastrointestinal tract. A better understanding of the possible mechanism of the crosstalk among the distant organs will be beneficial in identifying therapeutic strategies for mucosal inflammatory diseases such as IBD and allergy.