Lizette Vila Duckworth

A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die of infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared with their younger counterparts, the elderly do not respond to severe infection or injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects do. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after posttrauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24-mo-old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an emergency myelopoietic response, engendering myeloid cells that fail to clear secondary infection. In addition, elderly people appeared unable to resolve their inflammatory response to severe injury effectively.

An Unusual Case of Systemic Inflammatory Myofibroblastic Tumor with Successful Treatment with ALK-Inhibitor

Systemic inflammatory myofibroblastic tumor is an exceedingly rare entity. A 45-year-old Hispanic female presented with a 6-month history of left-sided thigh pain, low back pain, and generalized weakness. PET/CT scan revealed abnormal activity in the liver, adrenal gland, and pancreas. MRI of the abdomen demonstrated two 6-7 cm masses in the liver. MRI of the lumbar spine demonstrated lesions in the L2 to L4 spinous processes, paraspinal muscles, and subcutaneous tissues, as well as an 8 mm enhancing intradural lesion at T11, all thought to be metastatic disease. A biopsy of the liver showed portal tract expansion by a spindle cell proliferation rich in inflammation. Tumor cells showed immunoreactivity for smooth muscle actin and anaplastic lymphoma kinase 1 (ALK1). Tissue from the L5 vertebra showed a process histologically identical to that seen in the liver. FISH analysis of these lesions demonstrated an ALK (2p23) gene rearrangement. The patient was successfully treated with an ALK-inhibitor, Crizotinib, and is now in complete remission. We present the first reported case, to our knowledge, of inflammatory myofibroblastic tumor with systemic manifestations and ALK translocation. This case is a prime example of how personalized medicine has vastly improved patient care through the use of molecular-targeted therapy.

Plexiform Fibromyxoma: Report of Two Pediatric Cases and Review of the Literature

Plexiform fibromyxoma is a distinctive mesenchymal neoplasm usually arising in the gastric antrum. We report 2 cases of this entity in pediatric patients, including the first case arising in the esophagus. The patients were a 16-year-old female who presented with chest pain and was found on computed tomographic scan to have a midesophageal mass at the level of the carina, and an 11-year-old female with a gastric mass. Both patients underwent surgical resection of their tumors, which histologically exhibited a plexiform growth pattern with multiple nodules in the muscularis propria and infiltrative borders. The nodules were composed of a rich myxoid stroma with bland uniform spindle cells, no mitoses or necrosis, and delicate blood vessels in the background. Immunohistochemical studies demonstrated that the tumor cells were immunoreactive with smooth muscle actin and not reactive with S-100, CD34, desmin, and c-kit (CD117). We report the first case of plexiform fibromyxoma originating in the esophagus, emphasize its occurrence in pediatric patients, and review the related literature.

Interobserver Variability of Mitotic Index and Utility of PHH3 for Risk Stratification in Gastrointestinal Stromal Tumors

OBJECTIVES Accurate grading of gastrointestinal stromal tumors (GISTs), based on mitotic index, can be problematic. METHODS In this study, we compared interobserver variability in detecting mitosis on H&E with PHH3 immunohistochemistry (IHC). In addition, we examined the correlation between H&E mitosis and Ki-67 and the association of PHH3 and Ki-67 with overall survival. Four pathologists independently reviewed 50 GIST cases. RESULTS Intraclass correlation coefficients showed good interobserver variability for mitotic counts on both H&E (0.918; 95% confidence interval [CI], 0.874-0.950) and PHH3 IHC (0.923; 95% CI, 0.882-0.953). Nineteen (38%) cases were graded higher and five (10%) cases were downgraded by at least one observer using PHH3 compared with H&E. Using receiver operating characteristic curve analysis, a PHH3 cutoff of seven or more mitoses was associated with worse overall survival (P = .028). Ki-67 showed poor correlation with H&E mitotic counts and overall survival (P = .077). CONCLUSIONS PHH3 may thus be a valuable adjunct for risk stratification in GISTs.

Intrathyroidal Parathyroid Carcinoma: Report of an Unusual Case and Review of the Literature

Intrathyroidal parathyroid carcinoma is an exceedingly rare cause of primary hyperparathyroidism. A 51-year-old African American female presented with goiter, hyperparathyroidism, and symptomatic hypercalcemia. Sestamibi scan revealed diffuse activity within an enlarged thyroid gland with uptake in the right thyroid lobe suggestive of hyperfunctioning parathyroid tissue. The patient underwent thyroidectomy and parathyroidectomy. At exploration, a 2.0 cm nodule in the usual location of the right inferior parathyroid was sent for intraoperative frozen consultation, which revealed only ectopic thyroid tissue. No parathyroid glands were identified grossly on the external aspect of the thyroid. Interestingly, postoperative parathyroid hormone levels normalized after removal of the thyroid gland. Examination of the thyroidectomy specimen revealed a 1.4 cm parathyroid nodule located within the parenchyma of the right superior thyroid, with capsular and vascular invasion and local infiltration into surrounding thyroid tissue. We present only the eighth reported case of intrathyroidal parathyroid carcinoma and review the literature.

Mullerian cysts of the posterior mediastinum: report of two cases and review of the literature

Cystic lesions can be occasionally be found in the mediastinum, and typically include bronchogenic cysts, esophageal duplication cysts, and neuroenteric cysts. In 2005, Hattori described the first mediastinal cyst with Mullerian differentiation. Since that time, three other authors have described similar cysts occurring in the posterior mediastinum. Here we present two cases of patients with ciliated cysts with Mullerian differentiation with expression of estrogen receptor, progesterone receptor, PAX8 and Wilms tumor 1, occurring in the posterior mediastinum and review the related literature.

Calciphylaxis of the Breast: A Case Report and Literature Review

Calciphylaxis, or calcific uremic arteriolopathy, is a rare but particularly morbid condition involving systemic medial calcification of arterioles causing ischemia and subsequent tissue necrosis. Although most commonly occurring over the abdomen and proximal extremities, calciphylaxis can present on nearly any skin surface with a tendency toward areas of increased adiposity. We report a case of a 53‐year‐old female with end‐stage renal disease who presented with bilateral palpable breast masses and overlying skin changes. Diagnostic mammography and percutaneous biopsy of the lesion facilitated the diagnosis of calciphylaxis and she was treated with medical therapy, local wound care, and eventual tissue extirpation. Due to the morbidity attributed to calciphylaxis and associated wound complications, surgical extirpation is at times unavoidable. Once malignancy has been excluded, we recommend nonoperative management with prompt referral to Nephrology for medical optimization, reserving surgical debridement for nonhealing wounds and superinfection.

Endoscopic Submucosal Dissection Is Superior to Endoscopic Mucosal Resection for Histologic Evaluation of Barrett’s Esophagus and Barrett’s-Related Neoplasia

Endoscopic Submucosal Dissection Is Superior to Endoscopic Mucosal Resection for Histologic Evaluation of Barrett’s Esophagus and Barrett’s-Related Neoplasia

NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations

The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents. In the present study, we have identified a novel orphan molecule NSC30049 (NSC49L) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk and FOLFOX-resistant cell lines in culture with minimal effect on normal colonic epithelial cells. It also inhibits the sphere forming activity of CRC stem cells, and decreases the expression levels of mRNAs of CRC stem cell marker genes. Results showed that NSC49L induces 5-FU-mediated S-phase cell cycle arrest due to increased load of DNA damage and increased γ-H2AX staining as a mechanism of cytotoxicity. The pharmacokinetic analysis showed a higher bioavailability of this compound, however, with a short plasma half-life. The drug is highly tolerated by animals with no pathological aberrations. Furthermore, NSC49L showed very potent activity in a HDTX model of CRC stem cell tumors either alone or in combination with 5-FU. Thus, NSC49L as a single agent or combined with 5-FU can be developed as a therapeutic agent by targeting the Chk1 pathway in 5-FU-resistant CRC heterogeneous bulk and CRC stem cell populations.

EGFR family and cMet expression profiles and prognostic significance in esophagogastric adenocarcinoma

BACKGROUND Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA. METHODS This retrospective analysis included all sequential patients with esophageal or gastroesophageal junction (GEJ) adenocarcinoma who underwent primary resection, without neoadjuvant therapy or HER2 inhibition, with adequate tissue, at the University of Florida from 2001 to 2011. Central blinded immunohistochemistry (IHC) was performed on tumor specimens with EGFR, HER2, HER3, HER4 and cMet expression scored as low (0, 1+) or high (2+, 3+). Demographic and tumor characteristics were compared using Fisher exact test. Kaplan-Meier curves and univariate analysis compared survival among different receptors. RESULTS Total 52 patients were included in the study with median age 66 years. High expression of EGFR (73%), HER2 (40%), HER3 (75%), HER4 (35%) and cMet (69%) was detected among the study group. HER3 and HER4 co-expression was found in 18 (35%) cases. Pan expression of all four EGFR family members with cMet was noted in only 17% of cases. On univariate analysis, tumor stage and depth correlated with survival, while cMet + HER3 +/- EGFR receptor co-expression trended towards a worse survival. CONCLUSIONS EGFR family and cMet are frequently co-expressed in treatment naïve resected EGA or GEJ tumors. Although our data do not significantly show receptor status as a prognostic factor, the co-expression profiles support for further investigation to improve targeting of this signal transduction axis.