Two Thymomas of Different Histological Subtypes Arising in a Giant Thymolipoma: Case Report and Review of the Literature.

Thymolipoma is a rare benign tumor of the anterior mediastinum. Only a few reports describing thymoma arising within a thymolipoma have been documented in the literature. We report herein a detailed description of thymolipoma giving rise to 2 thymomas of different histological subtypes. A 74-year-old male with history of metastatic papillary thyroid carcinoma gradually developed 2 soft tissue nodules within a large right hemithorax fatty mass that was present for the past 20 years. Computed tomography (CT)-guided needle biopsy revealed one of the soft tissue nodules to be a thymoma, and the entire mass was surgically resected. Final pathological examination demonstrated the mass to be a thymolipoma containing a micronodular thymoma with lymphoid stroma as well as a WHO type B1 thymoma. No evidence of disease recurrence was seen at the time of his 7-year follow-up. This case documents a rare presentation of thymolipoma harboring 2 thymomas of different histological subtypes and highlights the need for early surgical resection of thymolipomas, as they may harbor malignant nodules.

Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation.

Pulmonary tumor embolism secondary to soft tissue and bone sarcomas: a case report and literature review.

BACKGROUND: Tumor embolisms (TE) are an underappreciated source of pulmonary embolisms in sarcoma. Most evidence in the literature is limited to case reports and none have described the presence of TE secondary to myxofibrosarcoma. We report the first case of myxofibrosarcoma TE and perform a review of the literature for TE secondary to bone and soft tissue sarcomas (STS). CASE PRESENTATION: A 36-year-old female presented with debilitating pain of the right upper extremity secondary to a recurrent soft tissue sarcoma. She had distant metastasis to the lung. An MRI revealed a 25-cm shoulder mass involving the proximal arm muscles with encasement of the axillary artery, vein, and brachial plexus. A palliative forequarter amputation was performed and tumor thrombus was evident within the axillary artery and vein. Postoperatively, she developed an acute onset of dyspnea and hypoxia. A computed tomography scan revealed a pulmonary saddle embolism. A bilateral lower extremity venous duplex was negative. She became hemodynamically unstable despite resuscitation and was placed on vasopressor support. A transthoracic echocardiogram revealed elevated pulmonary artery pressure, tricuspid regurgitation, right heart dilation, and reduced right heart systolic function consistent with acute cor pulmonale. The patient did not want to pursue a median sternotomy with pulmonary artery embolectomy and expired from cardiopulmonary arrest within 24 h of the operation. The final pathology revealed a 25 × 16 × 13 cm high-grade myxofibrosarcoma with invasion into the bone, skin, and neurovascular bundle as well as evidence of tumor thrombus. CONCLUSION: TE is a rare but deadly cause of pulmonary embolism in sarcoma. A high index of suspicion is necessary in individuals who present with respiratory-related symptoms, especially dyspnea. Diagnostic confirmation with a computed tomography scan of the chest and echocardiogram should be rapid. Unlike venous thromboembolism, pulmonary embolectomy remains the preferred therapeutic approach.

Thymoma and parathyroid adenoma: false-positive imaging and intriguing laboratory test results.

IMPORTANCE: Parathyroid hormone (PTH)-secreting thymomas are an exceedingly rare entity. A PTH-secreting thymoma was discovered in the workup of a patient with primary hyperparathyroidism. A concomitant parathyroid adenoma was removed from the same patient. We present the intriguing clinical course and review the literature on this rare entity. In addition, we discuss the use of scanning with technetium Tc 99m sestamibi, the PTH assay, and cervical ultrasonography in the workup of a parathyroid adenoma. OBSERVATIONS: Scanning with technetium Tc 99m sestamibi demonstrated false-positive uptake of the mediastinal thymoma and false-negative uptake of the true cervical parathyroid adenoma. After removal of the thymoma, the parathyroid adenoma demonstrated appropriate uptake on a follow-up scan. After removal of the parathyroid adenoma, the hyperparathyroidism was cured. CONCLUSIONS AND RELEVANCE: Given the extremely rare incidence of a PTH-secreting thymoma with a concurrent parathyroid adenoma, we do not recommend alterations in the diagnostic algorithm for primary hyperparathyroidism. However, in this case, the need for 2 separate operations may have been avoided by obtaining an ultrasonogram to further explore the findings on the technetium Tc 99m sestamibi scan. We recommend that both studies be considered in unclear cases of primary hyperparathyroidism.

Advanced malignant mesothelioma mimicking acute contained thoracic aortic rupture.

In the emergent setting, patients presenting with acute interscapular pain along with haemodynamic instability require immediate evaluation. We describe the case of a patient in which computed tomographic scanning demonstrated a large hyper-dense, periaortic collection on post-contrast imaging. Urgent endovascular repair was performed for descending thoracic aortic rupture. Her postoperative course, however, was atypical with a readmission 1 week after discharge with symptoms similar to her primary presentation. Alternative pathologies were then considered in a more elective setting in which the correct diagnosis of diffuse malignant mesothelioma was ultimately discovered in a patient with no previous exposure to occupational toxins. The tumour burden was advanced and the patient opted for palliative care. Herein, we suggest a consideration for oncological thoracic pathology in patients presenting with signs and symptoms mimicking acute thoracic aortic rupture or dissection, who may demonstrate atypical symptoms.

Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database.

BACKGROUND: Anastomotic leak is an important cause of morbidity and mortality after esophagectomy. Few studies have targeted risk factors for the development of leak after esophagectomy. The purpose of this study is to use The Society of Thoracic Surgeons Database to identify variables associated with leak after esophagectomy. METHODS: The Society of Thoracic Surgeons Database was queried for patients treated with esophagectomy for esophageal cancer between 2001 and 2011. Univariate and multivariate analysis of variables associated with an increased risk anastomotic leak was performed. RESULTS: There were 7,595 esophagectomies, with 804 (10.6%) leaks. Thirty-day mortality and length of stay were higher for patients with anastomotic leak. Mortality in patients requiring surgical management was 11.6% (38 of 327) compared with 4.4% (20 of 458) in medically managed leaks (p < 0.001). The leak rate was higher in patients with cervical anastomosis compared with those with intrathoracic anastomoses, 12.3% versus 9.3%, respectively (p = 0.006). There was no difference in leak-associated mortality between the two approaches. Factors associated with leak on univariate analysis include obesity, heart failure, coronary disease, vascular disease, hypertension, steroids, diabetes, renal insufficiency, tobacco use, procedure duration greater than 5 hours, and type of procedure (p < 0.05). Multivariable regression analysis associated heart failure, hypertension, renal insufficiency, and type of procedure as risk factors for the development of leak (p < 0.05). CONCLUSIONS: Anastomotic leak after esophagectomy is an important cause of postoperative mortality and increased length of stay. We have identified important risk factors for the development of esophageal anastomotic leak after esophagectomy. Further studies aimed at risk reduction are warranted.

Fusion positron emission/computed tomography underestimates the presence of hilar nodal metastases in patients with resected non-small cell lung cancer.

BACKGROUND: The 5-year survival for patients with resected stage II (N1) non-small cell lung cancer ranges from 40% to 55%. No data exist addressing the benefit of neoadjuvant therapy for patients with stage II disease. This is largely in part due to the lack of a reliable, minimally invasive method to assess hilar nodes. This study is aimed at determining the ability of fusion positron emission/computed tomography (PET/CT) to identify hilar metastases in patients with resected non-small cell lung cancer. METHODS: A retrospective review of surgically resected patients with fusion PET/CT within 30 days of resection was performed. The sensitivity, specificity, positive predictive value, and negative predictive value for PET/CT in detecting hilar nodal metastases was calculated for a range of maximum standardized uptake values (SUVmax). Hilar nodes from patients with falsely positive PET/CT scans were analyzed for the presence of histoplasmosis. Additionally, the impact of hilar node size greater than 1 centimeter on the calculated values was assessed. RESULTS: There were 119 patients evaluated. The number of lymph nodes resected ranged from 1 to 12 (X=2.98). There was decreased sensitivity and increased specificity with higher SUVmax cutoff values. At the standard SUVmax value of 2.5, the sensitivity and specificity were only 48.5% and 80.2%. The addition of size of hilar node by CT led to a modest improvement in sensitivity at all SUVmax cutoff values. CONCLUSIONS: Fusion PET/CT lacks sensitivity and specificity in identifying hilar nodal metastasis in patients with resected non-small cell lung cancer. Further prospective studies assessing the utility of PET/CT versus alternative sampling techniques are warranted.

Giant asymptomatic primary esophageal schwannoma.

Primary esophageal schwannomas are uncommon. We describe a case of a large asymptomatic primary esophageal schwannoma in a 65-year-old patient. Computed tomography and positron emission tomography revealed an (18)F-fluorodeoxyglucose-avid 11-cm mass arising from the esophagus. A preoperative diagnosis was made via endoscopic ultrasound. The patient underwent a three-field esophagogastrectomy with cervical esophagogastric anastomosis. He remains well and free of recurrence 10 months after treatment.

Family size and perinatal circumstances, as mental health risk factors in a Scottish birth cohort.

PURPOSE: Higher maternal parity and younger maternal age have each been observed to be associated with subsequent offspring suicidal behaviour. This study aimed to establish if these, and other variables from the perinatal period, together with family size, are also associated with other psychiatric morbidity. METHODS: Linked datasets of the Scottish Morbidity Record and Scottish death records were used to follow up, into young adulthood, a birth cohort of 897,685. In addition to the index maternity records, mothers' subsequent pregnancy records were identified, allowing family size to be estimated. Three independent outcomes were studied: suicide, self-harm, and psychiatric hospital admission. Data were analysed using Cox regression. RESULTS: Younger maternal age and higher maternal parity were independently associated with increased risk in offspring of suicide, of self-harm and of psychiatric admission. Risk of psychiatric admission was higher amongst those from families of three or more, but, compared with only children, those with two or three siblings had a lower risk of self harm. CONCLUSION: Perinatal and family composition factors have a broad influence on mental health outcomes. These data suggest that the existence of younger, as well as elder siblings may be important.

The role of echocardiography in the management of patients supported by extracorporeal membrane oxygenation.

Extracorporeal life support can be viewed as a spectrum of modalities based on modifications of a cardiopulmonary bypass circuit to provide cardiac and respiratory support, which can be used for extended periods, from hours to several weeks. Extracorporeal membrane oxygenation (ECMO) is among the most frequently used forms of extracorporeal life support. It can be configured for venovenous blood flow, to provide adequate oxygenation and carbon dioxide removal in isolated refractory respiratory failure, or in a venoarterial configuration, when support is required for cardiac and/or respiratory failure. Echocardiography plays a fundamental role throughout the entire journey of a patient supported on ECMO. It provides information that assists in patient selection, guides the insertion and placement of cannulas, monitors progress, detects complications, and helps in determining cardiac recovery and the weaning of ECMO support. Although there are extensive published data regarding ECMO, particularly in the pediatric population, there is a paucity of data outlining the role of echocardiography in guiding the management of adult patients supported by ECMO. ECMO is likely to become an increasingly used form of cardiorespiratory support within the critical care setting. Hence, clinicians and sonographers who work within echocardiography departments at institutions with ECMO programs require specific skills to image these patients.

Extended transsternal thymectomy.

The two primary indications for thymectomy are the treatments of patients with thymoma and patients with myasthenia gravis. Several different methods have been described to remove the thymus gland, including transcervical-transsternal "maximal" thymectomy, extended transsternal thymectomy, classic transsternal thymectomy, (extended) transcervical thymectomy, and video-assisted thoracoscopic thymectomy. The purpose of this article is to focus on the technical aspects of performing an extended transsternal thymectomy and the published results of extended transsternal thymectomy as compared with other techniques available.

A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro.

Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small-cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then reimplanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared with normal lung, primary tumors, xenografts, and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture and that was not regained when the tumors were reestablished as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development.

Daily regulation of serum and urinary hepcidin is not influenced by submaximal cycling exercise in humans with normal iron metabolism.

Hepcidin and hemojuvelin (HJV) are two critical regulators of iron metabolism as indicated by the development of major iron overload associated to mutations in hepcidin and HJV genes. Hepcidin and HJV are highly expressed in liver and muscles, respectively. Intensive muscular exercise has been reported to modify serum iron parameters and to increase hepcidinuria. The present study aimed at evaluating the potential impact of low intensity muscle exercise on iron metabolism and on hepcidin, its key regulator. Fourteen normal volunteers underwent submaximal cycling-based exercise in a crossover design and various iron parameters, including serum and urinary hepcidin, were serially studied. The results demonstrated that submaximal ergocycle endurance exercise did not modulate hepcidin. This study also indicated that hepcidinuria did not show any daily variation whereas serum hepcidin did. The findings, by demonstrating that hepcidin concentrations are not influenced by submaximal cycling exercise, may have implications for hepcidin sampling in medical practice.

Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer.

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.

A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing.

Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.

Developmental signalling pathways in lung cancer.

Hedgehog, Notch and Wnt signalling are all essential for axial patterning and progenitor cell fates in signalling pathways conserved from flies to humans. Aberrant activation of these pathways is observed in a wide variety of cancers, suggesting that these embryonic signalling pathways contribute in a fundamental way to the evolution and maintenance of a malignant phenotype. Because all three of these pathways participate in lung development, recent studies have begun to explore the connection between lung development, airway epithelial repair and lung cancer. Development, repair and malignant transformation of the neuroendocrine lineage are all accompanied by aberrant Hedgehog pathway activation, whereas Notch and Wnt signalling may be important in other airway cell types. Small molecule targeting of these pathways may provide therapeutic opportunities in lung cancer. The plant-derived alkaloid cyclopamine is a naturally occurring Hedgehog pathway inhibitor that shows therapeutic promise in small cell lung cancer, a highly aggressive neuroendocrine tumour. A more detailed understanding of how embryonic signalling pathways participate in airway epithelial repair and tumourigenesis may reveal more novel therapeutic vulnerabilities in lung cancer.