Elizabeth C. Burton

Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development.

The Vanishing Nonforensic Autopsy

Despite the benefits of autopsies, they are performed after less than 10% of all deaths in the United States. Drs. Kaveh Shojania and Elizabeth Burton discuss the trends in U.S. autopsy rates.

Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation

TSLP released from human breast cancer cells promotes OX40L expression on DCs, and these OX40L-expressing DCs drive development of inflammatory Th2 cells which promote breast tumor development.

Intravascular thrombosis and thromboembolism during liver transplantation: antifibrinolytic therapy implicated?

This case report describes a patient who underwent orthotopic liver transplantation and developed extensive hyperacute venous and arterial intravascular thromboses and thromboemboli intraoperatively. The patient was receiving antifibrinolytic therapy with aprotinin. The safety of routine aprotinin therapy in liver transplantation is examined. The value of the thrombelastograph (TEG) as a qualitative assessment of the coagulation system is emphasized. (Liver Transpl 2004;10:310–314.)

Overestimation of clinical diagnostic performance caused by low necropsy rates

Background: Diagnostic sensitivity is calculated as the number of correct diagnoses divided by the sum of correct diagnoses plus the number of missed or false negative diagnoses. Because missed diagnoses are generally detected during clinical follow up or at necropsy, the low necropsy rates seen in current practice may result in overestimates of diagnostic performance. Using three target conditions (aortic dissection, pulmonary embolism, and active tuberculosis), the prevalence of clinically missed cases among necropsied and non-necropsied deaths was estimated and the impact of low necropsy rates on the apparent sensitivity of antemortem diagnosis determined. Methods: After reviewing case series for each target condition, the most recent study that included cases first detected at necropsy was selected and the reported sensitivity of clinical diagnosis adjusted by estimating the total number of cases that would have been detected had all decedents undergone necropsy. These estimates were based on available data for necropsy rates, time period, country (US v non-US), and case mix. Results: For all three target diagnoses, adjusting for the estimated prevalence of clinically missed cases among non-necropsied deaths produced sensitivity values outside the 95% confidence interval for the originally reported values, and well below sensitivities reported for the diagnostic tests that are usually used to detect these conditions. For active tuberculosis the sensitivity of antemortem diagnosis decreased from an apparent value of 96% to a corrected value of 83%, with a plausible range of 42–91%; for aortic dissection the sensitivity decreased from 86% to 74%; and for pulmonary embolism the reduction fell only modestly from 97% to 91% but was still lower than generally reported values of 98% or more. Conclusions: Failure to adjust for the prevalence of missed cases among non-necropsied deaths may substantially overstate the performance of diagnostic tests and antemortem diagnosis in general, especially for conditions with high early case fatality.

The Autopsy: A Professional Responsibility in Assuring Quality of Care

Forty years ago, the value of autopsies was widely recognized as new diseases were discovered or clarified and scientific technology advanced greatly. Despite the autopsys strong foundation, its value is not currently being properly conveyed to physicians or patients. Although autopsy-related policy exists, these policies have had little effect on increasing or even maintaining adequate autopsy rates. More recently, the autopsy has fallen on hard times, with US hospital rates now below 5%. The reasons for the decline in rates are multifaceted and include a lack of direct reimbursement for the procedure, lack of defined minimum rate standards, overconfidence in diagnostic technology, and the fear of litigation. Regardless of the reasons for the declining rates, the ethical and professional reasons for increasing the number of autopsies are far more important.

Pulmonary invasive mucormycosis in a patient with secondary iron overload following deferoxamine therapy.

Mucormycosis (zygomycosis) is an acute and often fatal opportunistic fungal infection. Predisposing factors in the development of mucormycosis are nonspecific and include hyperglycemia, hematologic malignancies, neutropenia, pharmacologic immunosuppression, solid organ or bone marrow/stem cell transplantation, burns, trauma, malnutrition, and intravenous drug use. Mucormycosis has also been described in patients with iron and aluminum overload, patients on dialysis, and patients receiving iron chelating therapy. We describe a 75-year-old man with myelodysplastic syndrome and iron overload secondary to multiple red blood cell transfusions who had been treated with deferoxamine chelation therapy. He was admitted to the hospital for atrial fibrillation, developed multiple organ failure, and died. Pulmonary invasive mucormycosis was demonstrated at autopsy. This case further documents an association between invasive mucormycosis, iron overload, and deferoxamine therapy.

Full Blown Cardiovascular Syphilis with Aneurysm of the Innominate Artery

The investigators report the case of a 44-year-old man who presented acutely and was found to have saccular aneurysm of the innominate artery, narrowed or totally occluded aortic arch arteries, and marked thickening of the thoracic aorta except for the wall behind the sinuses of Valsalva. The abdominal aorta was entirely normal. Results of the serologic test for syphilis were strongly positive. Because cardiovascular syphilis appears to be a disease that affects the vasa vasora and because these channels are limited to the thoracic aorta, the abdominal aorta is uninvolved, as demonstrated so nicely in the patient described in this case report. Because most patients with cardiovascular syphilis are much older than the patient described, it is unusual to see a perfectly normal abdominal aorta, as in the present patient. In conclusion, syphilis producing aneurysm of the innominate artery is unusual but is always associated with syphilitic involvement of the thoracic aorta.

Carcinoid Heart Disease Without the Carcinoid Syndrome but With Quadrivalvular Regurgitation and Unsuccessful Operative Intervention

A 53-year-old woman is described who underwent mitral and aortic valve replacement and tricuspid valve annuloplasty for pure regurgitation at all 3 valve sites for unrecognized carcinoid heart disease without the carcinoid syndrome 22 days before death. Metastatic carcinoid was not recognized until necropsy, which disclosed a probable ovarian primary but with large hepatic metastases and left-sided cardiac involvement either greater than or equal to the right-sided involvement. Pulmonary hypertension, very unusual in carcinoid heart disease, persisted postoperatively and probably played a role in the patients early death. Hepatic metastasis with ovarian primary is most unusual in this circumstance.

Diagnosing cardiac sarcoidosis clinically without tissue confirmation

A 52-year-old woman is described in whom cardiac sarcoidosis was diagnosed clinically on the basis of high-grade heart block, recurring ventricular tachyarrhythmias, and acute cardiac decompensation. Confirmation of sarcoidosis was not determined until necropsy. When it causes cardiac dysfunction, sarcoidosis rarely causes dysfunction of another body organ, although small sarcoid granulomas may also be present in noncardiac organs or tissues. In the present patient, neurosarcoidosis accompanied the cardiac sarcoidosis, but it was the latter that produced the life-threatening symptoms and was fatal.