Chagas disease in the immunosuppressed patient.

This review addresses relevant aspects of Chagas disease in the immunocompromised host. Chagas disease--one of the world's most neglected diseases-has become a global public health concern. Novel transmission modalities, such as organ transplantation, evidence of parasite persistence in chronically infected individuals--with the potential for reactivation under immunosuppression--and the prolonged survival of immunosuppressed patients call for an appraisal of the disease in this particular setting. The management and outcome of solid organ transplantation in the infected recipient with special focus on heart transplantation is addressed. The guidelines for management and the outcome of the recipients of organs from infected donors are discussed, and comments on haematopoietic stem cell transplantation are included. Finally, Chagas disease in other situations of impairment of the immune system, such as HIV/AIDS and autoimmune diseases, are considered. Immunosuppression has become an increasingly frequent condition that might modify the natural history of Trypanosoma cruzi infection. A number of strategies are available for Chagas disease management in the immunosuppressed patient. First, according to recent recommendations from the health authorities in Argentina, most infected patients would benefit from being treated at diagnosis. This has not been validated for patients with different immunosuppressive disorders. A different strategy would involve treating only patients with documented reactivation (either parasitaemia or clinical manifestations). These different approaches are discussed. To reach a diagnosis of parasitaemia, monitoring is essential, either with conventional methods or with molecular techniques that are not yet available in all centres. Collaborative studies are needed to improve the level of evidence, which will allow for better guidelines.

Early molecular diagnosis of acute Chagas disease after transplantation with organs from Trypanosoma cruzi-infected donors.

Organ transplantation (TX) is a novel transmission modality of Chagas disease. The results of molecular diagnosis and characterization of Trypanosoma cruzi acute infection in naïve TX recipients transplanted with organs from infected deceased donors are reported. Peripheral blood and cerebrospinal fluid samples from the TX recipients of organs from infected donors were prospectively and sequentially studied for detection of T. cruzi by means of kinetoplastid DNA polymerase chain reaction (kDNA-PCR). In positive blood samples, a PCR algorithm for identification of T. cruzi Discrete Typing Units (DTUs) and quantitative real-time PCR (qPCR) to quantify parasitic loads were performed. Minicircle signatures of T. cruzi infecting populations were also analyzed using restriction fragment length polymorphism (RFLP)-PCR. Eight seronegative TX recipients from four infected donors were studied. In five, the infection was detected at 68.4 days post-TX (36-98 days). In one case, it was transmitted to two of three TX recipients. The comparison of the minicircle signatures revealed nearly identical RFLP-PCR profiles, confirming a common source of infection. The five cases were infected by DTU TcV. This report reveals the relevance of systematic monitoring of TX recipients using PCR strategies in order to provide an early diagnosis allowing timely anti-trypanosomal treatment.

Trypanosoma cruzi discrete typing units in Chagas disease patients from endemic and non-endemic regions of Argentina.

Genetic diversity of Trypanosoma cruzi may play a role in pathogenesis of Chagas disease forms. Natural populations are classified into 6 Discrete Typing Units (DTUs) Tc I-VI with taxonomical status. This study aimed to identify T. cruzi DTUs in bloodstream and tissue samples of Argentinean patients with Chagas disease. PCR-based strategies allowed DTU identification in 256 clinical samples from 239 Argentinean patients. Tc V prevailed in blood from both asymptomatic and symptomatic cases and Tc I was more frequent in bloodstream, cardiac tissues and chagoma samples from immunosuppressed patients. Tc II and VI were identified in a minority of cases, while Tc III and Tc IV were not detected in the studied population. Interestingly, Tc I and Tc II/VI sequences were amplified from the same skin biopsy slice from a kidney transplant patient suffering Chagas disease reactivation. Further data also revealed the occurrence of mixed DTU populations in the human chronic infection. In conclusion, our findings provide evidence of the complexity of the dynamics of T. cruzi diversity in the natural history of human Chagas disease and allege the pathogenic role of DTUs I, II, V and VI in the studied population.

Pandemic influenza A/H1N1 and organ donation.

One of the concerns regarding the pandemic of novel influenza A/H1N1 virus is its potential to hamper transplant programs if the decision is made that organs from donors with influenza A/H1N1 should not be used. Evidence of transmissibility through organ transplantation is speculative at best. We report the outcome of 2 kidney transplant recipients who received kidneys from the same deceased donor, in whom the diagnosis of infection by the novel virus became available only after engraftment. The donor also had received a complete course of antiviral treatment before donation. The recipients were transplanted at 2 different facilities and were managed differently. Neither recipient developed flu syndrome, and both had an uneventful outcome. It is possible to speculate that kidneys from donors who have had confirmed influenza A/H1N1 and who have received antiviral treatment can be safely used in transplantation.

Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study.

OBJECTIVE: To analyze risk factors for Pneumocystis carinii pneumonia (PCP) in kidney transplant recipients. STUDY DESIGN: In a case-control study, 17 PCP cases diagnosed between July 1994 and July 2000 were matched with two controls each (previous and subsequent kidney transplant recipients who did not develop PCP during the same follow-up period). Demographics, organ origin, human leukocyte antigen (HLA) mismatches, use of poly- or monoclonal anti-CD3 antibodies (Po/MoAb) for induction or rejection treatment, rejection episodes, cumulative steroid dose for rejection treatment, immunosuppressive regimens, and other infections were analyzed. RESULTS: No significant differences were seen in gender (male 10 vs. 15), mean age (39.7 vs. 35.4 years), organ origin (cadaver donor 13 vs. 19), HLA mismatches, or Po/MoAb use in induction treatment. Significant differences were observed in PCP cases for rejection history (P=0.02), and median and total number of rejection episodes (P=0.0018). The relative risks for PCP for 1, 2, and > or =3 rejection treatments vs. no such treatment were 1, 1.05, and 6.30, respectively (P=0.021). The relative risk for PCP for steroid-resistant rejection was 4.34 (95% confidence interval [CI], 1.04-18.89) (P=0.019), and that for the use of Po/MoAb for rejection treatment was 7.23 (95% CI, 1.28-49.34) (P=0.006). The relative risk for PCP for 0, 1, and > or =2 previous or concomitant cytomegalovirus (CMV) infection vs. no such infections were 1.0, 2.32, and 13.0, respectively (P=0.012). The relative risks for PCP for tuberculosis (TB) was 18 (95% CI, 1.76-852.03), that for bacterial pneumonia was 14.22 (95% CI, 2.16-150.23), and that for hepatitis C virus infection was 5.25 (95% CI, 1.03-28.91). Immunosuppressive regimens with tacrolimus, mycophenolate mofetil (MMF), steroids (P=0.06), and MMF as a single variable (P=0.05) were more frequently used in cases. Primary trimethoprim-sulfamethoxazole prophylaxis failure was observed in 12 patients in association with heavy immunosuppression and concomitant infections. CONCLUSIONS: The risk of PCP in kidney transplant recipients is related to the number and type of rejection treatments. It is also related to the occurrence of CMV infection, and to other immunomodulating infections such as TB and hepatitis C, and might also be increased with the use of newer and more potent immunosuppressive agents. Primary prophylaxis failure may occur in association with some of these risk factors.

Tuberculosis in renal transplant recipients.

Tuberculosis (TB) has been described in kidney transplant recipients as an infection with predominantly pulmonary involvement. We report the impact of TB in kidney transplantation. Clinical records of adult kidney recipients, transplanted between 1 January 1986 and 31 December 1995 were analyzed for sex, age, graft origin, immunosuppressive therapy, TB sites, diagnostic methods and concomitant infections. Annual incidence, mean time of onset, relation to rejection treatment, tuberculin skin test (PPD) and outcome were analyzed. Patients with a history of TB or graft loss in the first month were excluded. TB was diagnosed in 14 of 384 (3.64%). Mean age at transplantation was 35 years. Twelve of these received the graft from a living donor. All had triple immunosuppression with cyclosporine. Ten had pulmonary TB, three extrapulmonary infection and one disseminated disease. In 13 cases an invasive diagnostic procedure was performed. Mycobacterium tuberculosis cultures were positive in all cases; microscopy revealed acid-fast bacilli (AFB) in 6, and adenosine deaminase was elevated in CSF and pleural effusion in 2. Annual incidence varied from 0% to 3.1%. At the time of TB presentation 8 patients had other concomitant infections (cytomegalovirus, nocardia, Pneumocystis carinii, disseminated herpes simplex virus). Median time of onset was 13 months. Diagnostic results became available post-mortem in 2 cases, and one had TB in a failing allograft. TB was treated with 4 drugs including rifampin in 10 patients. Cyclosporine was discontinued in one, lowered in one and increased in 8. During treatment 5 patients had rejection episodes. At 1 year, graft survival was 72.7% and patient survival 90.9%. TB was more prevalent when recipient and donor were both PPD positive. In summary: although TB is a growing threat in the transplant setting, early and aggressive diagnosis with meticulous monitoring of immunosuppression allows a successful outcome for both patient and graft. Optimal prophylaxis guidelines have yet to be completely defined.

Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer.

During the past two decades we have witnessed the identification of an expanding list of immunohistochemical and molecular markers linked to histopathologically defined subtypes of tumors. These markers offer new insights and approaches to the classification of tumors with important prognostic and/or therapeutic implications. We review the potentially diagnostic immunohistochemical and molecular markers of soft tissue tumors (STTs). The immunohistochemical markers reviewed include vimentin, cytokeratin, desmin, HHF35, S100, myoD1, alpha1-antitrypsin, vascular markers (factor VIII, CD31, CD34), MIC2, and others. The potentially diagnostic chromosomal translocations and associated genes identified in STT include Ewing's/PNET t(11;22)(q24;q12)(FLI1;EWS), t(21;22)(q22;q12)(ERG; EWS); t(7;22)(p22;q12)(ETV1;EWS); desmoplastic small round cell tumor t(11;22)(p13;q12)(WT1;EWS); extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) (TEC(CHN);EWS); malignant ectomesenchymoma t(11;22)(q24;q12)(FLI1;EWS); alveolar rhabdomyosarcoma t(2;13)(q35;q14)(PAX-3;FKHR); t(1;13) (p36;q14)(PAX-7;FKHR); myxoid and round cell liposarcoma t(12;16)(q13;p11)(CHOP;TLS(FUS)); synovial sarcoma t(X;18)(p11;q11)(SSX1&2;SYT), and others. The nature, utility, and limitations of these markers in diagnostic settings are explored.

Lobular neoplasia. Long term risk of breast cancer and relation to other factors.

BACKGROUND: Lobular neoplasia (LN), also known as lobular carcinoma in situ, is an incidental histologic finding in tissue removed at breast surgery. Patients with LN are known to be predisposed to develop invasive or intraductal carcinoma (CA). This study investigates factors that influence the cancer risk in LN patients. METHODS: Analysis of data concerning long term follow-up (median: 18 yrs) of 236 patients with LN identified in a pathologic review of more than 2000 biopsy specimens with benign epithelial proliferative breast disease. RESULTS: The probability of CA developing in either breast in long term survivors after a biopsy that contained LN was approximately 1/3, which is 5.4 times (95% CI: 4.2 - 7.0) the rate in the general population. The relative risk (RR) tended to decrease with increasing age at diagnosis, but was approximately doubled (RR: 1.8; 95% CI: 1.1-3.2) for patients with benign epithelial breast disease preceding their initial diagnosis of LN. CA risk remained markedly elevated for at least 20 years, and increased substantially if there was a second operation showing LN- from 4.9 (95% CI: 3.7-6.4) after a single operation with LN to 16.1 (95% CI: 6.9-31.8) after a second such operation. CONCLUSIONS: LN is a marker of increased CA risk that is further exacerbated by episodes of preexisting benign breast epithelial proliferative changes, and that remains substantially elevated for many years.

Regression of skin recurrences of breast carcinomas treated with intralesional injections of natural interferons alpha and gamma.

Two groups of patients with disseminated breast carcinomas who had failed radiotherapy, chemotherapy, and hormonotherapy were treated with natural interferon alpha (nIFN-alpha) alone or in combination with nIFN-gamma delivered in cycles of 10-12 intralesional (i.l.) injections to recurrent and metastatic lesions. In group, I, 16 skin lesions in 12 patients received nIFN-alpha alone resulting in 7 complete regressions verified histologically (CR), 7 partial regressions (PR), and no regressions (NR) in 2. Group II included 4 patients in whom 7 cutaneous recurrences were treated with nIFN-alpha/nIFN-gamma (5 CR, 2 PR), 2 were injected with nIFN-alpha alone (1 CR, 1 PR), and 1 received nIFN-gamma alone (PR). Two additional patients in group II were given i.l. injections of nIFN-alpha/nIFN-gamma to lymph node metastases (1 CR, 1 PR). Clinical toxicity was experienced by 5 of 12 patients in group I and by all the patients in group II and was controlled in most instances by antipyretics. Systemic antitumor effects were not appreciable clinically. Nevertheless, noninjected lesions exposed only to systemic levels of IFNs, when studied immunohistochemically, displayed an immunological response similar to that of IFN-injected lesions, although less intense. Therefore, IFNs can be useful in controlling locoregional recurrences of breast cancer even in patients who are not responding to other forms of therapy. Furthermore, in addition to the local antitumor actions, they appear to be capable of eliciting systemic immunological effects.

Reproducibility and validity of pathologic classifications of benign breast disease and implications for clinical applications.

BACKGROUND: Research studies on the relationship between benign breast diseases and cancer risk typically identify certain conditions as risk factors, and others as carrying no prognostic significance. This study addresses several issues concerning the relevance of such research results for advising individual patients in a clinical setting. METHODS: Data were obtained as part of a "blinded" retrospective pathology review of benign breast biopsies. A random sample of cases was reviewed twice, providing information about reliability. Comparisons with diagnoses that used information from the operative reports and gross pathology descriptions as well as microscopic histology were used to assess validity. RESULTS: Among cases that were reviewed twice, excellent agreement was achieved for diagnosing carcinoma and lobular neoplasia, good agreement for adenosis and intraductal papilloma, and relatively poor agreement about levels of hyperplasia and atypia, and whether ducts or lobules were involved. Distinctions among levels of hyperplasia also apparently were influenced by the number of slides available for review. The "blinded" review diagnoses frequently differed from the diagnoses that used all information available at the time of surgery in detecting the presence or absence of gross cystic disease, and in distinguishing solitary from multiple papillomas. CONCLUSIONS: Problems with reliability of precise distinctions among levels and sites of hyperplasia and atypia seem to limit the usefulness of such classifications as guidelines for individual patient care. For conditions with some clinical manifestations, diagnoses based exclusively on histologic review of biopsy specimens often are not accurate.

Prognostic significance of benign proliferative breast disease.

BACKGROUND: Recent studies concerning an association between benign breast diseases and risk of subsequent breast cancer have focused on benign proliferative lesions recognized in biopsy specimens. Some have implicated atypical hyperplasia as being associated with the greatest risk. METHODS: The histologic sections of specified benign breast lesions from 1799 women were reviewed and reclassified, using published criteria for proliferative disease. Prognostic significance was assessed by relating the pathologic findings to the development of breast cancer observed during an average 21 years of follow-up, in which time 157 women developed the disease. RESULTS: Benign proliferative changes were recognized in 85% of the patients, with a corresponding relative risk of subsequent carcinoma equal to 2.2 times population rates (95% confidence limits, 1.9 and 2.6). Increasing levels of hyperplasia and atypia in lobules or ducts were associated with modest increases in risk, ranging from 2.1 to 2.3 to 3.0 for proliferative changes with no atypia, mild atypia, and moderate to severe atypia, respectively. This trend was not statistically significant. The most significant risk indicators in this study were the presence of adenosis (relative risk, 3.7), and moderate or severe atypia in ducts (relative risk, 3.9). CONCLUSIONS: Benign proliferative breast disease recognized in biopsy specimens is associated with an increased risk of future breast cancer, but fine distinctions among levels of hyperplasia and atypia did not significantly distinguish risk among patients in this study.

The epidemiology of gross cystic disease of the breast confirmed by biopsy or by aspiration of cyst fluid.

This study concerns 3443 patients treated by 1 physician for benign breast conditions, with follow-up on 94% of the patients averaging 19 years. Over three quarters of these patients had gross cystic disease (GCD) of the breast confirmed by aspiration of cyst fluid or by biopsy. Diagnosis of GCD by microscopic pathology review alone is shown to have high error rates when compared with information in the operative report and the gross pathology report. The risk of subsequent breast cancer for GCD patients was more than double the rates in the general population, and about the same as that of patients with no GCD who had biopsy findings of benign proliferative disease. Among patients with aspirations for GCD and no biopsy, there was a trend of increasing risk of subsequent breast cancer with increasing numbers of aspirations, with a sixfold relative risk for patients with ten or more aspirations.

Lipoblastic meningioma: "vacuolated meningioma".

This report describes and illustrates seven cases of benign meningeal tumors, including one in the retro-bulbar region of the orbit, which were characterized by vacuolated signet-ring cells. Occasional typical meningothelial areas were also seen; however, the signet-ring cells were the dominant feature. The vacuoles were consistently negative with the various stains for mucin. In one single case in which nonparaffin-embedded tissue was still available, the vacuoles were positive for fat stains. Immunohistochemical stains done in three of the cases showed that the tumor cells were positive for vimentin. S-100 protein was definitely positive in two cases and weakly positive in one. One of the three cases was positive for cytokeratin and another was positive for epithelial membrane antigen. The name "lipoblastic meningioma" appears to be acceptable as a descriptive term, since these tumors are, in our opinion, of definite meningeal origin, probably representing a predominantly mesenchymal (lipocytic) differentiation of the arachnoidal cells. This term, however, does not imply a clinical behavior analogous to that of true liposarcoma. In fact, these tumors have consistently behaved as benign local problems, analogous to the biologic course of ordinary meningioma.

Percutaneous transluminal aortic angioplasty: techniques and results.

Percutaneous transluminal angioplasty of the infrarenal abdominal aorta has been reported by a few authors. In the present series, aortic stenoses in 32 patients were treated with various percutaneous angioplasty techniques. Isolated aortic stenoses and primary aortic stenoses extending into the iliac arteries were successfully dilated. The initial success rate was 100%, without evidence of rupture, thrombosis, dissection, or distal embolization. In only three of the 28 patients who returned for follow-up did symptoms recur or noninvasive vascular laboratory indexes deteriorate (mean follow-up, 25 months). Percutaneous transluminal aortic angioplasty has proved safe and efficacious in the treatment of atherosclerotic aortic stenoses.

Cystosarcoma phyllodes. Report of an unusual case, with death due to intraneural extension to the central nervous system.

Cystosarcoma phyllodes tumors of the breast occasionally exhibit malignant behavior, including chest wall invasion, hematogenous spread or, rarely, metastasis by lymphatic routes. An unusual case of cystosarcoma is presented in which death was apparently caused by perineural and intraneural extension of the tumor along intercostal nerves, to the sympathetic chain, and then to the brain stem by spinal roots, with no evidence of embolic metastasis.