Necrosis pulmonar masiva por micosis / Massive pulmonary necrosis due to mycosis

Introducción: La aspergilosis es una infección micótica oportunista que se presenta fundamentalmente en pacientes inmunodeprimidos y su principal fuente de transmisión lo constituyen las esporas presentes en el aire de salones de operaciones y unidades de cuidados intensivos. Objetivo: Presentar un caso de una micosis pulmonar masiva por una variante angioinvasiva de Aspergillus. Caso clínico: Se presenta un paciente con aspergilosis pulmonar grave, diagnosticada después de la resección de un tumor mediastinal. Se describen las características de la primera intervención, la evolución postoperatoria que condujo a la segunda, se muestran las imágenes tomográficas, quirúrgicas, microbiológicas y anátomo-patológicas que permitieron definir el diagnóstico. Conclusiones: La posibilidad de una micosis pulmonar debe tenerse en cuenta, aun cuando sea una afección rara y de manejo difícil, en pacientes inmunodeprimidos, con condensación pulmonar rebelde al tratamiento(AU)

Introduction: Aspergillosis is an opportunistic fungal infection that occurs mainly in immunosuppressed patients and its main source of transmission is the spores present in the air of operating rooms and intensive care units. Objective: To present a case of a massive pulmonary mycosis due to an angioinvasive variant of Aspergillus. Clinical case: A patient with severe pulmonary aspergillosis, diagnosed after resection of a mediastinal tumor, is presented. The characteristics of the first intervention are described, the postoperative evolution that led to the second one, the tomographic, surgical, microbiological and anatomo-pathological images that allowed to define the diagnosis are shown. Conclusions: The possibility of a pulmonary mycosis should be taken into account, even when it is a rare and difficult-to-handle condition, in immunocompromised patients, with pulmonary condensation that is rebellious to treatment. Aspergillosis is an opportunistic fungal infection that occurs mainly in immunosuppressed patients and its main source of transmission is the spores present in the air of operating rooms and intensive care units(AU)

Other Rare Sinonasal Malignant Tumours Involving the Anterior Skull Base.

Sinonasal tumours are rare, and among these there exist a small number of histologic subtypes that are infrequently encountered and rarely mentioned in the literature. These have been presented as either case reports or small case series, and their very low incidence makes prospective studies practically impossible. This review analyses the available literature, including our own experience and endeavours to outline management strategies, which involve a high index of suspicion and counselling of patients. In most instances, these tumours require aggressive multimodal treatment to improve survival outcomes. The overall prognosis remains dismal.

Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site.

Bispecific antibodies are proteins that bind two different antigens and may retarget immune cells with a binding moiety specific for a leukocyte marker. A binding event in blood could in principle prevent antibody extravasation and accumulation at the site of disease. In this study, we produced and characterized two tetravalent bispecific antibodies that bind with high affinity to the alternatively-spliced EDB domain of fibronectin, a tumor-associated antigen. The bispecific antibodies simultaneously engaged the cognate antigens (murine T cell co-receptor CD3 and hen egg lysozyme) and selectively accumulated on murine tumors in vivo. The results, which were in agreement with predictions based on pharmacokinetic modeling and antibody binding characteristics, confirmed that bispecific antibodies can reach abluminal targets without being blocked by peripheral blood leukocytes.

Targeted tumor therapy with a fusion protein of an antiangiogenic human recombinant scFv and yeast cytosine deaminase.

In adults, endothelial cell division occurs only in wound healing, during menstruation, or in diseases such as wet age-related macular degeneration or development of benign or malignant tissues. Angiogenesis is one of the major requirements to supply the fast developing tumor tissue with oxygen and nutrients, and enables it to spread into other tissues far from its origin. We selected the extradomain B (ED-B), a splice variant of fibronectin, which is exclusively expressed in ovaries, uterus, during wound healing, and in tumor tissues, as a target for the development of an innovative antiangiogenic, prodrug-based targeted tumor therapy approach. We designed a fusion protein termed L19CDy-His, consisting of the antibody single chain fragment L19 for targeting ED-B and yeast cytosine deaminase for the conversion of 5-fluorocytosine into cytotoxic 5-fluorouracil. We purified high amounts of the fusion protein from Pichia pastoris that is stable, enzymatically active, and retains 75% of its activity after incubation with human plasma for up to 72 hours. The binding of L19CDy-His to ED-B was confirmed by an enzyme-linked immunosorbent assay and quantified by surface plasmon resonance spectroscopy determining a KD value of 81±7 nM. L19CDy-His successfully decreased cell survival of the murine ED-B-expressing teratocarcinoma cell line F9 upon addition of the prodrug 5-fluorocytosine. Our data demonstrate the suitability of targeting ED-B by L19CDy-His for effective prodrug-based tumor therapy.

Suppression of teratocarcinoma growth by soluble TRAIL gene expression driven by the progression-elevated gene-3 promoter.

A plasmid expressing the soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligand, sTRAIL (amino acids 114-281 of TRAIL), driven by rat progression-elevated gene-3 (rPEG) promoter was constructed and evaluated. Transfection of embryonal carcinoma (EC) cells with the plasmid resulted in significant cellular apoptosis and elevated expression of death receptor 4 (DR4) and death receptor 5 (DR5). Direct intratumoral injection of DNA:liposome complexes suppressed tumor growth significantly and prolonged the survival of teratocarcinoma-bearing mice. Histological examination and serum analyses showed the absence of detectable toxicity in all examined tissues, including liver. Our results demonstrate that sTRAIL gene expression driven by the rPEG promoter may enable effective gene therapy against teratocarcinoma.

Chemotherapy-induced neuronal maturation in sinonasal teratocarcinosarcoma--a unique observation.

Sinonasal teratocarcinosarcoma (SNTCS) is a rare and highly malignant tumour with combined features of a teratoma and carcinosarcoma. We report the first case of a SNTCS in 23 year old male treated with neo-adjuvant chemotherapy followed by cranio-facial resection. The resection specimen displayed cellular maturation in the neuroectodermal component. The patient presented with a short history of nasal obstruction, epistaxis and headache. On imaging, a bone destroying lesion of left paranasal sinuses and nasal cavity was identified. The diagnosis of SNTCS could be offered only on the third biopsy which showed heterogeneous admixture of primitive neuroectodermal, epithelial and mesenchymal elements. An adequate sampling with high index of suspicion is needed to catch hold this rare tumor. Tumor was excised after 4 cycles of neo-adjuvant chemotherapy. On microscopic examination, it showed similar epithelial and mesenchymal components as the pretreatment biopsies. However, the primitive neuroectodermal component displayed extensive neuronal maturation. The undifferentiated neuroectodermal cells were completely absent in the post chemotherapy specimen. This case throws light on the morphologic evidence of chemotherapy induced maturation in the neuroectodermal component within SNTCS, an event hitherto not reported in the literature in case of SNTCS.

Teratocarcinosarcoma rinosinusal: reporte de un caso / Rhinosinusal teratocarcinosarcoma: a case report

Teratocarcinosarcoma rinosinusal es una neoplasia maligna infrecuente y rara, que combina elementos de teratoma y carcinosarcoma. Se compone de epitelio benigno o maligno (fibroblastos), mesénquima (cartílago, hueso o músculo liso) y elementos neurales. Hasta el año 2008 se han reportado un total de 63 casos de ubicación rinosinusal. Presentamos el caso de un teratocarcinosarcoma de fosa nasal, en un hombre de 67 años de edad, que consultó por obstrucción nasal rápidamente progresiva. La lesión se resecó completamente por abordaje endoscópico. El diagnóstico fue confirmado por histopatología e inmunohistoquímica. Se realizó tratamiento complementario con radioterapia, sin evidencia de recidiva al año después de la cirugía.

Rhinosinusal teratocarcinosarcoma is a rare malignant neoplasm, which combines teratoma and carcinoma elements. It is composed of benign or malignant epithelium (fibroblasts), mesenchymatic (cartilage, bone or smooth muscle) and neural elements. Until 2008, a total of 63 cases of rhinosinusal location have been reponed. We present the case of a nasal cavity teratocarcinosarcoma ín a 67 year old man that presented with rapidly progressing nasal obstruction. The lesion was completely resected by endoscopic approach. Diagnosis was confirmed by histological pathology and immunohistochemistry Additional treatment by radiotherapy was administered, with no evidence of recurrences a year after surgery.

Sinonasal teratocarcinosarcoma of the head and neck: a report of 10 patients treated at a single institution and comparison with reported series.

OBJECTIVES: To present the clinicopathologic features of 10 sinonasal teratocarcinosarcomas managed at a single center. Teratocarcinosarcoma is a rare morphologically heterogeneous and highly malignant neoplasm. Previous reports of these tumors have focused on their differential diagnosis and histogenesis and consisted of individual case reports and consultation based series. DESIGN: Review of patient medical records and microscopic slides of all tumor tissues. The histopathologic features for each tumor and the demographic, clinical, treatment, and follow-up information were recorded for each patient. Also, a comparison with previously reported series was performed. SETTING: The University of Texas M. D. Anderson Cancer Center. PATIENTS: Ten men ranging in age from 35 to 69 years (mean age, 53 years) were included in the study. They all experienced a short course of symptoms, with an average duration of 3.5 months, and 9 presented with nasal obstruction and epistaxis. Nine patients were treated with both surgery and irradiation. RESULTS: Histologically, the tumors showed primitive neuroepithelial elements and various malignant epithelial and mesenchymal components. Six patients had no evidence of disease by the end of follow-up, which ranged from 72 to 372 months. Three patients died of disease, and 1 patient was lost to follow-up. CONCLUSION: Sinonasal teratocarcinosarcoma of the head and neck is a histologically and biologically heterogeneous malignant neoplasm that is best managed with surgery and postoperative radiotherapy.

Evaluation of anti-VEGFR-3 specific scFv antibodies as potential therapeutic and diagnostic tools for tumor lymph-angiogenesis.

Vascular endothelial growth factor receptor-3 (VEGFR-3) plays a major role in lymph-angiogenesis, tumor growth and metastatic tumor cell dissemination. The receptor is over-expressed on lymphatic vessels in the vicinity of tumors and on the tumor vasculature and therefore may be an excellent target for an effective cancer intervention. We generated and characterized single chain antibody fragments (scFv) recognizing VEGFR-3 by phage display technology and expression in P. pastoris and analyzed selected antibodies in vitro and in vivo. The scFvs were functionalized by the introduction of cysteines at the C-terminal end of the proteins. The scFvs are species cross-specific and bind to recombinant human and mouse VEGFR-3. ScFv AFC5 showed specific tumor accumulation in an hVEGFR-3 expressing F9 terato-carcinoma mouse model, which was also used for tumor visualization by combined single proton emission computed tomography (SPECT/CT) and immunohistochemical analysis. This antibody also inhibited binding of hVEGF-C to its receptor and reduced proliferation of human lymphatic endothelial cells. Thus, the generated VEGFR-3 specific scFv antibodies represent a valuable tool for novel cancer therapies and diagnostic applications.

The antibody-mediated targeted delivery of interleukin-15 and GM-CSF to the tumor neovasculature inhibits tumor growth and metastasis.

Tumor-targeting immunocytokines represent a new class of anticancer pharmaceutical agents, which often display a superior therapeutic index compared with the corresponding unconjugated cytokines. In this article, we have studied the anticancer properties of interleukin-15 (IL-15) and granulocyte macrophage colony-stimulating factor (GM-CSF), fused to the human antibody fragment scFv(L19), specific to the EDB domain of fibronectin, a marker of angiogenesis. The immunocytokines L19-IL-15 and L19-GM-CSF were expressed in mammalian cells and purified to homogeneity, revealing no loss of cytokine activity in in vitro assays. Furthermore, the ability of the two immunocytokines to selectively localize to tumors in vivo was confirmed by biodistribution analysis with radioiodinated protein preparations. L19-IL-15 and L19-GM-CSF displayed a potent antitumor activity both in s.c. and in metastatic F9 and C51 murine models of cancer in immunocompetent mice. This therapeutic action was superior compared with IL-15-based and GM-CSF-based fusion proteins, containing antibodies of irrelevant specificity in the mouse, which were used as non-tumor-targeting controls. For both L19-IL-15 and L19-GM-CSF immunocytokines, CD8(+) T cells seemed to mostly contribute to the therapeutic action as shown by in vivo cell depletion experiments. The results presented in this article are of clinical significance, considering the fact that the sequence of EDB is identical in mouse and man and that the tumor-targeting ability of the L19 antibody has been extensively shown in clinical trials in patients with cancer.

Cervical mature teratoma 17 years after initial treatment of testicular teratocarcinoma: report of a late relapse.

BACKGROUND: Late relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma. CASE PRESENTATION: A 20-year-old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma. CONCLUSION: This is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life.

Potential gene therapy strategies for cancer stem cells.

To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.

Pharyngeal teratocarcinosarcoma: review of the literature and report of two cases.

Teratocarcinosarcomas are rare malignant neoplasms histologically characterized by the presence of benign and malignant epithelial and mesenchymal elements. They are seen almost exclusively in the sinonasal tract of men. We report two cases of teratocarcinosarcomas involving the posterior pharyngeal wall in a 55-year-old male and 60-year-old men. The tumors consisted of epithelial components including squamous, neuroendocrine, and glandular structures; neuroepithelium, and mesenchymal components with prominent rhabdomyoblastic, osteoblastic and chondroid differentiation. Immunohistochemical studies demonstrated markers characteristic of each component. The tumors were resected, and the patients received postoperative radiation therapy. One patient is alive with recurrent tumor 33 months after treatment and the other died 26 months after radiation therapy with distant metastasis.

Cytotoxicity of a novel fibroblast growth factor receptor targeted immunotoxin on a human ovarian teratocarcinoma cell line.

Basic fibroblast growth factor (bFGF) is an important tumor-associated growth factor that contributes to proliferation and angiogenesis of tumor. The high-affinity receptor for bFGF, fibroblast growth factor receptor (FGFR), is found to be overexpressed in a number of tumor cells. For the purpose of exploring the significance of bFGF/FGFR in tumor-targeted therapy, a recombinant immunotoxin contained the N-terminal 389 residues of diphtheria toxin (DT), and the full length of human bFGF was designed, expressed, and purified. The bioactivity of the product was evaluated by testing the cytotoxicity on PA-1 cells (a human ovarian teratocarcinoma cell line with high-level expression of FGFR) in vitro. The immunotoxin showed a significant cytotoxicity on PA-1 cells (IC(50) 8 - 9 ng/mL), and this effect could be antagonized by equine diphtheria antitoxin (DAT), bFGF, anti-bFGF monoclonal antibody (MAb), and anti- FGFR polyclonal antibody (PAb), respectively. Additionally, Chinese hamster ovary (CHO) cells and Hep-2 cells (a human epidermoid laryngocarcinoma cell line) with low expression of FGFR were tested to be resistant to the immunotoxin. The results indicated that FGFR might be an effective target for tumor therapy, and bFGF-mediated immunotoxin could be a potential candidate in the treatment of cancer.

Of mice and men: teratomas and teratocarcinomas.

Teratomas and teratocarcinomas are tumors containing tissue derivatives of all three germ-layers. They can be induced by transplantation of animal embryos to ectopic microenvironment. Development of malignant teratocarcinomas depends on embryonic stage, species-specificity and immunological competence of the host. In the man, teratomas and teratocarcinomas usually represent a subtype of germ-cell tumors but sacrococcygeal teratomas arise from the remnants of the pluripotent primitive streak. Undifferentiated embryonal carcinoma (EC) cells are responsible for the malignancy of experimental mouse teratocarcinomas. Mouse EC cells injected to the adult give rise to tumors and upon injection to early embryos to differentiated tissues--thus resembling normal mouse embryonic stem cells (mESC). Epigenetic changes rather than mutations are associated with transformation of mESC to EC cells. Human EC and ES cell-lines (hESC) contain chromosomal abnormalities and can form teratocarcinoma after transplantation. ES cells are among those proposed for cell replacement therapy in the man. Suicide gene introduction should be recommended prior to their use in vivo to ablate them in case of malignant transformation.

Rationale for individualized therapy in Sinonasal Teratocarcinosarcoma (SNTC): case report.

BACKGROUND: Sinonasal Teratocarcinosarcoma (SNTC) is a very unusual and aggressive neoplasm characterized by the combination of malignant teratoma and carcinosarcoma features. We present the first case of malignant SNTC treated with individualized multimodal therapy including a histology-specific chemotherapy. CASE REPORT: A 31-year-old man presented with an obstruction of the right pansinus. Histology showed an SNTC with major parts of small cell, poorly differentiated carcinoma and a small proportion of highly differentiated embryonal rhabdomyosarcoma. An operation was performed followed by intraoperative application of a 5-FU ointment. Adjuvant chemotherapy with cisplatin, etoposid and ifosfamid were given in regard to the major components of this heterogeneous tumor. Radiotherapy up to 59.4 Gy was applied. CONCLUSION: 36 months after the end of therapy, there is no sign of tumor recurrence or metastasis in our patient. We suggest that surgery, radiotherapy and a histology-specific multidrug chemotherapy seems to be a therapeutic approach that is appropriate for this heterogeneous tumor.

Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha.

The potent antitumor activity of certain cytokines is often achieved at the expense of unacceptable toxicity. One avenue to improve the therapeutic index of cytokines in cancer therapy consists of fusing them to monoclonal antibodies capable of a selective localization at the tumor site. We have constructed fusion proteins of interleukin-12 (IL-12) and tumor necrosis factor (TNF-alpha) with L19, an antibody fragment specific to the extradomain B of fibronectin which has been shown to target tumors in animal models and in patients with cancer. These fusions display a potent antitumor activity in several immunocompetent murine models of cancer but do not lead to complete remissions of established aggressive tumors. In this article, we have evaluated the tumor-targeting properties and the anticancer activities of combinations of the two antibody-cytokine fusion proteins, as well as of a triple fusion protein between IL-12, L19, and TNF-alpha. Although all fusion proteins were active in vitro, the triple fusion protein failed to localize to tumors in vivo and to show significant therapeutic effects. By contrast, the combination of IL-12-L19 and L19-TNF-alpha displayed potent synergistic anticancer activity and led to the eradication of F9 teratocarcinomas grafted in immunocompetent mice. When cured mice were rechallenged with tumor cells, a delayed onset of tumor growth was observed, indicating the induction of a partial antitumor vaccination effect. Potent anticancer effects were achieved at doses of IL-12-L19 and L19-TNF-alpha (2 micro g + 2 micro g/mouse), which were at least 5-fold lower than the maximal-tolerated dose. The combined administration of the two fusion proteins showed only a modest increase in toxicity, compared with treatments performed with the individual fusion proteins. These results show that the targeted delivery of cytokines to the tumor environment strongly potentiates their antitumor activity and that the combination treatment with IL-12-L19 and L19-TNF-alpha appears to be synergistic in vivo.

Soluble tissue factor induces coagulation on tumor endothelial cells in vivo if coadministered with low-dose lipopolysaccharides.

OBJECTIVE: This study was performed to evaluate the mechanisms leading to tumor vessel occlusion by tissue factor-based drugs, which are used in vascular targeting approaches for the treatment of malignant tumors. METHODS AND RESULTS: The effects of nontargeted soluble tissue factor were evaluated in vitro and in vivo. Tumor-bearing mice were treated with (1) the extracellular portion of tissue factor (soluble tissue factor), (2) low nontoxic doses of lipopolysaccharides, or (3) a combination thereof. The combination treatment showed the best effects and resulted in selective thrombosis of tumor vessels. On the basis of our data from subsequent in vitro analyses, including surface plasmon resonance measurements and endothelial cell based coagulation assays, we propose a model on how soluble tissue factor, although lacking its membrane anchor, can promote selective tumor vessel occlusion. CONCLUSIONS: To our knowledge, this is the first report to describe the molecular mechanisms of coagulation induction by untargeted soluble tissue factor in vivo. Combination treatments including soluble tissue factor might represent an alternative vascular targeting approach for the treatment of malignant tumors.

Quantitation of the tumor-targeting properties of antibody fragments conjugated to cell-permeating HIV-1 TAT peptides.

Human monoclonal antibodies are promising agents for the development of more selective anticancer therapeutics. However, the tumor-targeting efficiency of most anticancer antibodies is severely limited by their poor penetration into the tumor mass. Recent studies have shown that a peptide derived from the HIV TAT protein could improve the distribution of cytoplasmic reporter proteins when administered systemically as fusion proteins or cross-linked chimeras. In this article, we tested by quantitative biodistribtution analysis whether conjugation to TAT peptides could improve the tumor targeting properties of scFv(L19)-Cys: an engineered human antibody fragment specific for the ED-B domain of fibronectin, a marker located in the modified extracellular matrix surrounding tumor neovasculature. Our results show that TAT peptides, consisting either of L-amino acids or D-amino acids, can efficiently transduce target cells when conjugated to fluorophores and/or antibody fragments, suggesting a receptor-independent cell entry mechanism. However, conjugation of scFv(L19)-Cys to TAT peptides resulted in a severely reduced tumor targeting performance compared to the unconjugated antibody, as measured in murine F9 teratocarcinoma-bearing mice, after intravenous injection of the radiolabeled antibody preparations. Our results outline the usefulness of TAT peptides for the efficient in vitro transduction of cells with globular proteins. In particular, the use of TAT peptides composed of D-amino acids may significantly reduce proteolytic degradation. At the same time, the poor biodistribution properties of antibody-TAT conjugates cast doubts over the applicability of this methodology for the delivery of biopharmaceuticals in vivo.

The flt-1 promoter for transcriptional targeting of teratocarcinoma.

Flt-1, a receptor for vascular endothelial growth factor, is known to display dysregulated expression in both tumor vasculature and tumor cells per se, suggesting that the flt-1 promoter might be a useful candidate to achieve tumor-specific transgene expression. In addition, adenoviral vectors containing transgenes under the control of the flt-1 promoter achieve very low levels of expression in the normal liver, the major organ responsible for blood clearance of adenoviruses and inadvertent transgene-related toxicity. Thus, we assessed the ability of adenoviral vectors containing the flt-1 promoter to achieve transgene expression in a range of gynecological and breast tumor lines. High transgene expression levels were detected in teratocarcinoma lines, correlating with levels of flt-1 mRNA. These results suggest that the flt-1 promoter could be useful for transcriptionally targeted gene expression to teratocarcinoma, and that evaluation in other flt-1-positive tumors is warranted.