Soft tissue sarcomas with complex genomic profiles

Soft tissue sarcomas (STS) with complex genomic profiles (50% of all STS) are predominantly composed of spindle cell/pleomorphic sarcomas, including leiomyosarcoma, myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, extraskeletal osteosarcoma, and spindle cell/pleomorphic unclassified sarcoma (previously called spindle cell/pleomorphic malignant fibrous histiocytoma). These neoplasms show, characteristically, gains and losses of numerous chromosomes or chromosome regions, as well as amplifications. Many of them share recurrent aberrations (e.g., gain of 5p13-p15) that seem to play a significant role in tumor progression and/or metastatic dissemination. In this paper, we review the cytogenetic, molecular genetic, and clinicopathologic characteristics of the most common STS displaying complex genomic profiles. Features of diagnostic or prognostic relevance will be discussed when neede

High expression of peptide receptors as a novel target in gastrointestinal stromal tumours

Recent significant advances in understanding the biology of gastrointestinal stromal tumours (GIST) have led to the introduction of a new targeted therapy (imatinib mesylate, Glivec). Hopes of a new era of a specific cancer therapy, however, have been tempered by the recognition that a significant proportion of patients who initially respond to the drug eventually become resistant to it. Given the successful development of peptide receptor scintigraphy and radiotherapy for neuroendocrine tumours, we postulated that a similar approach could offer a valid alternative in the diagnosis and therapy of GIST. Using in vitro receptor autoradiography to measure peptide receptors, we found that 16/19 GIST expressed bombesin subtype 2 receptors, 16/19 expressed vasoactive intestinal peptide subtype 2 receptors (VPAC2) and 12/19 expressed cholecystokinin subtype 2 receptors, in most cases in extremely high densities. All GIST metastases were shown to express two or more of these peptide receptors in very high density. Receptors were also expressed in non-responders to Glivec or after chemo-embolisation. Conversely, somatostatin subtype 2, cholecystokinin subtype 1, bombesin subtype 1 and 3, and neuropeptide Y subtype Y1 and Y2 receptors were not or only rarely expressed. These data represent a strong molecular basis for the use of radiolabelled bombesin, vasoactive intestinal peptide and/or cholecystokinin analogues as targeting agents to localise GIST tumours in patients by in vivo scintigraphy and/or to perform targeted radiotherapy to destroy GIST primaries, metastases and recurrences, including those resistant to Glive

The human telomerase RNA gene (hTERC) is regulated during carcinogenesis but is not dependent on DNA methylation

Telomerase, the ribonucleoprotein complex involved in telomere maintenance, is composed of two main components: hTERT and hTERC. hTERT seems to be the rate-limiting factor for telomerase activity, although hTERC expression was also shown to correlate to a certain extent with telomerase reactivation. To determine whether the absence of hTERC expression could be the consequence of DNA methylation, we quantified hTERC RNA in 60 human samples (19 telomerase-negative normal tissues, nine telomerase-positive and 22 telomerase-negative tumor tissues, eight telomerase-positive and two telomerase-negative cell lines) using a quantitative dot blot on RT-PCR products. Most of the normal tissues did not express hTERC whereas, in telomerase-positive cell lines and in telomerase-positive tumor tissues, a strong up-regulation was observed, suggesting that hTERC transcription is up-regulated during tumorigenesis. The two telomerase-negative cell lines did not express hTERC. In a series of 22 telomerase-negative soft tissue sarcomas (STS), half did not express hTERC at all, or only weakly, whereas a wide range of expression was observed in the other half. As methylation might be involved in hTERC silencing, we examined the methylation pattern in all samples by direct sequencing and methylation-specific single stand conformation analysis after bisulfite modification. hTERC methylation was never observed, neither in normal nor in tumor tissues. Furthermore, there was no correlation between hTERC expression and proliferation, telomere length or hTERT expression in telomerase-negative STS. In contrast, three of eight telomerase-positive cell lines and the two telomerasenegative cell lines were found to be hypermethylated, suggesting that the methylation observed may occur during cell line establishment. In conclusion, this study shows that hTERC expression is indeed regulated during carcinogenesis, but this regulation is unlikely to depend on hTERC methylation, cell proliferation rate, telomere length or hTERT expressio

Determination of the threshold of cardiac troponin I associated with an adverse postoperative outcome after cardiac surgery: a comparative study between coronary artery bypass graft, valve surgery, and combined cardiac surgery

ABSTRACT: BACKGROUND: To compare postoperative cardiac troponin I (cTnI) release and the thresholds of cTnI that predict adverse outcome after elective coronary artery bypass graft (CABG), valve, and combined cardiac surgery. METHODS: Six hundred and seventy five adult patients undergoing conventional cardiac surgery with cardiopulmonary bypass were retrospectively analyzed. Patients in the CABG (n=225) and valve surgery groups (n=225) were selected after matching (age, sex) with those in the combined surgery group (n=225). cTnI was measured preoperatively and 24 h after the end of surgery. The main endpoint was a severe postoperative cardiac event (sustained ventricular arrhythmias requiring treatment, need for inotropic support or intra-aortic balloon pump for at least 24 h, postoperative myocardial infarction) and/or death. Data are medians and odds ratio [95% confidence interval]. RESULTS: Postoperative cTnI levels were significantly different among the three groups (Combined 11.0 [9.5-13.1] vs. CABG 5.2 [4.7-5.7] and Valve 7.8 [7.6-8.0] ng.mL-1, respectively, P<0.05). The thresholds of cTnI predicting severe cardiac event and/or death were also significantly different among the three groups (Combined 11.8 [11.5-14.8] vs. CABG 7.8 [6.7-8.8] and Valve 9.3 [8.0-14.0] ng.mL-1 respectively, P<0.05 level). An elevated cTnI above the threshold in each group was significantly associated with severe cardiac event and/or death (odds ratio, 4.33 [2.82-6.64]). CONCLUSIONS: The magnitude of postoperative cTnI release is related to the type of cardiac surgical procedure. Different thresholds of cTnI must be considered according to the procedure type to predict early an adverse postoperative outcom

Primary clear cell sarcoma of the ileum: an uncommon and misleading site

A clear cell sarcoma, arising primarily in the ileum of a 35-year-old man, is reported. Histologically, the neoplasm infiltrated the full thickness of the intestinal wall. It consisted of strands and sheets of round to spindle-shaped cells with clear to eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli. Vascular invasion was present at diagnosis. Tumour cells expressed S-100 protein, melan-A and tyrosinase. They were negative for HMB45, CD117, cytokeratins, epithelial membrane antigen, smooth muscle actin, desmin, CD31, CD34, chromogranin and synaptophysin. Reverse transcription-polymerase chain reaction analysis performed on paraffin-embedded tissue showed EWS-ATF1 fusion transcripts representative of the t(12;22) (q13;q12) clear cell sarcoma reciprocal translocation. The patient, who developed liver metastases 2 months after diagnosis, died of disease at 15 months. This case demonstrates that the gastrointestinal tract is a potential site for primary clear cell sarcoma of soft tissues, and, furthermore, that cytogenetics and/or molecular techniques play a central role in the diagnosi

Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC

Objective: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III N2 non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. Methods: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. Results: Group I and II comprised T1/2 tumors in 47 and 28%, T3 tumors in 45 and 41%, and T4 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a R0-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P≪0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. Conclusions: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of T4 tumors were admitted to radiochemotherap

The eruptive chronology of the Yucamane-Calientes compound volcano: a potentially active edifice of the Central Andes (Southern Peru)

We have reconstructed the eruptive chronology of the Yucamane–Calientes compound volcano in southern Peru based on extensive fieldwork and a large dataset of geochronological (40K–40Ar, 40Ar–39Ar, U-Pb and 14C) and geochemical (major and trace element) analyses. This compound volcano is composed of two edifices that have experienced discontinuous volcanic activity from the Middle Pleistocene to the Holocene. The Calientes volcano has been constructed in four successive stages: Calientes I is composed of andesitic lava flows that were dated at ~500 ka. Then, the Callazas ignimbrite (Calientes II stage) was emplaced (~160-190 ka), followed by the main cone-building stage (Calientes III), which was dated at ~125 ka. Finally, the Holocene Caliente domes were emplaced and represent the last eruptive products of this edifice. The Yucamane volcano has been constructed in three stages: Yucamane I stage consists of a sequence of andesitic lava flows exposed at the base of the volcano with an age older than 37-40 ka. Yucamane II stage (~36-24 ka) comprises a thick sequence of block-and-ash deposits that represents a dome-growth episode that predates the younger Yucamane cone (Yucamane III stage) since 20-25 ka. During the Holocene, the Yucamane had shown vulcanian to sub-Plinian activity resulting in the emplacement of tephra fallout and pyroclastic density current deposits. The last sub-Plinian eruption occurred ca. 3085 ± 35 aBP and emitted a pumice fall deposit associated with a pumice flow deposit. Most samples from the Calientes volcano are andesites and dacites (60.1-67.7 wt.% SiO2), while rocks of the Yucamane volcano correspond to basic andesites to dacites (53.4-66.9 wt.% SiO2). These rocks show a mineral assemblage of plagioclase, amphibole, biotite, ortho- and clino-pyroxene, olivine, and Fe-Ti oxides. All of the analyzed samples belong to a high-K, calc-alkaline series. Calientes volcano erupted mostly andesitic magmas and is punctuated by rare eruptions involving silica-rich magmas. In contrast, Yucamane volcano displays a different pattern, characterized by a gradual decrease of silica content through post-glacial time, from moderate (VEI <=2) vulcanian events comprising basic andesitic magmas to the large (VEI 3) sub-Plinian eruption of ~3 ka, involving andesitic magma. On the basis of this recurrent low-to-moderate explosive activity, Yucamane must be considered as an active and potentially threatening volcano, which may affect the province of Candarave with about 12 000 inhabitants