O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET as a potential selection tool for second surgery in glioblastoma patients.

BACKGROUND: Treatment-related changes still represent a diagnostic challenge in the management of patients with suspect of recurrent glioblastoma. The specificity of conventional MRI in detecting recurrence remains limited. Brain PET imaging provides information on tumor metabolism and can contribute to improving the diagnostic accuracy of cerebral neoplasms. We performed a retrospective analysis to evaluate the clinical value of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET in the diagnosis of glioblastoma recurrence. METHODS: A retrospective analysis on patients considered suitable for salvage surgery for recurrence glioblastoma was performed. 18F-FET-PET was performed to investigate gadolinium enhancement suspected for recurrence. Static and kinetic 18F-FET parameters were analyzed and related to O-6-methylguanine-DNA methyltransferase (MGMT) status. RESULTS: Forty-two of the 51 patients who underwent 18F-FET-PET were re-operated. In each case, neuropathological diagnosis of tumor recurrence was confirmed. pMGMT hypermethylation was detected in 21 patients. Mean tumor-to-brain ratios (TBR) max was 3.87 (range 2.6-6.0). Static and kinetic 18F-FET parameters were similar according to MGMT status. CONCLUSIONS: 18FET-PET can be a reliable tool to improve the selection of patients suitable for salvage surgery for glioblastoma recurrence.

Surgical management of skull base meningiomas and vestibular schwannomas.

PURPOSE OF REVIEW: The aim of this study is to discuss surgical management of meningiomas and schwannomas of skull base. RECENT FINDINGS: Meningiomas and schwannomas are typically benign neoplasm with a good prognosis after surgery. Patients should be treated individually related to several features: size and localization of tumor and its proximity with deep critical neurovascular structures, neurological status, age and comorbidity. Also, the widespread use of neuroimaging and the progressive and constant aging of the populations inevitably result in the increase of detection rate of incidental (asymptomatic) neoplasm.Nowadays, there are still controversies about the correct management strategy. SUMMARY: Surgery represents the gold standard treatment, with the objective of gross total resection; however, it is not always feasible due to localization, encasement of neuro-vascular structure, invasion of cranial nerve and brain parenchyma. Stereotactic radiosurgery and radiation therapy are important to achieve a satisfactory functional outcome and tumor control in case of residue or recurrence. A multidisciplinary approach is pivotal.

Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

Assessment of right ventricular function by strain rate imaging in chronic obstructive pulmonary disease.

The purpose of the current study was to compare right ventricular (RV) myocardial wall velocities (tissue Doppler imaging) and strain rate imaging (SRI) parameters with conventional echocardiographic indices evaluating RV function in chronic obstructive pulmonary disease (COPD) patients. In total, 39 patients with COPD and 22 healthy subjects were included in the current study. Seventeen patients had pulmonary artery pressure <35 mmHg (group I) and 22 patients had pulmonary artery pressure >35 mmHg (group II). Tissue Doppler imaging, strain and strain rate (SR) values were obtained from RV free wall (FW) and interventricular septum. Respiratory function tests were performed (forced expiratory volume in one second/vital capacity (FEV(1)/VC) and carbon monoxide diffusion lung capacity per unit of alveolar volume (D(L,CO)/V(A))). Strain/SR values were reduced in all segments of group II patients compared with group I patients and controls with lowest values at basal FW site. A significant relationship was shown between peak systolic SR at basal FW site and radionuclide RV ejection fraction. A significant relationship was shown between peak systolic SR at basal FW site and D(L,CO)/V(A) and FEV(1)/VC. In conclusion, in chronic obstructive pulmonary disease patients, strain rate imaging parameters can determine right ventricular dysfunction that is complementary to conventional echocardiographic indices and is correlated with pulmonary hypertension and respiratory function tests.

Assessment of severity of mechanical prosthetic mitral regurgitation by transoesophageal echocardiography.

OBJECTIVE: To evaluate the ability of colour Doppler transoesophageal echocardiography (TOE) to assess quantitatively prosthetic mitral valve insufficiency. METHODS: 47 patients were studied with multiplane TOE and cardiac catheterisation. Proximal jet diameter was measured as the largest diameter of the vena contracta. Regurgitant area was measured by planimetry of the largest turbulent jet during systole. Flow convergence zone was considered to be present when a localised area of increased systolic velocities was apparent on the left ventricular side of the valve prosthesis. Pulmonary vein flow velocity was measured at peak systole and diastole. RESULTS: Mean (SD) proximal jet diameter was 0.63 (0.16) cm, with good correlation with angiographic grades (r = 0.83). Mean (SD) maximum colour jet area was 7.9 (2.5) cm2 (r = 0.69) with worse correlation if a single imaging plane was used for measurements (r = 0.62). The ratio of systolic to diastolic peak pulmonary flow velocity averaged 0.7 (1.3) cm (r = -0.66) with better correlation (r = -0.71) if patients with atrial fibrillation were excluded. Mean (SD) regurgitant flow rate was 168 (135) ml/s and regurgitant orifice area was 0.56 (0.43) cm2, with good correlation with angiography (r = 0.77 and r = 0.78, respectively). CONCLUSIONS: TOE correctly identified angiographically severe prosthetic mitral regurgitation, mainly by the assessment of the flow convergence region and the proximal diameter of the regurgitant jet.

Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeria monocytogenes infection.

CD8(+) T cells are required for protective immunity against intracellular pathogens such as Listeria monocytogenes. In this study, we used class Ia MHC-deficient mice, which have a severe reduction in circulating CD8(+) T cells, to determine the protective capacity of class Ib MHC-restricted T cells during L. monocytogenes infection. The K(b-/-)D(b-/-) mutation was backcrossed onto a C.B10 (BALB/c congenic at H-2 locus with C57BL/10) background, because BALB/c mice are more susceptible to Listeria infection than other commonly studied mouse strains such as C57BL/6. C.B10 K(b-/-)D(b-/-) mice immunized with a sublethal dose of L. monocytogenes were fully protected against a subsequent lethal infection. Adoptive transfer of Listeria-immune splenocyte subsets into naive K(b-/-)D(b-/-) mice indicated that CD8(+) T cells were the major component of this protective immune response. A CD8(+) T cell line isolated from the spleen of a Listeria-infected class Ia MHC-deficient mouse was shown to specifically recognize Listeria-infected cells in vitro, as determined by IFN-gamma secretion and cytotoxicity assays. Adoptive transfer of this T cell line alone resulted in significant protection against L. monocytogenes challenge. These results suggest that even a limited number of class Ib MHC-restricted T cells are sufficient to generate the rapid recall response required for protection against secondary infection with L. monocytogenes.

Multigenic control of Listeria monocytogenes susceptibility in mice.

We have used a novel quantitative trait locus model to study the genetics of survival of F2 progeny of susceptible BALB/cByJ and resistant C57BL/6ByJ mice that have been infected with Listeria monocytogenes. This allowed us to map modifiers of L. monocytogenes susceptibility to chromosomes 5 and 13.

CD8+ T cells recognize an inclusion membrane-associated protein from the vacuolar pathogen Chlamydia trachomatis.

During infection with Chlamydia trachomatis, CD8(+) T cells are primed, even though the bacteria remain confined to a host cell vacuole throughout their developmental cycle. Because CD8(+) T cells recognize antigens processed from cytosolic proteins, the Chlamydia antigens recognized by these CD8(+) T cells very likely have access to the host cell cytoplasm during infection. The identity of these C. trachomatis proteins has remained elusive, even though their localization suggests they may play important roles in the biology of the organism. Here we use a retroviral expression system to identify Cap1, a 31-kDa protein from C. trachomatis recognized by protective CD8(+) T cells. Cap1 contains no strong homology to any known protein. Immunofluorescence microscopy by using Cap1-specific antibody demonstrates that this protein is localized to the vacuolar membrane. Cap1 is virtually identical among the human C. trachomatis serovars, suggesting that a vaccine incorporating Cap1 might enable the vaccine to protect against all C. trachomatis serovars. The identification of proteins such as Cap1 that associate with the inclusion membrane will be required to fully understand the interaction of C. trachomatis with its host cell.

Activation of transcription at divergent urea-dependent promoters by the urease gene regulator UreR.

The Proteus mirabilis and plasmid-encoded urease loci contain seven contiguous structural and accessory genes (ureDABCEFG) and the divergently transcribed ureR, which codes for an AraC-like transcriptional activator. Previously, it was shown that the plasmid-encoded ureR to ureD intergenic region contained divergent promoters (ureRp and ureDp). Transcription from these promoters required both the effector molecule urea and the activator protein UreR. In this report, we demonstrate that the P. mirabilis urease gene cluster contains similar divergent urea- and UreR-dependent promoters. The ureR gene products from either urease locus were able to activate transcription at both the plasmid-encoded and P. mirabilis promoters. The minimal concentration of urea required to activate transcription at ureRp or ureDp from either gene cluster was approximately 4 mM. The transcriptional start sites for the plasmid-encoded and P. mirabilis divergent promoters were similar in an Escherichia coli DH5 alpha background, as determined by primer-extension analysis. However, in P. mirabilis HI4320, transcription of ureR initiated predominately at an alternative site. Physical mapping and inhibition studies were used to localize the UreR-binding sites within the plasmid-encoded ureRp and ureDp intergenic sequences to regions of 68 bp and 86 bp, respectively. Gel shift analysis demonstrated that UreR bound to a 135 bp fragment in the approximate centre of the plasmid-encoded ureR to ureD intergenic region. The results presented here suggest that the P. mirabilis and plasmid-encoded urease gene clusters utilize similar mechanisms of transcriptional activation in response to urea.

UreR activates transcription at multiple promoters within the plasmid-encoded urease locus of the Enterobacteriaceae.

Urease activity is produced by members of the family Enterobacteriaceae that contain the plasmid-encoded urease locus only when urea is present in the growth medium. The plasmid-encoded urease locus contains seven tandem urease structural and accessory genes (ureDABCEFG). Previously we showed that transcription of the first gene in this cluster, ureD, is initiated at a urea-dependent promoter (ureDp). Expression from ureDp requires the product of ureR, which is transcribed divergently from the plasmid-encoded ureDABCEFG. From DNA sequence analysis, UreR is predicted to be a 34 kDa protein with identity to the AraC family of transcriptional activators. In this report we demonstrate that there are two additional urea and UreR-dependent promoters within the plasmid-encoded urease locus: ureRp and ureGp. A low-level constitutive promoter was also identified upstream of ureE (ureEp). Three major mRNA transcripts were induced when urea was present in the growth medium: a transcript containing ureDABCEF, a transcript corresponding to ureG, and a transcript corresponding to ureR. These results indicate that expression of each of the plasmid-encoded urease genes is transcriptionally regulated in response to urea and suggest that there is autogenous regulation of ureR. Therefore UreR is one of three AraC family members described thus far that are positively auto-regulated.

Lung cancer surgery in the octogenarian.

From 1981 through 1991, 40 patients 80 years of age or older underwent thoracotomy for curative resection of bronchogenic carcinoma. There were 22 males and 18 females with a mean age of 82.7 years (range 80-88). In three patients, the operation was aborted due to unexpected metastatic disease discovered at the time of thoracotomy. The remaining 37 patients underwent 5 pneumonectomies, 26 lobectomies and 6 segmentectomies or wedge resections. Three of these patients (1 pneumonectomy, 1 lobectomy, and 1 wedge resection) underwent concomitant en bloc chest wall resection. The overall operative mortality rate (in hospital or within 30 days) was 15% (6/40) while there was a 16% mortality rate (6/37) for resected patients. Complications occurred in 18 of 40 patients (45%) but were major in only 12 (30%). Major complications included respiratory insufficiency (6), pneumonia (4), prolonged air leak (2), stroke (1), urinary retention prostatectomy (1), and one unexplained sudden death 2 weeks following discharge. Postoperative stay in the 34 operative survivors averaged 14 +/- 8.8 days (range 3-47). Univariate analysis revealed that neither gender, extent of lung resection, preoperative NYHA class, history of heart disease nor chronic obstructive pulmonary disease (COPD) were predictive of operative mortality in the 37 patients undergoing lung resection. Age was the only predictor of mortality (survivors 82.2 +/- 2.2, non-survivors 84.3 +/- 2.6; P < 0.05). The need for chest wall resection approached but did not quite achieve significance (P < 0.08). Actuarial survival for all 40 patients at 1 and 3 years is 55% and 40%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial ureases: structure, regulation of expression and role in pathogenesis.

The nickel metalloenzyme urease catalyses the hydrolysis of urea to ammonia and carbamate, and thus generates the preferred nitrogen source of many organisms. When produced by bacterial pathogens in either the urinary tract or the gastroduodenal region, urease acts as a virulence factor. At both sites of infection urease is known to enhance the survival of the infecting bacteria. Ammonia resulting from the action of urease is believed to increase the pH of the environment to one more favourable for growth, and to injure the surrounding epithelial cells. In addition, in the urinary tract urease activity can result in the formation of urinary calculi. Bacterial urease gene clusters contain from seven to nine genes depending upon the species. These genes encode the urease structural subunits and accessory polypeptides involved in the biosynthesis of the nickel metallocentre. So far, three distinct mechanisms of urease gene expression have been described for ureolytic bacteria. Some species constitutively produce urease; some species produce urease only if urea is present in the growth medium; and some species produce urease only during nitrogen-limiting growth conditions. For either the urea-inducible genes or the nitrogen-regulated genes transcription appears to be positively regulated. In the nitrogen-regulated systems, urease gene expression requires Nac (nitrogen assimilation control), a member of the LysR family of transcriptional activators. Urea dependent expression of urease requires UreR (urease regulator), a member of the AraC family of transcriptional activators. An evolutionary tree for urease genes of eight bacterial species is proposed.

The plasmid-encoded urease gene cluster of the family Enterobacteriaceae is positively regulated by UreR, a member of the AraC family of transcriptional activators.

Ureolytic clinical isolates of Providencia stuartii, Salmonella spp., and some Escherichia coli strains contain large urease-encoding plasmids. Expression of urease activity from these isolates is induced at least 20-fold by urea. In order to facilitate studies on the regulatory mechanism controlling this urea-inducible expression, the plasmid-encoded urease genes were inserted into the low-copy-number vector pRK415, to form pSEF70. Deletion mutagenesis of pSEF70 demonstrated that between 1.3 and 1.6 kb of DNA upstream of ureD (the first of seven urease genes clustered in an operon-like fashion) was required for a urease-positive phenotype. An open reading frame coding for a 34.1-kDa polypeptide was found in the DNA sequence of this upstream region. This open reading frame has been designated ureR, for urease regulator. A urea-inducible promoter region was identified upstream of ureD. Transcription from this promoter was activated only when ureR was present in trans. The predicted ureR gene product contains a helix-turn-helix motif and shows significant amino acid similarity to the AraC family of transcriptional activators. We conclude that urea-dependent expression from the plasmid-encoded urease gene cluster requires ureR and that ureR codes for a positive regulatory element controlling transcription of at least one essential urease gene, ureD.

Characterization of a plasmid-encoded urease gene cluster found in members of the family Enterobacteriaceae.

Plasmid-encoded urease gene clusters found in uropathogenic isolates of Escherichia coli, Providencia stuartii, and Salmonella cubana demonstrated DNA homology, similar positions of restriction endonuclease cleavage sites, and manners of urease expression and therefore represent the same locus. DNA sequence analysis indicated that the plasmid-encoded urease genes are closely related to the Proteus mirabilis urease genes.

Mitral valve replacement: randomized trial of St. Jude and Medtronic-Hall prostheses.

To better define the merits of the bileaflet and tilting-disc valves, we prospectively randomized 102 patients (mean age, 57 years; range, 11 to 85 years) to receive either the St. Jude (n = 55) or the Medtronic-Hall (n = 47) mitral valve prosthesis between September 1986 and May 1991. The two groups were not different with respect to preoperative New York Heart Association class, incidence of mitral stenosis and insufficiency, angina score, extent of coronary artery disease, ventricular function, completeness of revascularization, or cross-clamp or bypass time. The hospital mortality (14.5% versus 10.6%, St. Jude versus Medtronic-Hall) and late mortality (7.3% versus 2.1%) were not significantly different. Follow-up was complete in 84 of 89 hospital survivors (94%) with a mean of 26 months (range, 1 to 60 months). The linearized rates of valve-related events and the 3-year actuarial survival demonstrated no significant differences between both cohorts. Comparison of the clinical outcome and echocardiographic parameters obtained at the time of follow-up demonstrated no significant differences between the two prostheses. These data indicate that the Medtronic-Hall and St. Jude mitral prostheses are similar with respect to their rates of valve-related complications and hemodynamic profiles. This study suggests that there is no difference between the St. Jude and Medtronic-Hall prostheses with regard to early clinical performance or hemodynamic results and therefore does not support the preferential selection of either prosthesis.

Thoracotomy in the octogenarian.

Octogenarians are rarely referred for thoracic operations, presumably owing to the perceived morbidity of thoracotomy and the presumed frailty and limited life span of the 80-year-old patient. To determine if these concerns are valid, we reviewed our operative experience in 50 patients 80 years of age or older (mean age, 82.7 years; range, 80 to 91 years; 29 men, 21 women) undergoing thoracotomy between Nov 1, 1980, and May 1, 1990, for cancer (39 patients) and benign disease (11 patients). Procedures included 25 lobectomies (24 cancer, 1 abscess), 4 pneumonectomies (all cancer), 3 esophagectomies (1 perforation, 2 cancer), 3 explorations for cancer, 2 bullectomies, 12 wedge or segmental resections (5 open lung biopsies, 5 cancer, and 1 each for benign nodule and hemoptysis), and 1 thymectomy. Five patients (10%) were operated on emergently for massive hemoptysis (1), Boerhaave's syndrome (1), or rapidly progressive respiratory insufficiency (3) with an operative mortality of 80%. Mortality for elective cases was significantly lower (13%, p less than 0.01). Major complications occurred in 19 patients (38%). Univariate analysis performed to identify predictors of operative mortality demonstrated no significant relationship between operative death and patient age, sex, type of operation, diagnosis of malignancy, or the presence of either cardiac disease or chronic obstructive lung disease. Twenty-three patients are alive 2 months to 5 years after thoracotomy. Actuarial survival for the 45 elective patients was 56% and 44% at 1 and 2 years, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Squamous carcinoma metastatic to the sternum.

A 63-year-old man had a 10 x 16-cm sternal mass 18 months after a second aortocoronary bypass operation. The resected lesion was a metastatic tumor of squamous histology. No primary tumor was found. The diagnostic work-up and treatment options are presented.

Ultrasonography: an alternative to x-ray-guided needle localization of nonpalpable breast masses.

Preoperative ultrasonography was used as an alternative to x-ray mammography to localize 92 breast lesions encountered in 82 patients. Recommendation for biopsy was made on the basis of the ultrasonographic finding of a nonpalpable mass or an area of architectural distortion, or in the presence of equivocal physical findings if sonomammography demonstrated a solid or an anechoic mass. Sonomammography was performed in the operating room, just before anticipated biopsy, with a hand-held high-resolution scanner. When the suspicious area was imaged and its precise location noted, the breast was then prepared and draped in the usual manner, and a biopsy was performed. If the suspicious area could not be easily localized after the incision was made and the breast explored, the transducer was "gowned" and used directly in the wound to help find the lesion. This technique has proven effective and accurate. In selected patients ultrasonography may be used as well as, or instead of, x-ray needle localization for the precise excision of nonpalpable breast lesions, excluding calcifications.

Ultrasonographic localization of non-palpable breast masses.

Preoperative ultrasound was used as an alternative to x-ray mammography to localize 92 breast lesions encountered in 82 patients. Recommendation for biopsy was made based upon the ultrasonographic finding of a nonpalpable mass or an area of architectural distortion, or in the presence of equivocal physical findings if sonomammography demonstrated a solid or anechoic mass. Sonomammography was performed in the operating room, just prior to anticipated biopsy, using a hand-held, high resolution scanner. When the suspicious area was imaged, and its precise location noted, the breast was then prepped and draped in the usual manner, and biopsy performed. If the suspicious area could not be easily localized after the incision was made and the breast explored, the transducer was "gowned" and used directly in the wound to help find the lesion. This technique has proven effective and accurate. In selected patients, ultrasound may be used instead of, and as well as, x-ray needle localization for the precise excision of non-palpable breast masses and areas of parenchymal distortion. Microcalcifications must still be addressed by x-ray mammography and needle localization with specimen radiography.