Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

An original fibular shortening osteotomy technique in tibiotalar arthrodesis.

Tibiotalar arthrodesis (TTA) is the gold-standard treatment for advanced ankle osteoarthritis. We describe an original fibular shortening osteotomy (FSO) performed during TTA, to allow complete talar ascension and reduce the nonunion rate. Forty-two FSOs were associated to TTA (19 fixed by cross-screwing and 23 by anatomic plates) and assessed clinically and radiographically. At 24.7 months' follow-up, fusion rates were 97.6% for TTA and 100% for FSO, with mean fusion time of 5.2 months. One infection and 1 nonunion (4.7%) required further surgery, with complete resolution. Radiological and clinical outcome in TTA, lack of specific complications of FSO and ease of implementation encourage us to publish the technique.

[Minimally invasive dynamic hip screw technique: Shorter surgical time with similar post-surgical results compared to conventional DHS technique. A retrospective cohort study]. / Técnica DHS mínimamente invasiva: menor tiempo quirúrgico con similares resultados en el postoperatorio inmediato respecto al DHS convencional. Estudio retrospectivo de cohortes.

AIM: The treatment of intertrochanteric fractures using a minimally invasive dynamic hip screw (MIDHS) technique has been reported to provide better results than the conventional technique (CDHS). The present study aims to determine whether there are any differences in terms of transfusion needs, morbidity, length of hospital stay, and economical costs, based on a study of two retrospective cohorts. MATERIAL AND METHOD: Cohorts study of 80 patients with intertrochanteric femoral fractures (31-A1 and 31-A2.1) who underwent DHS procedure from July 2005 to September 2007; 40 of them were treated using the traditional technique (CDHS), and the other 40 using the minimally invasive technique (MIDHS). RESULTS: No differences were found in terms of blood loss, transfusion requirements or morbidity. Mean hospital stay for MIDHS group was 1.3 days lower, reducing the costs regarding the CDHS group by €306.3, but this difference was not statistically significant (P=.3). The time required to perform the surgery was shorter for the MIDHS group: 49.3 versus 78.8minutes (p=0.0001). DISCUSSION: Contrary to previous studies published, the present study did not show any advantage for the MIDHS technique, except for a shorter surgical time to perform the procedure. We consider that the MIDHS could help in improving operating room productivity and efficiency.

Prevalence of antibodies against Kilham virus in experimental rat colonies of Argentina.

The Kilham rat virus (KRV) is a parvovirus originally isolated from a rat sarcoma in the late 1950s. The clinical signs associated with a natural KRV infection include foetal resorption in dams, runting, ataxia, cerebellar hypoplasia and jaundice in suckling rats, and sudden death, scrotal cyanosis, abdominal swelling and dehydration in juvenile rats. The ability of this virus to produce persistent infections has resulted in a high frequency of contamination of cell cultures and transplantable-tumor system. In addition, the virus may interfere with research in other ways. The remarkable resistance to environmental conditions determines the importance of the detection and control of this agent, especially in the laboratory animal production. This study determines the seroprevalence of Kilham antibodies from sera of adult rats from conventional facilities, using the haemagglutination inhibition test. The seroprevalence varied between 27.8% and 75%. This result confirms that the virus is circulating in Argentinean conventional facilities and might be interfering with research. The recognized Kilham virus may be prevented from supply sources by implementing a health monitoring schedule including a regular serological surveillance, and by keeping the animals under barrier systems.

Percutaneous implantation of an aortic valve prosthesis.

Recently, percutaneous aortic valve implantation has become an alternative technique to surgical valve replacement in patient at high risk for surgery. Our animal experimentation evaluated the technical feasibility of aortic valve replacement using a bovine pericardium valve sutured on a self-expandable stent in a sheep model. Precise implantation with satisfactory attachment on the adjacent tissues and absence of migration was obtain in 8 out of 14 animals. This study confirmed the feasibility of the endovascular implantation of a pericardium valve sutured on a self-expandable stent in a sheep model.

Desarrollo de un antígeno para diagnóstico del parvovirus de las ratas (virus Kilham) por la técnica de inhibición de la hemaglutinación / [Development of an antigen for the diagnosis of Kilham rat parvovirus by hemagglutination inhibition test]

An antigen of rat parvovirus (Kilham virus) was developed for the diagnosis of viral infection in rat colonies by using hemagglutination inhibition (HAI) test. Primary cell cultures from rat embryos were infected with Kilham rat virus. Infected cells obtained at different time post infection were scraped, centrifuged, concentrated one hundred times, sonicated and centrifuged again. The supernatants obtained were titrated by hemagglutination. The specificity was confirmed with positive and negative reference sera. Ninety eight serum samples were studied by using HAI test. The results coincided with those obtained in a reference laboratory. Kilham rat parvovirus antigen obtained from 5 days-infected-cells was specific, sensitive, easy to prepare, with a high yield and it is useful to detect this virus in experimental and production rat colonies.

[Acute encephalitis concurrent with primary infection by Schistosoma mansoni]. / Encéphalite aiguë contemporaine d'une primo-invasion bilharzienne à Schistosoma mansoni.

A 24-year-old man returning from a trip to Mali was hospitalized for acute encephalitis and fever in association with acute primary infection by Schistosomiasis mansoni. Bilharziasis was suspected from the epidemiological context and presence of eosinophilia. Diagnosis was confirmed by serological testing. Specific treatment using praziquantel and corticotherapy was successful. Central nervous system involvement attributable to embolization of eggs or ectopic migration of adult worms has been reported in association with chronic Schistosomiasis by S. japonicum or S. mansoni. There have been few reports of acute neuroschistosomiais during the acute primary phase of infestation by S. mansoni. Etiology probably involves immunoallergic mechanisms.

[Disseminated and central nervous system Histoplasma capsulatum infection mimicking neoplasm: difficulties in diagnosis, failure in management]. / Miliaire cérébrale pseudonéoplasique révélatrice d'une histoplasmose disséminée à Histoplasma capsulatum: difficultés diagnostiques, échec thérapeutique.

INTRODUCTION: Infection with Histoplasma capsulatum (Hc) is a rare importing disease in metropolitan France, the most often minor but sometimes letal in its spread form. EXEGESIS: A 58 years old French man, HIV seronegative, was admitted for an alteration of its general condition, disorder and buccal ulcerations. He had a prostate cancer history and came back in France after 17 years in Central Africa. The imaging showed numerous cerebral nodes, a bilateral adrenal tumor, and pulmonary calcifications. Histoplasmosis diagnosis has been done after neurosurgical cerebral biopsy which displayed characteristic Hc. The sick man died 4 months later with multivisceral failures, in spite of amphotericine B treatment followed by oral then intraveinous itraconazole. CONCLUSION: Even in an old tropical residence, ones can be able to conjure up a deep exotic fungal infection, and most specifically Hc histoplasmosis, in front of meaningful multivisceral lesions. Disseminated histoplasmosis (HD) with neurological location is misleading, mimicking tuberculosis or cancer. In order to obtain formal mycological evidence, ones have to make adapted biopsies. Antifungal agents must take into account medicinal interaction. Therefore, prognosis is bad, according to inoculum, immunodeficiency, age of disease and diagnosis delay.

Global experience in cervical carotid artery stent placement.

The purpose of this article is to review and update the current status of carotid artery stent placement in the world. Surveys to major interventional centers in Europe, North and South America, and Asia were initially completed in June 1997. Subsequent information from these 24 centers in addition to 12 new centers has been obtained to update the information. The survey asked the various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 5,210 procedures involving 4,757 patients. There was a technical success of 98.4% with 5,129 carotid arteries treated. Complications that occurred during the carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 134 transient ischemic attacks (TIAs) for a rate of 2.82%. Based on the total patient population, there were 129 minor strokes with a rate of occurrence of 2.72%. The total number of major strokes was 71 for a rate of 1.49%. There were 41 deaths within a 30-day postprocedure period resulting in a mortality rate of 0.86%. The combined minor and major strokes and procedure-related death rate was 5.07%. Restenosis rates of carotid stenting have been 1.99% and 3.46% at 6 and 12 months, respectively. The rate of neurologic events after stent placement has been 1.42% at 6-12-month follow-up. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative for vascular surgery, especially for patients that are high risk for standard carotid endarterectomy. The periprocedure risks for major and minor strokes and death are generally acceptable at this early stage of development and have not changed significantly since the first survey results. Cathet. Cardiovasc. Intervent. 50:160-167, 2000.

Retinoic acid acts during peri-implantational development to alter axial and brain formation.

All-trans retinoid acid (RA) induces a stereotypic spectrum of stage-specific malformations in vertebrate conceptuses. The present work evaluated the anatomic and biochemical effects of exposure to RA in mouse embryos at a peri-implantational stage of development - gestational day (GD) 5. The RA receptors (RARs) beta and gamma, the retinoid X receptors (RXRs) alpha and beta, and the cellular retinoid acid binding proteins (CRABPs) I and II were detected by RT-PCR in both control and treated individual GD 5 decidua/embryo complexes 3 h after RA injection, indicating the presence of the mRNAs coding for the proteins that mediate the effects of RA. In contrast, the RAR alpha mRNA was detected in some but not all decidua/embryo complexes, both control and treated, suggesting that its expression is initiated at approximately GD 5, while RXR gamma mRNA was not detected. Examination of the control and RA-exposed embryos on GD 10, 12, or 17 showed that greater than 50% of the RA-exposed embryos were adversely affected, many with defects found only after serial histopathological examination. The malformations were localized primarily in the central nervous system, the branchial arches, and their derivatives. These terata included excessive folding and elevation of the neural tube floor plate, exencephaly (with detachment of the cephalic neuroepithelium and rarefied cephalic mesenchyme), persistent patency of Rathke's pouch, small trigeminal ganglia, neural diverticula (chiefly from the spinal cord), and/or various optic and otic defects. Unexpectedly, limb reduplications were not apparent in RA-exposed fetuses. Those litters examined on GD 17 had a high percentage of resorbed or malformed implantations, and the few apparently normal fetuses were developmentally delayed with respect to bone ossification. These data confirm that the development of neural- and neural crest-derived structures are severely disrupted by RA exposure prior to initial specification of the neural plate and suggest that many of the proteins that regulate RA signaling are available in early vertebrate embryos at this developmental stage.

Coronary stenting in diabetics: immediate and mid-term clinical outcome.

Balloon angioplasty in diabetics is associated with acceptable immediate results but with high rates of restenosis, target vessel revascularization, and late mortality. The impact of coronary stenting on the outcome of these patients remains controversial. We reported the immediate and mid-term clinical outcome of 272 consecutive diabetic patients, representing 12.5% of the population undergoing coronary stenting between May 1995 and April 1997. Diabetes mellitus was insulin-requiring in 58 patients and non-insulin-requiring in 214. Stenting performed on large vessels (mean diameter >/=3 mm) was successful in 99.2% of nondiabetic patients and in all cases in diabetics. During in-hospital stay, the complications rate, including mortality, nonfatal myocardial infarction, emergency coronary bypass surgery, and stent subacute thrombosis, was similar in nondiabetic patients, insulin-requiring, and non-insulin-requiring diabetics (2.55%, 0%, and 2.0%, respectively). No complication occurred in the insulin-requiring group. One patient (0.5%) died from myocardial infarction and another (0.5%) presented a nonfatal myocardial infarction (subacute stent thrombosis) in the non-insulin-requiring group. The clinical follow-up (mean length 13 +/- 8 months) was obtained in 93% and 97% of the insulin-requiring and non-insulin-requiring diabetics, respectively. Overall mortality was significantly higher in insulin-requiring patients (9.3% vs. 2.4%). Nonfatal myocardial infarction and target lesion revascularization rates were similar in the two groups (0% vs. 0.5% and 8.2% vs. 10.5%). These results suggest that coronary stenting in diabetics could be performed with acceptable immediate and mid-term results. Cathet. Cardiovasc. Intervent. 47:279-284, 1999.

Results of stenting of unprotected left main coronary artery stenosis in patients at high surgical risk.

From March 1994 to September 1996, 39 patients underwent stenting of the unprotected left main coronary artery because of high surgical risk. Stenting appeared to improve clinical outcome, but there was a significant mortality rate at long-term follow-up.

[Implantation of coronary stents in diabetic patients. Short- and medium-term clinical results]. / Implantation d'endoprothèses coronaires chez les patients diabétiques. Résultats cliniques à court et moyen terme.

Coronary balloon angioplasty is associated with a high incidence of restenosis in diabetics and of revascularisation of the culprit lesion and increased long-term mortality. The authors report the short and medium-term results of coronary stenting in diabetics. Between May 1995 and April 1997, 2,182 patients underwent coronary stenting. This population included 272 diabetics : 58 insulin-dependent and 214 non-insulin dependent (oral antidiabetics). Stents were implanted in vessels with mean diameters of 3 mm and over. During the hospital period, the complication rate (mortality, non-fatal myocardial infarction, emergency coronary bypass surgery, subacute thrombosis of the stent) was comparable in non-diabetics, insulin-dependent and non-insulin-dependent diabetics (2.55, 0 and 2.0% respectively). One patient (0.5%) died and another (0.5%) had non-fatal myocardial infarction (thrombosis of the stent) in the non-insulin-dependent group. No complications were observed in the insulin-dependent diabetic group. The mean clinical follow-up of 13 months (3-26 months) was respected in 93 and 97% of diabetics. The non-fatal myocardial infarction rate and revascularisation of the culprit lesion were comparable in the insulin and non-insulin-dependent groups (0 versus 0.5% and 8.2 versus 10.5% respectively) but global mortality was higher in the insulin-dependent diabetics (9.3 versus 2.4%).

Cognitive-behavioral techniques in the treatment of chronic low back pain: preliminary results.

Review of the literature reveals chronic low back pain has not responded well to conventional medical treatment with medication and surgery. The addition of cognitive-behavioral approaches to complement conventional medicine seems to improve the results and lessens pain in this group of patients.

Current global status of carotid artery stent placement.

Our purpose was to review the current status of carotid artery stent placement throughout the world. Surveys were sent to major interventional centers in Europe, North and South America, and Asia. Information from peer-reviewed journals was also included and supplemented the survey. The survey asked various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. Of the centers which were sent surveys, 24 responded. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 2,048 cases, with a technical success of 98.6%. Complications that occurred during carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 63 minor strokes, with a rate of occurrence of 3.08%. The total number of major strokes was 27, for a rate of 1.32%. There were 28 deaths within a 30-day postprocedure period, resulting in a mortality rate of 1.37%. Restenosis rates of carotid stenting have been 4.80% at 6 mo. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative to vascular surgery, especially for patients that are at high risk for standard carotid endarterectomy. The periprocedural risks for major and minor strokes and death are generally acceptable at this early stage of development.

Renal effects of fumonisin mycotoxins in animals.

Fumonisins are mycotoxins produced worldwide by Fusarium fungi, principally F. moniliforme. The fungus is present in virtually all harvested corn, but the toxins produced are variable. The toxins, especially fumonisin B1, cause mild to fatal diseases in animals, with peculiar species specificity for the dominant signs of toxicity. The mechanism of toxicity is poorly understood, but it appears to be related to interference with sphingolipid biosynthesis in multiple organs. Whereas brain, lung, and liver are well-known target organs, toxic effects on the kidney are also widespread and have only recently begun to be characterized. Increased urine volume and decreased osmolarity are early changes associated with the toxin, as are increased excretions of high- and low-molecular-weight proteins. Enzymuria in vivo, reduced ion transport in vitro, and elevation of free sphinganine in renal tissue and in urine are present. An increase in serum creatinine and blood urea nitrogen and histopathologic change in renal tubules occur later and at higher doses. The morphologic change principally affects the junction of cortex and medulla and includes prominent apoptosis of epithelial cells of proximal convoluted tubules. Nephrotoxicity has been reported in several species, and in rats and rabbits, the kidney appears to be the most sensitive target organ.