A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer

PURPOSE: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. METHODS AND MATERIALS: Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m(2) weekly) and 5-FU (225 mg/m(2)/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. RESULTS: A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. CONCLUSIONS: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.     

Serological response to pneumococcal vaccination in HAART-treated HIV-infected patients: one year follow-up study

The aim of this study was to evaluate specific IgG responses against pneumococcal serotypes 1, 6B, 14, 19F, 23F at baseline, 1 and 12 months after vaccination with the 23-valent polysaccharide pneumococcal vaccine in 89 HAART-treated HIV-infected patients, 24 antiretroviral "na?ve" HIV-infected and 30 non-HIV-infected healthy subjects. Levels of specific antipneumococcal IgG and the mean fold increase in IgG levels at 1 month as well as the kinetics of antibodies along the 12 months in all groups of HIV-infected patients and healthy subjects were similar. Neither CD4 cell count at baseline nor "nadir" CD4 cells correlated with the response to the vaccine. In conclusion, the immunogenicity conferred by the polysaccharide vaccine in HIV-infected patients under HAART is at least as good as that observed in healthy subjects.     

Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells

Methylation-associated silencing of tumor suppressor genes is recognized as being a molecular hallmark of human cancer. Unlike genetic alterations, changes in DNA methylation are potentially reversible. This possibility has attracted considerable attention from a therapeutics standpoint. Nucleoside-analogue inhibitors of DNA methyltransferases, such as 5-aza-2'-deoxycytidine, are able to demethylate DNA and restore silenced gene expression. Unfortunately, the clinical utility of these compounds has not yet been fully realized, mainly because of their side effects. A few non-nucleoside inhibitors of DNA methyltransferases have been reported, including the anti-arrhythmia drug procainamide. Following this need to find new demethylating agents, we have tested the potential use of procaine, an anesthetic drug related to procainamide. Using the MCF-7 breast cancer cell line, we have found that procaine is a DNA-demethylating agent that produces a 40% reduction in 5-methylcytosine DNA content as determined by high-performance capillary electrophoresis or total DNA enzyme digestion. Procaine can also demethylate densely hypermethylated CpG islands, such as those located in the promoter region of the RAR beta 2 gene, restoring gene expression of epigenetically silenced genes. This property may be explained by our finding that procaine binds to CpG-enriched DNA. Finally, procaine also has growth-inhibitory effects in these cancer cells, causing mitotic arrest. Thus, procaine is a promising candidate agent for future cancer therapies based on epigenetics.     

Evaluation of lung epithelial permeability

During the last few years a number of factors affecting the measurement of the rate of absorption of ^99mTc-DTPA across the alveolar-capillary membrane have been identified. These have helped to provide insights into the significance of lung epithelial permeability (LEP) measurements and their potential limitations. Pulmonary absorption of ^99mTc-DTPA has been studied in a variety of clinical conditions and the results are discussed.

     

Risk factors in histamine liberation: a prospective study in an anesthetized population

23,444 anaesthetic files were collected over a 12-month period from all the anaesthetic departments of the Regional Hospital in Nancy and three private clinics in town. The data were set out on a computer data-sheet aimed at defining the risk factors for histamine release. As a result, two groups are defined: a group of patients who released histamine (HL+; n = 212) and a group of patients who did not release histamine (HL-; n = 23,232). In increasing order of severity, the incidence of reactions were 1 in 143 for chest erythema, 1 in 630 for generalized erythema and Quincke's oedema, 1 in 230 for generalized erythema and hypotension, and 1 in 23,444 for fatal shock. The two groups were compared one with the other for each factor, using the chi-squared test or Fisher's test of exact probabilities. The statistically significant risk factors were: female patients, patients aged between 15 and 25 years, patients with an allergic history, a history of multiple anaesthesias, close one after the other, and exaggerated preanaesthetic anxiety. The drugs most often incriminated were: Althesin, propanidid, suxamethonium, alcuronium, gallamine and Haemaccel. A multifactorial analysis is being carried out to determine the part played by each factor in the release of histamine.     

Utility of 99mTc-sestamibi scintigraphy as a first-line imaging procedure in the preoperative evaluation of hyperparathyroidism

OBJECTIVE The use of preoperative imaging in patients with hyperparathyroidism remains controversial. Many of the available techniques are insufficiently sensitive and specific to justify their routine use. We have evaluated the Sensitivity and specificity of ^99mTc-sestamibi scintigraphy in the management of patients with different forms of hyperparathyroidism. DESIGN Preoperative imaging evaluation was carried out by sclntigraphic detection of pathological parathyroid glands using ^99mTc-sestamibi as a radiotracer; confirmation of scan findings was obtained surgically. PATIENTS A group of 25 patients with primary (n= 21) or secondary (n=4) hyperparathyroidism were studied. All were considered for surgical treatment. MEASUREMENTS In all cases parathyroid imaging was carried out by ^99mTc-sestamibi scintigraphy together with at least one other imaging technique which included CT-scan, ultrasonography, MRI or ²⁰¹TI/^99mTc subtraction scintigraphy. Blood tests included measurements of total calcium and PTH. RESULTS ^99mTc-sestamibi scintigraphy correctly localized 20 out of 21 adenomas, giving a sensitivity of 95.2%, markedly higher than that obtained with the other imaging techniques (ultrasonography 75%, ²⁰¹TI/^99mTc subtraction scintigraphy 57.1%, CT-scan 41.7% and MRI 33%). Of a total of 17 glands identified surgically as hyperplastic and confirmed by pathological examination, ^99mTc-sestamibi scintigraphy showed a positive image in 10, corresponding always to the larger abnormal glands (sensitivity 58.8%, higher than that observed with the other techniques). No false positive images were obtained with ^99mTc-sestamibi. All the ectopic adenomas (n= 3) were identified preoperatively, which contributed significantly to the surgical approach. CONCLUSION In patients with hyperparathyroidism, ^99mTc-sestamibi scintigraphy may be used as the single imaging technique as it shows a very high sensitivity and specificity in the preoperative localization of pathological parathyroid glands; the benefit of localizing parathyroid tissue prior to surgery in cases of ectopic adenomas clearly indicates that when an imaging procedure is required, this technique may be of great help in the management of hyperparathyroidism.     

Results and complications of induction treatment of acute leukemia in children. A personal series of 79 cases (1988-1989)]

In 1988 and 1989, 79 children have been treated for induction of acute leukemia. 68 presented an acute lymphoblastic leukemia (ALL) and 11 an acute non-lymphoblastic leukemia (ANLL). The complete remission rate was 92% (96% in ALL, 73% in ANLL). Fever occurred in 50% of the children, with positive blood cultures in 11 of them. One child died from streptococcal sepsis. No metabolic disorder was noted. Four patients were transferred into the intensive care unit. After 8 days, the treatment of ALL was continued in the outpatient clinic in more than 50% of the cases. The treatment of ANLL is frequently complicated by hemorrhages and sepsis and needs adapted supportive care in a specialized unit.     

Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis

Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.     

Effects of lead,cadmium, copper and zinc levels on the male reproductive function

This study aimed to investigate the effects of heavy metals on measures of male fertility. One hundred and two infertile men with occupational exposure and thirty fertile men were included in this study. Blood and urinary levels of lead, cadmium, zinc and copper were measured by atomic absorption spectrophotometry. Semen parameters and a motile sperm organelle morphology examination were also performed. Measures of hormonal levels, oxidation–reduction potential, DNA fragmentation index and chromatin condensation were assessed for all participants. Heavy metals levels, oxidative stress and DNA quality were significantly higher in the infertile group compared to controls. FSH and testosterone levels were lower in the infertile group. A urinary cadmium level was positively associated with abnormal sperm morphology (r = .225, p < .05). Normal morphology was inversely correlated with the duration of the exposure (r = −.227, p = .022). The blood lead level was positively related to the level of testosterone (r = .223, p = .031). Cadmium and lead blood levels were positively correlated with the level of chromatin decondensation (r = .528, p < .001; r = .280, p = .017). Our study showed that occupational exposure to heavy metals is very harmful to reproductive health. DNA quality and oxidative stress investigations must be recommended for reprotoxic exposed patients prior to in vitro fertilisation treatment.     

Summary of Recommendations and Key Points of the Consensus of Spanish Scientific Societies (SEPAR,SEMICYUC, SEMES; SECIP,SENEO, SEDAR,SENP) on the Use of Non-Invasive Ventilation and High-Flow Oxygen Therapy with Nasal Cannulas in Adult,Pediatric, and Neonatal Patients With Severe Acute Respiratory Failure

Non-invasive respiratory support (NIRS) in adult, pediatric, and neonatal patients with acute respiratory failure (ARF) comprises two treatment modalities, non-invasive mechanical ventilation (NIMV) and high-flow nasal cannula (HFNC) therapy. However, experts from different specialties disagree on the benefit of these techniques in different clinical settings. The objective of this consensus was to develop a series of good clinical practice recommendations for the application of non-invasive support in patients with ARF, endorsed by all scientific societies involved in the management of adult and pediatric/neonatal patients with ARF.To this end, the different societies involved were contacted, and they in turn appointed a group of 26 professionals with sufficient experience in the use of these techniques. Three face-to-face meetings were held to agree on recommendations (up to a total of 71) based on a literature review and the latest evidence associated with 3 categories: indications, monitoring and follow-up of NIRS. Finally, the experts from each scientific society involved voted telematically on each of the recommendations. To classify the degree of agreement, an analog classification system was chosen that was easy and intuitive to use and that clearly stated whether the each NIRS intervention should be applied, could be applied, or should not be applied.