Anterior resection syndrome: What should we tell practitioners and patients in 2018?

Multidisciplinary management of infra-peritoneal rectal cancer has pushed back the frontiers of sphincter preservation, without impairment of carcinological outcome. However, functional intestinal sequelae, grouping together several symptoms known under the name of anterior resection syndrome (ARS), have emerged and become an increasingly frequent concern for both patients and physicians. The pathophysiology is complex: ARS is a combination in various degrees of stool frequency, incontinence for flatus and/or stools, urgency, and disorders in discrimination and evacuation. The "Low Anterior Resection Score" (LARS), validated in 2012, is currently used to evaluate the severity of ARS and its impact on quality of life. While ARS can show improvement over the first two years, symptoms persist for longer than two years in nearly 60% of patients and in half of these patients, ARS is considered severe. The most frequently reported independent risk factors of severe ARS include neo-adjuvant radiation therapy, the extent of resection (total mesorectal excision that includes inter-sphincteric resection), absence of colonic pouch and anastomotic leak. In the absence of surgical complications and/or local recurrence, physicians can draw from a wide therapeutic armamentarium in order to improve the functional outcome of patients, including diet and lifestyle modifications, gut motility regulators, multimodal rehabilitation (biofeedback, electro-stimulation) and sacral nerve modulation. Permanent colostomy is an alternative of last resort, proposed only when all other solutions fail. A better understanding of the natural history of ARS, its risk factors as well as the array of therapeutic alternatives should provide better patient information and optimize management.

Cost effectiveness of posaconazole in the prophylaxis of invasive fungal infections in acute leukaemia patients for the French healthcare system.

BACKGROUND: Acute myeloblastic leukaemia (AML) patients are at high risk of suffering from invasive fungal infections (IFI). Posaconazole demonstrated higher efficacy than standard azole agents (SAA) in the prophylaxis of IFI in this population. The authors estimated the cost effectiveness of posaconazole versus SAA in France. METHODS: A decision-tree model was developed to compare posaconazole with SAA with the results of a published clinical trial. Clinical events were modelled with chance nodes reflecting probabilities of IFI, IFI-related death, and death from other causes. Medical resource consumption and costs were obtained from results of the clinical trial and from a dedicated survey on the costs of treating IFI using a retrospective chart review design. RESULTS: IFI treatment costs were estimated using medical files from 50 AML patients from six French centres, with a proven and probable IFI, who had been followed-up for 298 days on average. Direct costs directly related to IFI were estimated at €51,033, including extra costs of index hospitalisation, costs of antifungal therapy and additional hospitalisations related to IFI treatment. The model indicated that the healthcare costs for the posaconazole strategy were €5,223 (€2,697 for prophylaxis and €2,526 for IFI management), which was €859 less than the €6,083 in costs with SAA (€469 for prophylaxis and €5614 for IFI management). A sensitivity analysis indicated that there was an 80% probability that prophylaxis using the posaconazole strategy would be superior. CONCLUSION: The findings from this analysis suggest that posaconazole use is a clinically and economically dominant strategy in the prophylaxis of IFI in AML patients, given the usual limits of economic models and the uncertainty of costs estimates.

A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients.

The efficacy, safety, and tolerability of voriconazole and fluconazole were compared in 391 immunocompromised patients with mycology- and biopsy-proven esophageal candidiasis. Primary efficacy analysis (256 patients) of esophageal treatment as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole. The 95% confidence interval for the difference in success rates ranged from -1.0% to 7.5%. The overall safety and tolerability of both antifungals were acceptable. Fewer patients discontinued voriconazole treatment because of insufficient clinical response (4 patients [2.0%] vs. 5 patients [2.6%]). More patients discontinued voriconazole than fluconazole treatment because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). The most frequent adverse events (23%) with voriconazole were mild, transient visual disturbances. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as fluconazole in the treatment of biopsy-proven esophageal candidiasis in immunocompromised patients.

Cloning, chromosomal localization and promoter analysis of the human transcription factor YY1.

Yin Yang 1 (YY1) is a protein that activates and represses transcription of a large number of cellular and viral genes. In addition, studies suggest that YY1 may play an important role in development and differentiation. Here, we report the isolation and analysis of a YY1 genomic clone from a lambda human liver library. Fluorescence in situ hybridization with the YY1 clone has localized the YY1 gene to chromosome 14 band q32. A major YY1 gene transcription initiation site has been mapped to 478 bp upstream of the ATG translation start site. The proximal promoter contains multiple Sp1 transcription factor binding sites but lacks a consensus TATA or CCAAT box. Transient transfections and detailed deletion analyses localized the promoter to no more than 277 bp upstream from the major transcription start site. Finally, we have found that overexpression of the adenovirus E1A protein represses expression of a reporter gene directed by the YY1 promoter.

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Localization of a gene for a glutamate binding subunit of a NMDA receptor (GRINA) to 8q24.

A glutamate binding subunit gene, GRINA, has been previously mapped to human chromosome 8. A form of inherited epilepsy, benign familial neonatal convulsions (BFNC), has also been localized to chromosome 8. As NMDA receptors have been implicated in the pathogenesis of epilepsy, we were interested in determining whether GRINA mapped to the same region of chromosome 8 as BFNC. Fluorescence in situ hybridization localized GRINA to band 8q24, distal to the thyroglobulin gene. The strongest signal was seen at 8q24.3. A panel of 97 radiation hybrids (RH) was used to verify the localization. The RH mapping results placed GRINA as the most telomeric marker on our map of 8q24, distal to the interval defined for BFNC.

Successful treatment of a brain abscess due to Trichoderma longibrachiatum after surgical resection.

A case of brain abscess due to Trichoderma longibrachiatum in a leukemic patient with prolonged neutropenia is reported. Definitive cure was achieved after neurosurgical resection of the abscess and prolonged antifungal therapy. Trichoderma is a filamentous fungus species, which is only exceptionally pathogenic in humans. This genus and particularly the species Trichoderma longibrachiatum should be added to the growing list of fungi causing infection in immunocompromised patients.

Fluconazole concentrations in saliva from AIDS patients with oropharyngeal candidosis refractory to treatment with fluconazole.

Fluconazole (FCZ) has been extensively used as a primary therapy for oropharyngeal candidosis in AIDS patients. Clinical resistance to FCZ is now encountered, often related to decreased susceptibility of the isolate in vitro. We wondered if low levels in saliva play a role in the therapeutic failure, especially in patients complaining of dry mouth. Sixteen AIDS patients treated for oropharyngeal candidosis with FCZ were studied. MICs for the isolates were determined. Serum and saliva samples were collected to measure FCZ levels with a bioassay using paper disks loaded with the clinical specimens. We showed that (i) paper disks were convenient for collecting saliva in patients with dry mouth; (ii) levels in saliva depended on the FCZ dosage regimen but did not correlate with the response to therapy; (iii) correlation between concentrations in saliva and serum was poor and independent of clinical response to treatment, other therapies, or decreased salivation; and (iv) levels in saliva were always lower than MICs in patients who failed to respond to treatment. In conclusion, therapeutic failures are more likely to be related to in vitro resistance of the isolate to FCZ or insufficient dosage regimen than to decreased salivary secretion.

Candida albicans genotyping in studies with patients with AIDS developing resistance to fluconazole.

We characterized Candida albicans strains responsible for recurrent oropharyngeal candidosis (OPC) in four patients with AIDS who developed clinical and mycological resistance to fluconazole (FCZ). Karyotype and restriction fragment length polymorphism analyses were performed on the clonal populations to differentiate relapse from reinfection, and the results were assessed with those of serotype and FCZ MICs. Despite the polymorphism in chromosomal bands larger than 2.2 Mbp related to an intraclonal variation, karyotype analysis showed a single strain type attributable to each patient. On the other hand, EcoRI and HinfI restriction fragments revealed a polymorphism for one patient between the first sample and the subsequent ones, relevant to the acquisition of a new strain causing the following episodes of OPC. This result coincided with switching of the serotype and with the acquisition of a resistance to FCZ. For the other three patients, the similarity of the DNA electrophoretic patterns and the serotype of the samples suggested that recurrence can be due to the initial strain that generates FCZ resistance. Although useful for epidemiological studies, molecular typing methods seem to be inadequate to detect the acquisition of FCZ resistance.

Evaluation of HLA-haplotype disparate parental marrow grafts depleted of T lymphocytes by differential agglutination with a soybean lectin and E-rosette depletion for the treatment of severe combined immunodeficiency.

The factors that impact upon successful bone marrow transplantation leading to immunologic reconstitution in severe combined immune deficiency (SCID). Wiskott-Aldrich syndrome, and in other lethal congenital immunodeficiencies are reviewed. Evidence is presented that graft-versus-host disease (GVHD) can be abrogated by the depletion of T cells, even from histoincompatible marrow grafts. However, graft resistance or restricted immune reconstitution has been observed with significant frequency. The bases for T cell reconstitution and limitations in B cell humoral immune recovery in the postgrafting period are reviewed, together with emerging evidence that pretransplant cytoreduction might obviate some of these problems.

Laboratory and clinical assessment of ketoconazole in deep-seated mycoses.

Forty-eight cases of deep mycoses were studied and treated with ketoconazole, each with in vitro evaluation of the minimum inhibitory concentrations (MIC) of the causative fungi, in vivo pharmacokinetic, clinical, and mycologic evaluations, several months to two years after the treatment was stopped. Excellent results were obtained in six cases of chronic mucocutaneous candidiasis, with restoration of immunologic disturbances; 23 cases of systemic candidiasis, including new aspects of heroin addicts with cutaneous, ocular, or osteoarticular manifestations; eight cases of histoplasmosis, five due to Histoplasma capsulatum and three to Histoplasma duboisii, with cure in seven and remission in one; one case of African blastomycosis (Blastomyces dermatitidis); three cases of mycetoma, two due to Monosporium apiospermum, one due to a dematiacious fungus; three cases of entomophthoromycosis with cure; one case of fungal arthritis, due to new hyphomycete similar to M. apiospermum, pathogenic for laboratory animals; one case of Drechslera longirostrata causing vertebral arthritis, following a fungal endocarditis and cured by combination of ketoconazole with amphotericin B, each agent alone being ineffective; and other deep mycoses.

In vitro synergy and antagonism of antifungal agents against yeast-like fungi.

Some antifungal agents have been tested qualitatively in various associations against species of Candida, Cryptococcus and Torulopsis. The method used was the channel test and the results are confirmed by comparison with the serial dilution test in agar. The antagonism in vitro with the combination of amphotericin B imidazole suggests that caution must be exercised before prescribing the antifungal drugs in combination for man. The frequent synergy of flucytosine with econazole is, however, encouraging because of the low toxicity of the 2 drugs. Under the limited conditions described, the combination of flucytosine and amphotericin B was not found synergistic but additive on the strains of C. albicans used in this study. This combination was found synergistic for a strain of C. parapsilosis and is useful for avoiding resistance to flucytosine.