Epidemiology of treatment-associated mucosal injury after treatment with newer regimens for lymphoma, breast, lung, or colorectal cancer

Goals of work: Oral and gastrointestinal (GI) mucositis are frequent complications of chemotherapy and radiotherapy for cancer, contributing to not only the morbidity of treatment but its cost as well. The risk associated with specific chemotherapeutic agents, alone and in combination, has been characterized previously. In the current study, we sought to estimate the risk associated with newer regimens for the treatment of non-Hodgkin’s lymphoma (NHL) and common solid tumors. Methods: We reviewed published studies reporting phase II and III clinical trials of dose-dense regimens for breast cancer and NHL, TAC (docetaxel, adriamycin, cyclophosphamide) chemotherapy for breast cancer, and infusional 5-fluorouracil-based regimens for colorectal cancer. Platinum-, gemcitabine-, and taxane-based regimens for lung cancer, either alone or in combination with radiotherapy, were also considered. Using modified meta-analysis methods, we calculated quality-adjusted estimates of the risk for oral and GI mucositis by tumor type and regimen. Case reports are used to emphasize the relevance of the findings for patient care. Main results: Our findings demonstrate that mucosal toxicity remains an important complication of cancer treatment. Moreover, innovations in drug combinations, scheduling, or mode of administration significantly modulate the risk for both oral and GI mucositis. Conclusions: Ongoing review of the clinical trial experience will remain important as newer, targeted agents enter standard clinical practice.     

Hypnotic analgesia for chronic pain in persons with disabilities: a case series

Thirty-three adults with chronic pain and a disability were treated with hypnotic analgesia. Analyses showed significant pre- to posttreatment changes in average pain intensity that was maintained at 3-month follow-up. Significant changes were also found in pain unpleasantness and perceived control over pain but not in pain interference or depressive symptoms. Hypnotizability, concentration of treatment (e.g., daily vs. up to weekly), and initial response to treatment were not significantly associated with treatment outcome. However, treatment-outcome expectancy assessed after the first session showed a moderate association with treatment outcome. The findings support the use of hypnotic analgesia for the treatment of pain in persons with disabilities for some patients but not the use of pretreatment measures of hypnotizability or treatment-outcome expectancy for screening patients for treatment.     

Demonstration of surface antigens on bronchoalveolar lavage cells using the immunoalkaline phosphatase method

The immunoalkaline phosphatase procedure is described as a method for labelling bronchoalveolar lavage cellular specimens with monoclonal antibodies. This method has several advantages over conventional immunofluorescent techniques: it can be performed on cytocentrifuge preparations stored for long periods before staining; cell morphology can be observed in detail in positive and negative cells; the staining is permanent and stable, and, the reaction can be evaluated with a light microscope. Normal values for lymphocyte subpopulations in smokers and nonsmokers are also reported.     

Clinical and genetic characteristics of Mexican Huntington's disease patients

We report the characteristics of 691 Mexican patients with Huntington's disease (HD). These patients, representing 401 families, constitute the largest series of Mexican HD cases as yet described in the literature. We found the clinical characteristics of these patients to be similar to those of other populations, but we observed a higher frequency of infantile cases, a shorter disease duration and a lower suicide rate. In 626 cases, for which molecular analyses were available, CAG‐trinucleotide expansion size ranged from 37–106 repeats. The large number of CAG repeats (19.04 ± 3.02) in normal alleles and the presence of new mutations suggest that the overall prevalence of HD in the Mexican population could be expected to be within range of, or higher than, that reported for Europeans. © 2009 Movement Disorder Society     

Role of Complement in Host Defense against Pneumococcal Otitis Media

Strategies to limit complement deposition on Streptococcus pneumoniae are established as virulence features for invasive disease, but their role in respiratory tract infection requires further analysis. We evaluated complement C3 protein deposition on discordant S. pneumoniae isolates of the same serotype (6A) and their capacity to cause nasopharyngeal (NP) colonization and experimental otitis media (EOM) in an animal model. We compared C3 binding to five 6A isolates from asymptomatic NP carriers with five 6A strains that caused invasive disease, and we observed less C3 (∼10-fold less fluorescence) binding to invasive isolates. We selected two high-level C3-binding carriage and two low-level C3-binding invasive 6A isolates for further study. In the EOM model, 11/12 (92%) ears challenged with a low-level C3-binding 6A strain became infected. Only 2/8 (25%) ears challenged with the discordant high-level C3-binding 6A isolate developed disease (P = 0.005). Results with the second discordant 6A isolate pair were comparable. Cobra venom factor (CoVF) treatment, which depletes C3 and consumes complement, restored virulence of the high-level C3-binding strain; 8/8 (100%) ears in CoVF-treated animals developed EOM compared to only 25% of ears in naïve animals (P = 0.007). These studies demonstrate the critical role for complement evasion in pneumococcal EOM. Colonization with carriage isolates that bound high levels of C3 caused EOM in fewer animals compared to low-level C3-binding invasive strains. Thus, limiting C3 deposition on the surface of S. pneumoniae correlates with increased incidence of EOM following NP colonization and barotrauma in the animal model.The pathogenesis of Streptococcus pneumoniae infection involves initial colonization of the nasopharynx, followed by its spreading to the middle ear, sinus, or lower respiratory tract and, in some cases, invasion of the bloodstream. To successfully cause disease, the pneumococcus has evolved a number of mechanisms to avert complement-mediated opsonization and phagocytosis. Pneumococci possess a broad variety of specialized surface proteins, some of which are adapted to interact with host defenses during colonization or dissemination in humans. Being a gram-positive bacterium, it is resistant to the bactericidal activity of complement (24) because its rigid cell wall prevents lysis by the membrane attack complex. The capsular polysaccharide is critical for resistance to complement deposition (32) and may also mask cell wall-associated complement from being recognized by the complement receptors on phagocytes (6). Additionally, select surface proteins can degrade native C3 proteins, thereby preventing or diminishing binding of C3b and iC3b to the bacterial surface, which are necessary components for opsonization (3). Furthermore, an important role for complement is suggested by the association of increased risk for invasive infections in individuals (or animal models) with deficiencies of complement proteins such as C2 and C3 and of complement receptors such as CR3 (2, 16). Type-specific antibody formation is an important host defense mechanism against infections caused by S. pneumoniae. However, the efficacy of opsonization of pneumococci by either immunoglobulin M (IgM) or IgG is related to their ability to enhance complement deposition on the bacterial surface, thus making complement essential for recovery from pneumococcal disease (6, 9).Colonization of mucosal surfaces is often the first step in the development of disease. Studies of S. pneumoniae support recent acquisition as the critical event preceding the development of pneumococcal otitis media. S. pneumoniae has evolved specific characteristics that are critical in dictating initial success for establishing colonization within a competitive niche of the mucosal surface of the nasopharynx. Often the success of an organism in establishing carriage depends on its ability to resist innate clearance mechanisms generated in the setting of polymicrobial stimulation. Lysenko and colleagues have demonstrated that complement and polymorphonuclear leukocytes are necessary host defenses for the elimination of S. pneumoniae from the nasopharynx in the presence of nontypeable Haemophilus influenzae (NTHi) (29).Prior work from our laboratory demonstrated that complement was an important host defense mechanism against protection of the middle ear from infection with NTHi (15). We hypothesized that complement would also be relevant for protection against S. pneumoniae respiratory tract infection (RTI). We evaluated the role of complement by comparing the capacities of four isolates of S. pneumoniae, all belonging to serotype 6A but differing in their abilities to bind complement to their surface to cause otitis media following nasopharyngeal (NP) colonization. Our goal was to determine whether evasion of complement deposition was an important virulence feature in the pathogenesis of RTI, using a model for experimental otitis media (EOM). The model requires initial NP colonization followed by ascension through the Eustachian tube after barotrauma for establishing middle ear infection.     

Literature review on the safety of Toyocerin,a non-toxigenic and non-pathogenic Bacillus cereus var. toyoi preparation

Bacillus cereus var. toyoi is a naturally occurring, non-toxigenic and non-pathogenic strain of B. cereus. Safety studies were conducted on a B. toyoi preparation (Toyocerin^®), including but not limited to enterotoxicity, eye irritation, genotoxicity, acute, subchronic and chronic toxicity studies and human clinical trials. In rabbits, Toyocerin^® did not exhibit enterotoxicity and was only slightly irritating to the eyes. It was non-mutagenic in an Ames assay at up to 10,000 μg/plate and did not exhibit clastogenic activity in a chromosomal aberration test at up to 450 mg/ml. It was non-toxic in acute and repeated-dose (30 and 60 days and 1 year) toxicity studies in rats and mice at up to 3 × 10¹¹ spores/kg bw/day. In an eight-day human clinical trial, Toyocerin^® did not cause any adverse effects in healthy male and female subjects at 1 × 10⁹ and 1 × 10¹⁰ spores/kg bw/day. In feeding trials, Toyocerin^® did not cause any adverse effects in rabbits, pigs, chickens, turkeys and cattle at doses ranging from 8.5 × 10⁷ to 4 × 10⁹ spores/kg bw/day for durations of 2 weeks to 18 months. Taken together, these studies demonstrate that Toyocerin^® is safe at the doses tested.