Nivolumab-induced lichenoid granulomatous stomatitis in a patient with advanced melanoma: A case report.

Lichenoid granulomatous reactions (LGR) are granulomatous inflammations of the skin and oral mucosa, also sharing features of lichenoid lesions. Thus, the present study refers to lichenoid granulomatous dermatitis (LGD) and lichenoid granulomatous stomatitis (LGS). LGR is a condition that can be triggered by drugs, diseases or environmental causes. In the present case study, anti-PD1 (nivolumab) medication had a detrimental effect on the oral mucosa, which clinicaly and histologicaly proved to be LGS. Checkpoint inhibitors consitute a cornerstone in the current treatment of several types of cancer, of which cutaneous melanoma is the best example. Oral lichenoid responses following anti-PD-1 therapy have been recorded in few case reports and small case series. To the best of our knowledhe, this is the first case of LGS being reported as a side effect of immune checkpoint inhibitor treatment.

Efficacy of prolonged antimicrobial chemotherapy for brucellar spondylodiscitis.

The standard treatment of brucellar spondylitis with a combination of two antibiotics for 6-12 weeks is associated with high rates of treatment failure and relapse. The present study aimed to assess the safety and efficacy of a treatment strategy based on the prolonged administration of a triple combination of suitable antibiotics. Eighteen patients with brucellar spondylitis were treated with a combination of at least three suitable antibiotics (doxycycline, rifampin, plus intramuscular streptomycin or cotrimoxazole or ciprofloxacin) until the completion of at least 6 months of treatment, when clinical, radiological and serology re-evaluation was performed. If necessary, the treatment was continued with additional 6-month cycles, until resolution or significant improvement of clinical and radiological findings, or for a maximum of 18 months. At presentation, the median age was 66 years (range, 42-85 years) with male predominance. The median duration of therapy was 48 weeks (range 24-72 weeks). Treatment was discontinued early because of side-effects in only one patient. Surgical intervention was required for three patients. At the end of treatment all patients had a complete response. After completion of treatment, all patients were followed up with regular visits. During the follow-up period (duration 1-96 months, median 36.5 months), no relapses were observed. In conclusion, prolonged (at least 6 months) administration of a triple combination of suitable antibiotics appears to be an effective treatment for brucellar spondylitis.

HPLC determination of mepiquat chloride in commercial pesticide formulations.

A simple, fast and precise High Performance Liquid Chromatographic method with diode array detector was developed and single laboratory validated for the determination of mepiquat chloride in soluble concentrate pesticide formulations. From the results obtained, the repeatability of the method expressed as relative standard deviation (%RSD) was found to be 0.3%, and the limit of detection was 0.02 microg/mL. The accuracy of the whole procedure estimated by the comparison of the results obtained with the reference values, and was found to be acceptable as t(cal) < t(crit). The precision of the method also considered acceptable as the experimental repeatability relative standard deviation (RSD(r)) was lower than the interlaboratory relative standard deviation (RSD(R)), calculated by the Horwitz equation.

Definition of permissible and immunogenic HLA antigens based on epitope analysis of the HLA specific antibodies produced in sensitized patients.

The goal of this study was to develop an accurate protocol whereby detection of acceptable HLA-A and -B mismatches is based on epitope analysis of HLA class I specific antibodies detected in the serum of highly sensitized patients awaiting a kidney retransplant. A total of 400 serum samples from 44 highly sensitized patients with panel reactive antibodies (PRA) of > or = 60% were collected during a 3-year follow-up period. All patients had been sensitized from a previous graft. In order to define the specificities of the HLA class I specific antibodies, two techniques were used in parallel: the antihuman globulin augmented complement-dependent cytotoxicity (CDC) technique and an enzyme-linked immunoabsorbent assay (ELISA) technique. Epitope identification was based on class I HLA antigen sequencing, where the unique epitope configuration on one HLA antigen represented the private epitope of the specific HLA antigen, and epitopes shared by more than one HLA antigen represented public determinants. The epitope prediction for the immunogenic HLA epitopes was based on an MHC database. For each highly sensitized patient, antibody specificities against actual and 'at risk' epitopes were defined. Following epitope analysis, all HLA antigens that did not express the actual and/or 'at risk' immunogenic epitopes were considered as acceptable mismatches of epitope analysis. The cytotoxicity of highly sensitized patients was determined using two different panels of selected, separated T lymphocytes. HLA class I specific IgG antibodies against 69 actual and 86 'at risk' epitopes were detected. In all patients, a large number of acceptable mismatches were defined. These included a large number of HLA antigens, corresponding to both HLA-A and -B loci. Our study introduces an accurate protocol for the detection of acceptable mismatches in highly sensitized patients. According to this protocol, the detailed description of immunogenic HLA specific epitope targets, against which HLA class I specific antibodies are directed, is a useful tool for the detection of acceptable mismatches in highly sensitized patients. This may lead to reduced production of HLA class I specific antibodies and, consequently, improved graft survival.

Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study.

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P<0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P< or =0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index < or =0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.

Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group.

A randomized, double-blind trial comparing oral fluconazole (400 mg daily) with placebo as prophylaxis for adult patients receiving intensive cytotoxic therapy for acute leukemia or autologous bone marrow transplantation was conducted in 14 Canadian university-affiliated hospitals. Although fluconazole prophylaxis did not obviate the need for parenteral antifungal therapy compared with placebo (81 [57%] of 141 vs. 67 [50%] of 133, respectively), its use resulted in fewer superficial fungal infections (10 [7%] of 141 vs. 23 [18%] of 131, respectively; P = .02) and fewer definite and probable invasive fungal infections (9 vs. 32, respectively; P = .0001). Fluconazole recipients had fewer deaths attributable to definite invasive fungal infection (1 of 15 vs. 6 of 15, respectively; P = .04) and achieved more frequent success without fungal colonization (52 [37%] of 141 vs. 27 [20%] of 133, respectively; P = .004; relative risk reduction, 85%) than did placebo recipients. Patients benefiting the most from fluconazole prophylaxis included those with acute myeloid leukemia who were undergoing induction therapy with cytarabine plus anthracycline-based regimens and those receiving marrow autografts not supported with hematopoietic growth factors. Fluconazole prophylaxis reduces the incidence of superficial fungal infection and invasive fungal infection and fungal infection-related mortality among patients who are receiving intensive cytotoxic chemotherapy for remission induction.

Candidemia at selected Canadian sites: results from the Fungal Disease Registry, 1992-1994. Fungal Disease Registry of the Canadian Infectious Disease Society.

BACKGROUND: Candida species are important bloodstream pathogens that are being isolated with increasing frequency. Despite the availability of effective antifungal therapy, the mortality rate associated with Candida infection remains high. With the objective of describing the epidemiology of candidemia, the Canadian Infectious Disease Society conducted a study of candidemia in Canada. METHODS: Fourteen medical centres across Canada identified all patients with candidemia from March 1992 to February 1994 through blood culture surveillance for Candida spp. Patient-related data for invasive fungal infection were compiled retrospectively by chart review using a standardized data-recording form developed for the Fungal Disease Registry of the Canadian Infectious Disease Society. Cases of Candidemia were studied in relation to underlying medical conditions, predisposing factors, concurrent infection, antimicrobial agents, antifungal treatment and deaths. RESULTS: In total, 415 cases of candidemia were identified, 48 (11.6%) in children and 367 (88.4%) in adults. The causative pathogens were C. albicans in 286 cases (68.9%), C. parapsilosis in 43 (10.4%), C. glabrata in 34 (8.2%), C. tropicalis in 27 (6.5%) and other Candida species in 18 (4.3%); polymicrobial candidemia occurred in 7 cases (1.7%). The overall mortality rate was 46%, and the rate of deaths clinically related to candidemia was 19%. However, only 13 (27%) of the children died. A univariate analysis indicated that significant risk factors for death were age greater than 60 years, therapy for concomitant bacterial infection, stay in an intensive care unit, concurrent malignant disease, cytotoxic chemotherapy and granulocytopenia, although only age and stay in an intensive care unit emerged as significant risk factors in the multivariate analysis. After adjustment for other predictors of death, only infection with C. parapsilosis was associated with a lower mortality rate than infection with C. albicans. Treatment was given in 352 (84.8%) of cases. Amphotericin B was the preferred agent in 244 cases (69.3% of those treated); fluconazole was used in 101 cases (28.7%) and ketoconazole in 5 cases (1.4%). INTERPRETATION: Candidemia in Canada is caused predominantly by C. albicans. The mortality rate associated with candidemia is high, but it varies with the species of Candida and is lower in children than in adults. Age greater than 60 years and stay in an intensive care unit were the most significant risk factors for overall mortality.

Antimicrobial regimens prescribed by Canadian physicians for chemotherapy-induced febrile neutropenic episodes.

OBJECTIVE: To study the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians. SETTING: A cohort of 274 cancer patients with severe neutropenia (ie, less than 0.5×10(9) neutrophils/L) who participated in a prospective double-blind, placebo controlled study on antifungal prophylaxis conducted in 14 Canadian university-affiliated centres. Antifungal prophylaxis (oral fluconazole 400 mg daily) was administered to 153 of 274 (56%) patients. RESULTS: Antibacterial prophylaxis with a quinolone was given to 87 patients (32%) at the onset of chemotherapy whereas trimethoprim/sulphamethoxazole was given to 56 (20%) patients. Fever (ie, 38°C or over) occurred in 216 (79%) patients after a median duration of neutropenia of four days (range one to 31 days). Empirical antibacterial antibiotics were administered in 214 febrile patients. In 164 (77%) patients antibiotics were started during the first 24 h of fever. Monotherapy with a third generation cephalosporin and duotherapy with a antipseudomonal beta-lactam and an aminoglycoside were prescribed in 69 (32%) and 61 (28%) of the febrile patients, respectively. Inclusion of vancomycin in the initial empirical regimen was noted in 32 (15%) patients. Modifications of the initial regimen occurred in 187 (87%) patients after a median of five days (range one to 28 days). Empirical systemic amphotericin B was added after a median duration of nine days (range one to 34 days) of the empirical antibacterial regimen. CONCLUSIONS: Overall, the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians follows the current guidelines promulgated by the Infectious Diseases Society of America.

Economic analysis of fluconazole versus amphotericin B for the treatment of candidemia in non-neutropenic patients.

Fluconazole (FLU) is an alternative to amphotericin B (AMB) for the treatment of candidemia in non-neutropenic patients. This agent has similar clinical efficacy but significantly reduced adverse effects compared with AMB. Using the database from a Canadian randomised multicentre comparative trial of FLU versus AMB in the treatment of non-neutropenic patients with candidemia, an economic analysis of antifungal therapy was conducted from a Canadian hospital perspective. Patient records were examined for information containing hospital resource consumption. This included the costs for primary intravenous therapy with either AMB or FLU, laboratory tests, patient clinical monitoring and adverse effects management. The robustness of the baseline results were then tested by a comprehensive sensitivity analysis. The mean duration of therapy in the AMB and FLU arms was 17.1 and 23.7 days, respectively (p < 0.001). Assuming that all of the FLU was administered intravenously, the outcomes of the baseline economic analysis revealed that the treatment cost for patients randomized to receive FLU was approximately 50% higher than that for patients treated with AMB [AMB: $Can2370 vs FLU: $Can3578; p = 0.001 ($Can = Canadian dollars)]. In the sensitivity analysis, substitution to oral FLU after 7 days of intravenous therapy produced economic differences that were no longer statistically significant (AMB: $Can2370 vs FLU: $Can2705; p = 0.10). These results suggest that the FLU administration regimen used in the Canadian randomized trial for the treatment of candidemia in non-neutropenic patients may result in increased hospital costs compared with AMB. However, comparable expenditures could be realized if FLU is administered intravenously for the first 7 days and then orally in patients whose condition allows for reliable oral therapy.

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group.

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due to Candida glabrata or Candida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p = 0.39; one-sided 95% CI, -8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p = 0.66: one-sided 95% CI, -12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p = 0.52; chi-square test) and remained similar throughout the course of follow-up, Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.

meso-Tetra(hydroxyphenyl)porphyrins, a new class of potent tumour photosensitisers with favourable selectivity.

We compared para-, meta- and ortho-isomers of meso-tetra(hydroxyphenyl)porphyrin (p-, m- and o-THPP) and the potassium salt of the para compound (K-p-THPP) with haematoporphyrin derivative (HpD) and Photofrin II in their ability to sensitise tumours, skin and brain to light. HpD and Photofrin II induced modest tumour photosensitisation at the cost of substantial skin and brain sensitisation. At doses low enough to keep sensitisation of these normal tissues within acceptable limits, tumour sensitisation was sufficient to give necrosis only approximately 2 mm deep after exposure to 10 J cm-2 light. In contrast, doses of p-THPP, K-p-THPP and m-THPP that produced skin and brain sensitivity within acceptable limits sensitised tumours enough to give 4-9 mm necrosis after 10 J cm-2 light. m-THPP was, on a molar basis, about 25-30 times as potent as HpD and Photofrin II in sensitising tumours. o-THPP was also a potent tumour photosensitiser, but induced a prohibitive degree of skin photosensitivity even at low doses. It is unlikely that these differences in relative selectivity are due to differences in such photophysical parameters as optimum activating wavelength (which would affect tissue penetration by light), or light absorption, and physicochemical factors that determine tissue localisation may be involved. The high tumour sensitising potency and favourable tissue selectivity of m-THPP, p-THPP and K-p-THPP make them promising candidates for clinical tumour phototherapy.

Photobilirubin II.

An improved preparation of photobilirubin II in ammoniacal methanol is described. Evidence is presented which distinguishes between the two structures proposed earlier for photobilirubin II in favour of the cycloheptadienyl structure. Nuclear-Overhauser-enhancement measurements with bilirubin IX alpha and photobilirubin II in dimethyl sulphoxide are complicated by the occurrence of negative and zero effects. The partition coefficient of photobilirubin II between chloroform and phosphate buffer (pH 7.4) is 0.67.