A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers.

Background: Recent randomized controlled trials (rcts) have contributed high-quality data about adjuvant therapy in curatively resected biliary tract cancer (btc); however, a standard approach to treating those patients still has not been developed. Methods: We conducted a systematic review of published studies and abstracts up to and including June 2018, choosing rcts involving patients with btc receiving adjuvant chemotherapy after complete surgical resection. Network meta-analysis methods were used for indirect comparisons of overall survival (os) and relapse-free survival (rfs) for various adjuvant therapies. Results: Five rcts were included in qualitative synthesis, and three rcts (bilcap, prodige 12-accord 18, and bcat) had data sufficient for inclusion in the meta-analysis. Results from the indirect comparison demonstrated no significant improvement in os for capecitabine compared with gemcitabine or with gemcitabine-oxaliplatin (gemox), the hazard ratios (hrs) being 0.82 [95% confidence interval (ci): 0.53 to 1.27] and 0.86 (95% ci: 0.56 to 1.34) respectively. Similarly, no significant improvement in rfs was observed for capecitabine compared with gemcitabine or gemox. Conclusions: Although in the present analysis, we found no statistically significant improvements in os or rfs for capecitabine compared with gemox or gemcitabine, capecitabine can-until further prospective trials are completed-be considered the standard of care in the adjuvant setting based on a single randomized phase iii study.

What is a clinically meaningful survival benefit in refractory metastatic colorectal cancer?

Assessment of the clinical benefit of cancer treatments can be highly subjective, influenced by both perspective and context. Such assessments are required in regulatory and policy decision-making, but consistency between jurisdictions is often lacking. Clear and consistent standards for determining when a treatment offers a meaningful benefit, relative to the current standard of care, can help to address issues of equity and transparency in health technology assessment. For metastatic colorectal cancer (mcrc), no standardized Canadian definition of clinically meaningful benefit has yet been proposed. Colorectal Cancer Canada therefore convened a group of medical oncologists expert in colorectal cancer to review the literature about clinical significance. The resulting consensus is intended to apply to any therapeutic agent being considered in the setting of chemotherapy-refractory mcrc. It was agreed that overall survival is the appropriate measure of clinical efficacy in chemorefractory mcrc. As quantitative targets for efficacy, an improvement of 2 months or more in median overall survival or a hazard ratio for survival of 0.75 or lower (or both) are proposed as the threshold for clinically meaningful benefit. That threshold could be influenced by a treatment's effect on quality of life. Treatment toxicity is also relevant to the assessment of clinical benefit in this setting, specifically when significant differences in treatment tolerability are evident.

Some factors affecting the expression of Epstein-Barr virus-associated membrane antigens.

The effect of two factors, L-arginine concentration and phytohemagglutinin (PHA) stimulation, on the expression of Epstein-Barr virus (EBV)-associated membrane antigens (MA) was evaluated. An EBV-producer cell line, AV-1, was cultivated in Eagle's basal medium with Earle's salts, supplemented with various L-arginine concentrations ranging from 0.0 to 20.0 mM. In most of the L-arginine concentrations, the number of cells expressing MA decreased within the first 24 hours. This decrease was followed by a marked increase in MA-positive cells at 48 hours and a slight decrease between 48 and 72 hours. Statistical evaluation, however, revealed no significant differences in the level of MA expression among cells exposed to the various L-arginine concentrations. These findings were discussed in relation to the cell cycle dependence of L-arginine-deficient media as a virus-activating agent. AV-1 cell cultures were treated with PHA and observed at 24-hour intervals for 72 hours. Within the first 24 hours, the percentage of cells showing MA was markedly increased. This was followed by a rapid decline in percentage of MA-positive cells within the next 24 hours. Treatment of an EBV-nonproducer cell line, NC37, with PHA resulted in the production of MA in approximately 11% of the cells within the first 24 hours. The number of MA-positive cells gradually declined over the next 48 hours. No viral capsid antigens were detected in these cells. The data suggested either complete or partial activation of the latent EBV genome by PHA.

Group A streptococcal bacteremia in intravenous drug abusers.

The clinical and microbiologic features of group A streptococcal bacteremia are described in 40 patients, all of whom were seen between January 1982 and June 1983 and all of whom were intravenous drug abusers. Eleven patients had endocarditis (two with left-sided and nine with right-sided), and 29 patients had bacteremia without endocardial involvement. Twenty-seven of the 29 patients without endocarditis had soft tissue infections, primarily groin abscesses. Constitutional symptoms were more severe in patients with endocarditis. The two patients with left-sided endocarditis died despite antimicrobial therapy; all nine patients with right-sided endocarditis and all 29 patients without endocarditis were cured of their infection. A predominant strain of group A streptococcus was identified by serologic typing, suggesting a common source for these cases.

Hodgkin's disease in American Negroes. Histologic classification of the disease in 143 untreated patients, and age distribution.

The Rye histologic classification of Hodgkin's disease has been applied to 143 previously untreated cases of Hodgkin's disease in Negro patients seen in four hospitals in Washington, D.C.,during a 16-year period (1959-1974). The frequencies and age distributions of histologic subtypes were compared with those in American and two African series. Those histologic subtypes associated with poor prognoses (mixed-cellularity and lymphocytic depletion) predominated in American Negroes and in Negroes from Ibadan, Nigeria, and Kampala, Uganda. In an American series from Connecticut (approximately 98% Caucasian) the histologic subtypes lymphocytic predominance and nodular sclerosis were preponderant. There were statistically significantly less of the nodular sclerosis subtype (P less than 0.005), and more of the mixed-cellularity subtype in American Negroes compared with the Connecticut series (P less than 0.001). In contrast to findings in predominantly Caucasian populations, there was a predilection of the nodular sclerosis subtype for males in American and in African Negroes. This study showed that Hodgkin's disease in American Negroes epidemiologically corresponds to the so-called "intermediate pattern" of the disease.

Haematological safety of long-term malarial prophylaxis with dapsone-pyrimethamine.

There are no published haematological data on the long-term (more than one year) use of dapsone-pyrimethamine (Maloprim, Folaprim; one tablet a week) for malarial prophylaxis. In a study of 373 male Papua New Guinean soldiers who had used this combination for five years, we found no haematological abnormalities attributable to dapsone-pyrimethamine. Furthermore, the haematological parameters of these soldiers were not clinically different from those of Papua New Guinean university students who did not ingest antimalarial drugs prophylactically. In a parallel study, 9 of 159 white persons (6 children and 3 adult females) who had used dapsone-pyrimethamine prophylaxis for more than one year had haematological abnormalities attributable to the drug. Additionally, the mean leucocyte count of children aged 1-9 years who took dapsone-pyrimethamine was markedly lower--although within the normal range--than that of similarly aged children who received chloroquine for malarial prophylaxis. The appreciable incidence of haematological abnormalities observed in children during malarial prophylaxis with dapsone-pyrimethamine demonstrates the need to select a dose for this group on a weight rather than an age basis and to use a liquid formulation to facilitate the administration of the appropriate dose of this combination. Haematological monitoring of the long-term use of dapsone-pyrimethamine is recommended and a suitable monitoring regimen is suggested.

From malate dehydrogenase to phenyllactate dehydrogenase. Incorporation of unnatural amino acids to generate an improved enzyme-catalyzed activity.

Malate dehydrogenase (MDH) from Escherichia coli is highly specific for its keto acid substrate. The placement of the active site-binding groups in MDH effectively discriminates against both the shorter and the longer keto dicarboxylic acids that could potentially serve as alternative substrates. A notable exception to this specificity is the alternative substrate phenylpyruvate. This aromatic keto acid can be reduced by MDH, albeit at a somewhat slower rate and with greatly diminished affinity, despite the presence of several substrate-binding arginyl residues and the absence of a hydrophobic pocket in the active site. The specificity of MDH for phenylpyruvate has now been enhanced, and that for the physiological substrate oxaloacetate has been diminished, through the replacement of one of the binding arginyl residues with several unnatural alkyl and aryl amino acid analogs. This approach, called site-specific modulation, incorporates systematic structural variations at a site of interest. Molecular modeling studies have suggested a structural basis for the affinity of native MDH for phenylpyruvate and a rationale for the improved catalytic activity that is observed with these new, modified phenyllactate dehydrogenases.

Reversible acute renal failure induced by indomethacin.

Acute renal failure occurred during indomethacin therapy in a patient with chronic pyelonephritis. Urinary prostaglandin E2 levels were diminished but returned to normal after discontinuation of drug therapy and recovery of renal function. Prostaglandins may be critical for the integrity of renal function, and the use of prostaglandin inhibitors such as indomethacin and other nonsteroidal anti-inflammatory drugs may be deleterious in patients with underlying renal disease.

Sex-related differences in plasminogen activator and plasminogen activator inhibiting activities in young and aged rats.

The purpose of this study was to determine whether aging influences the sex-related differences in fibrinolytic activity in rats. We measured plasminogen activator (PA) activity and plasminogen activator inhibiting (PAI) activity in 5-, 12-, 45-, and 60-week-old male and female rats. We also examined the effects of gonadectomy and sex hormone-treatments in adult male and female rats. The increase in age did not influence the PA activity in the male or female rats. However, the PA activity was higher in the female rats than in the males in all four age groups. Orchidectomy caused a significant increase in PA activity in the male rats. Estradiol treatment induced a significant increase of PA activity in ovariectomized female rats. Testosterone treatment resulted in a decrease of PA activity in orchiectomized male rats. The increase in age had an effect on PAI activity; the activity level in the 45- and 60-week-olds was stronger than that in the 12-week-old rats. The PAI activity was not significantly different between the normal rats of each sex. Gonadectomy did not influence the PAI activity in male or female rats, and testosterone and estradiol treatments also did not affect PAI activity in gonadectomized male and female rats. We found that the increase in age induced a decrease in the fibrinolytic system in the rats, and that there were sex-related differences in the fibrinolytic system in even 60-week-old rats.

Bacteremia caused by Achromobacter species in an immunocompromised host.

A case of bacteremia caused by Achromobacter species in an immunocompromised patient is described. The patient responded to antibiotic therapy. Detailed antibiotic susceptibility data are presented.

Human prostate carcinoma causes hypercalcemia in athymic nude mice and produces a factor with parathyroid hormone-like bioactivity.

The mechanism of the calcium and phosphorus abnormalities associated with metastatic prostate carcinoma (CaP) is not yet understood. A tumor model was recently established in which 9479, a human CaP from a patient with prostate carcinoma-induced osteomalacia, was heterotransplanted into athymic nude mice (ANM). In the present study the effect of 9479 on ANM was evaluated. Serum calcium (Ca), phosphorus (P), parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3(1,25-(OH)2D3) and urinary cAMP were measured. Ca was markedly elevated in ANM bearing 9479 vs. age-matched controls (C); the increased Ca returned to control level after tumor removal. Serum PTH was lower in 9479-bearing ANM vs. C while urinary cAMP and serum 1,25-(OH)2D3 levels were elevated. In the ANM bearing 9479, there was a decrease in serum P vs. C which returned to normal after tumor removal. Fractional P excretion was greater in 9479 animals than C. Extracts of 9479 were examined for the presence of parathyroid hormone-like bioactivity by measuring stimulation of intracellular cAMP in ROS 17/2.8 cells. Cyclic AMP stimulation which was found was shown to be inhibited by the competitive PTH antagonist [8Nle, 18Nle, 34Tyr]bPTH-(3-34) amide. These data suggest tumor induction of parathyroid hormone-like humoral modulation of calcium, phosphate and vitamin D metabolism in vivo associated with a parathyroid hormone-like prostate carcinoma product.

The effect of 4MA, a potent inhibitor of 5 alpha-reductase, on the growth of androgen-responsive human genitourinary tumors grown in athymic nude mice.

The five alpha-reductase inhibitors are a newly developed family of compounds that block the intracellular conversion of testosterone (T) to dihydrotestosterone (DHT). 17-beta-N, N-Diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstan-3-one (4MA), the most widely studied of these compounds, has been shown to inhibit the androgen-dependent growth of both normal animal tissues and of the Noble tumor, an experimental, hormone-responsive rat neoplasm. 4MA has been found to inhibit androgen-dependent growth without altering plasma levels of T or DHT. In the present study, we assessed the efficacy of 4MA in inhibiting the growth of PC-82 and R198, human androgen-responsive genitourinary malignancies. In the first experiment, 4MA was administered subcutaneously at a dose of 6 mg/kg/day to castrated and hormonally replaced groups of PC-82-bearing male athymic nude mice. 4MA therapy when compared to control therapy caused significant PC-82 growth inhibition in three different groups of hormonally replaced castrated mice: physiologic T-replaced (P less than .001), supraphysiologic T replaced (P less than .001), and supraphysiologic T and DHT replaced (P less than .001). There was no difference between the post therapy plasma levels of T or DHT in the control-treated and 4MA-treated mice. In the second experiment, the effect of 4MA (6 mg/kg/day S.Q.) was compared to that of castration and control therapy on the growth of R198. Both castration and 4MA therapy effectively inhibited R198 growth when compared to control therapy (P = .01 and .02, respectively), but there was no difference in the degree of growth inhibition seen with 4MA or castration (P = .45). Castration and 4MA-therapy significantly lowered plasma T levels when compared to control therapy; castration also significantly lowered plasma DHT levels, while 4MA and control therapy did not. These studies suggest that 4MA is effective in inhibiting the growth of human androgen-responsive tumors grown in athymic nude mice and that further studies with other 5 alpha-reductase inhibitors are indicated.