Association of Adjuvant or Metastatic Setting With Discontinuation of Cancer Drugs in Clinical Trials.

Importance: Adjuvant drugs are used to reduce the risk of tumor recurrence in patients with cancer who are successfully treated with first-line therapy. The same drugs used in the metastatic or first-line setting are often used in the adjuvant setting, and although the resulting adverse effects may be similar between the 2 settings, tolerability may be different. Objective: To compare the discontinuation rates of drugs in the adjuvant setting and in the metastatic setting in clinical trials of cancer drugs. Design, Setting, and Participants: This cross-sectional study examined clinical trials of cancer drugs with results published in major medical and oncology journals between July 2018 through June 2021. Because adjuvant drugs can be used in a metastatic setting, included trials were conducted in an adjuvant setting. Data were analyzed December 2021. Exposures: Drugs used in the adjuvant setting, which were also used in the metastatic setting for the same tumor indication. Main Outcomes and Measures: Discontinuation rates in the adjuvant and metastatic settings, which were calculated by dividing the total number of study participants who withdrew or discontinued because of adverse events by the number of participants allocated to the drug arm. Results: A total of 29 trials with a drug being used in the adjuvant and metastatic setting were found. In the adjuvant setting, the median (IQR) age for study participants was 58.0 (52.0-63.5) years, and the median (IQR) percentage of male participants was 55.5% (0.9%-64.8%). In the metastatic setting, the median (IQR) age for study participants was 61 years, and the median (IQR) percentage of male participants was 55.2% (2.0%-66.0%). Overall, a median (IQR) 21.4% (17.7%-29.4%) of participants discontinued because of adverse events or patient withdrawal in the adjuvant setting compared with a median (IQR) 15.9% (9.7%-21.3%) in the metastatic setting (P = .01). Checkpoint inhibitors (median [IQR] rate of discontinuation, 21.4% [18.6%-31.3%] vs 15.2% [9.9%-19.5%]; P = .01) and targeted drugs (median [IQR] rate of discontinuation, 27.7% vs 14.0%; P < .001) demonstrated a higher rate of discontinuation in the adjuvant setting while cytotoxic drugs (median [IQR] rate of discontinuation, 16.6% [12.2%-23.3%] vs 25.5% [19.8%-28.8%]; P = .07) showed no difference between the 2 settings. The largest differences between adjuvant and metastatic discontinuation rates were for sorafenib (renal cell carcinoma, 43.8% vs 5.5%; difference, 38.2%), imatinib (gastrointestinal stromal tumor, 37.4% vs 6.1%; difference, 31.2%), and erlotinib (non-small cell lung cancer, 37.5% vs 8.4%; difference, 29.0%). Conclusions and Relevance: In this cross-sectional study of clinical trials that involved novel cancer drugs, drugs used in the adjuvant setting were associated with significantly higher discontinuation rates than in the metastatic setting. This finding suggests that the proposed benefits of adjuvant therapy need to be taken in context of patient's drug tolerance.

Maximizing the Use of Scoring Systems in the Prediction of Outcomes in Acute Pancreatitis.

BACKGROUND/AIMS: No single classification system has so far effectively predicted the severity for Acute Pancreatitis (AP). This study compares the effectiveness of classification systems: Original Atlanta (OAC), Revised Atlanta (RAC), Determinant based classification (DBC), PANC 3, Harmless AP Score (HAPS), Japanese Severity Score (JSS), Symptoms Nutrition Necrosis Antibiotics and Pain (SNNAP), and Beside Index of Severity for AP (BISAP) in predicting outcomes in AP. METHODS: Scores for BISAP, Panc 3, HAPS, SNNAP, OAC, RAC, and DBC were calculated for 221 adult patients hospitalized for AP. Receiver Operating Characteristic curve analysis and Akaike Information Criteria were used to compare the effectiveness of predicting need for surgery, intensive care unit (ICU) admission, readmission within 30 days, and length of hospital stay. RESULTS: Both the RAC and the DBC strongly predict the length of hospital stay (p < 0.0001 for both) and ICU admission (p < 0.0001 for both). Additionally, both BISAP and PANC 3 showed weak predictive capacity at identifying length of stay and ICU admission. CONCLUSIONS: We suggest that BISAP and PANC3 be obtained within the initial 24 h of hospitalization to offer an early prediction of length of stay and ICU admission. Subsequently, RAC and DBC can offer further information later in the course of the disease.

AI-2/LuxS is involved in increased biofilm formation by Streptococcus intermedius in the presence of antibiotics.

Bacteria utilize quorum-sensing communication to organize their behavior by monitoring the concentration of bacterial signals, referred to as autoinducers (AIs). The widespread detection of AI-2 signals and its enzymatic synthase (LuxS) in bacteria suggests that AI-2 is an inter- and intraspecies communication signal. We have previously shown that antibiotic susceptibility is affected by AI-2 signaling in Streptococcus anginosus. Since chronic infections involve persistent biofilms resilient to antibiotic treatment, we explored the role of AI-2/LuxS in Streptococcus intermedius biofilm formation and cell viability when the organism was exposed to sub-MICs of ampicillin, ciprofloxacin, or tetracycline. The S. intermedius wild type (WT) and its isogenic luxS mutant, strain SI006, were exposed to sub-MICs of ampicillin, ciprofloxacin, or tetracycline. Biofilms were formed on polystyrene discs in microtiter plates. To assess planktonic cell viability, the ATP microbial viability assay was performed and the numbers of CFU were determined. For complementation assays, the AI-2 precursor dihydroxy pentanedione (DPD) was used as a supplement for SI006. Relative luxS expression was quantified by real-time PCR. The sub-MICs of all three antibiotics increased biofilm formation in S. intermedius WT. However, biofilm formation by SI006 was either unaffected or reduced (P < or = 0.05). Bacterial viability tests of biofilm and planktonic cell cultures indicated that SI006 was more susceptible to antibiotics than the WT. DPD complemented the luxS mutant phenotype. Real-time PCR revealed modest yet significant changes in luxS expression in the presence of antibiotic concentrations that increased biofilm formation. In conclusion, in S. intermedius, AI-2/LuxS was involved in antibiotic susceptibility and increased biofilm formation at sub-MICs of antibiotic.

AI-2 quorum sensing affects antibiotic susceptibility in Streptococcus anginosus.

OBJECTIVES: The concern over rising antibiotic resistance necessitates exploration of alternative approaches in antimicrobial therapy. Bacterial communities use the auto-inducer 2 (AI-2) quorum sensing signal at a specific threshold level for intra- and interspecies communication in order to regulate virulence behaviour. AI-2 signal production occurs in bacteria that possess a luxS homologue. In this study, we investigate for the first time the association between AI-2 signalling and susceptibility to antibiotics. METHODS: Streptococcus anginosus wild-type and its isogenic luxS mutant SA001 were exposed to erythromycin and ampicillin. Susceptibility to erythromycin and ampicillin was determined by measuring the cell density and viability. Complementation assays were conducted by exposing the mutant to wild-type supernatant or to the AI-2 precursor molecule dihydroxy-2,3-pentanedione (DPD). RESULTS: Disruption of luxS in S. anginosus resulted in a mutant with increased susceptibility to erythromycin and ampicillin. Supernatant from S. anginosus wild-type partially restored growth of SA001 in the presence of the two antibiotics. DPD restored growth of the luxS mutant in the presence of erythromycin and ampicillin to values similar to that of S. anginosus wild-type. CONCLUSIONS: Our results indicate that luxS-based AI-2 communication is associated with antibiotic susceptibility. Targeting the AI-2 signal communication may present a novel approach in antimicrobial therapy.

Dental caries prevalence and risk factors among 12-year old schoolchildren from Baghdad, Iraq: a post-war survey.

AIM: To examine the prevalence of dental caries in 12-year-old schoolchildren from Baghdad after the end of the United Nations' economic sanctions and to investigate related dental caries risk factors including gender, socio-demographic factors, oral hygiene and sugar intake. DESIGN: A cross-sectional dental caries examination and questionnaire survey was conducted in 10 schools from west Baghdad. METHODS: Dental examinations based on WHO criteria and questionnaire surveys were performed on 392 children. Water samples were collected and fluoride concentration assessed. RESULTS: The mean DMFT and DF were 1.7 and 1.3. The rate of caries experience (DMFT > 0) was 62%. DMFT increased significantly with higher education of the mother, not being embarrassed to smile, missing school due to dental pain and between-meals mode of drinking. Increased sugar consumption was associated with being a boy, having mothers with low education, living in a low socio-economic area and brushing at least once-a-day. Positive oral hygiene practices were higher for girls. Western sweet snacks were preferred and sweet tea was frequently consumed. The fluoride content in drinking water was too low for caries prevention. CONCLUSION: It is important to maintain the low prevalence of caries among children by increasing awareness and promoting oral health care strategies.

LuxS-mediated signalling in Streptococcus anginosus and its role in biofilm formation.

The autoinducer-2 signal (AI-2) produced by several Gram-positive and Gram-negative bacteria mediates interspecies communication. In this study we were able to identify an orthologue of luxS, required for the synthesis of AI-2 signals, in Streptococcus anginosus. Comparative analyses revealed conserved sequences in the predicted S. anginosus LuxS. Expression of luxS was highest during early exponential growth phase. Compared to other oral streptococci, conditioned media from growth of members of the anginosus group were the most efficient in inducing bioluminescence in Vibrio harveyi, indicative of AI-2 signalling. Disruption of luxS in S. anginosus resulted in a mutant deficient in biofilm formation, whereas no effect on planktonic growth rate was observed under various growth conditions. S. anginosus is part of the human flora found in biofilms of the oral cavity, as well as of the upper respiratory, gastrointestinal and urogenital tracts. Such habitats harbour large varieties of bacterial species, among which cell-cell communication may play an important role. S. anginosus has also been associated with purulent infections and cancer in the upper digestive tract. Knowledge about the molecular mechanisms involved in S. anginosus communication is important for understanding its commensalism and its pathogenic transition.