Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Determination of the in situ bactericidal activity of an essential oil mouthrinse using a vital stain method.

BACKGROUND: Recent research has indicated that bacteria within a biofilm may undergo changes in susceptibility to antimicrobial agents when compared to planktonic forms. This study was conducted to determine the bactericidal effect of an essential oil-containing mouthrinse (Listerine Antiseptic) on dental plaque bacteria in situ. METHODS: 1-day-old plaque in 17 subjects was sampled at baseline from the buccal surfaces of diagonally contralateral maxillary and mandibular bicuspids and 1st molars. Subjects were then randomly assigned either an essential oil mouthrinse or a sterile saline negative control and rinsed under supervision with 20 ml for 30 s. 30 min later, plaque was sampled from the remaining contralateral posterior teeth. Subjects repeated these procedures with their respective alternate rinse after 1 week. Pooled plaque samples from each subject at each sampling period were stained with a commercially-available fluorescent stain which fluoresces live and dead bacteria green and red, respectively. The stained plaque specimens were analyzed using computerized image analysis. A separate in vitro study was conducted to determine the relationship between the % red stain per sample and bacterial viability. RESULTS: Analysis of vital stained plaque specimens indicated that following rinsing with the essential oil mouthrinse, 78.7% of bacteria were dead compared to 27.9% following rinsing with the negative control (p<0.001). The in vitro findings demonstrated that the % red stain per sample is reflective of actual bacterial kill. CONCLUSIONS: This study confirms the findings of previous in vitro and in vivo studies which demonstrated the essential oil mouthrinse to have significant biocidal activity against oral micro-organisms. These studies all support the primacy of a bactericidal mechanism in producing the plaque and gingivitis reductions observed in numerous clinical trials conducted on the essential oil mouthrinse.

A rapid method for evaluating microbicidal activity of dentifrice formulations against salivary bacteria ex vivo.

A new rapid ex vivo method was developed for evaluating the short-term bactericidal activity of dentifrices against salivary microorganisms. Dentifrice aliquots of 0.25 or 1.0 g were rapidly dispersed into 3.5 mL of freshly pooled human saliva, and 1.0 mL aliquots of the dentifrice-saliva suspension were collected after 30 or 60 seconds of exposure, diluted in neutralizing broth and plated on non-selective agar media for enumeration of surviving total cultivable microflora. Eight experimental dentifrices containing increasing amounts (0 to 2.6%) of a fixed ratio of essential oils (thymol, menthol, methyl salicylate and eucalyptol) were dispersed in saliva at a 0.25:3.5 (w/v) dentifrice:saliva ratio. Recoverable CFUs/mL at 30 sec. were reduced in a dose-responsive manner from > 10(6) to < 10(4). Additional tests using both 0.25 and 1.0 g amounts of dentifrice prototypes containing 2.1% of the essential oil mixture showed that the experimental dentifrices exhibited highly significant (approximately 2.5 log) reductions in viable recoverable microorganisms relative to essential oil-free placebos after both 30- and 60-second exposures. When compared to in vitro models previously used to evaluate the antimicrobial activity of dentifrices, this method provides a rapid, reproducible, more biologically representative means of screening dentifrice formulations for microbicidal activity using dilutions and exposure times approximating those achieved during toothbrushing. However, since other factors may influence microbicidal activity of dentifrice formulations in vivo, conclusions drawn using this model require clinical confirmation.

Women and cancer.

Current concepts in the care of women with cancer are discussed. New diagnostic and treatment strategies for the four major cancers affecting women are discussed, including high-dose therapy with stem cell support for breast cancer. Genetic influences and their attendant ethical considerations are discussed. Finally, the psychosocial considerations specific to women with cancer are addressed.

Diarrhea associated with tube feeding in mechanically ventilated critically ill patients.

This study was undertaken to determine the incidence and duration of diarrhea associated with tube feeding in critically ill adult patients who require mechanical ventilation. Of the 73 subjects studied, 63% had diarrhea associated with tube feeding. This incidence is higher than that reported from other studies of critically ill patients who were not mechanically ventilated. Multiple logistic regression analysis revealed that three variables (higher rates of infusion, greater tube-feeding osmolality, and change of tube-feeding product) were statistically significant predictors of diarrhea incidence. Antibiotic use and serum albumin levels were not predictors. In a stepwise multiple regression analysis, the duration of diarrhea was predicted by frequency of diarrhea, within the first 5 days of tube-feeding onset, tube-feeding product osmolality, and rate of tube-feeding infusion. Serum albumin levels and frequency of diarrhea beyond 6 days of tube-feeding onset did not predict duration of diarrhea. Higher osmolality and infusion rates of tube-feeding products did contribute to prediction of both incidence and duration of diarrhea.

Comparison of the antimicrobial capability of an abrasive paste and chemical-soak denture cleaners.

The objective of this research was to compare the ability of the two most popular methods for denture cleaning to remove plaque microorganisms from dentures. Dentu-Creme abrasive denture paste and Efferdent alkaline peroxide denture-cleanser soak were selected for study. Two trials were completed in which these materials were used alone and in combination along with a no-treatment control to determine the level of recoverable plaque bacteria from removable dentures. Plaque was allowed to accumulate for 48 or 72 hours in individuals with healthy oral mucosa during which time they refrained from all denture hygiene procedures. The results of two studies following similar double-blind cross-over designs were consistent in that soaking with the denture cleanser caused a significantly greater reduction of microorganisms than did brushing with the denture paste. Further, combining brushing with the soak did not reduce the level of recoverable microorganisms significantly more than soaking alone. Overall, brushing alone did not consistently remove more microorganisms than were observed in the no-treatment group. The denture-cleanser soak displayed broad antimicrobial activity against gram-negative anaerobic rods (Fusobacterium sp.), gram-positive facultative cocci (streptococci), and gram-negative anaerobic cocci (Veillonella sp.), as well as total recoverable microorganisms, which were all equally reduced by the denture-cleanser treatment. These results support the need for use of a denture cleanser in addition to brushing with a denture paste for proper denture hygiene.

Mechanism of action of an antiseptic, anti-odor mouthwash.

Inter-related determinants of oral malodor were measured over a three-hour period in 30 human subjects after mouthwash treatments. Re-odoration was important to mouthwash activity for 30 min. At post-treatment times of 60-180 min, the anti-odor activity of the product is due solely to its anti-microbial action.