The risk of diarrhea and colitis in patients with lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (icis), including inhibitors of PD-1, PD-L1, and ctla-4, are relatively novel therapies for lung cancer, although their use might be limited by gastrointestinal toxicity. The aim of the present study was to determine the risk of diarrhea and colitis associated with icis in lung cancer and the rates of discontinuation because of those toxicities. Methods: Electronic databases were searched for prospective trials reporting the risk of diarrhea and colitis in patients with lung cancer treated with PD-1, PD-L1, and ctla-4 inhibitors. The incidences of diarrhea and colitis and their grades were assessed clinically using standardized reporting criteria. Pooled incidence and weighted relative risk estimates for diarrhea and colitis with 95% confidence intervals (cis) were estimated using a random effects model. The incidence of discontinuations for gi toxicity was also calculated. Results: Twenty-seven studies were included: sixteen studies with PD-1 inhibitors, nine studies with PD-L1 inhibitors, and four studies combining PD-based strategies with ctla-4 inhibitors. The incidence of all-grade diarrhea was 9.1% (95% ci: 7.8% to 10.5%) for anti-PD-1 therapy and 11.0% (95% ci: 7.5% to 14.5%) for anti-PD-L1 therapy. The incidence of all-grade colitis was 0.9% (95% ci: 0.4% to 1.3%) for anti-PD-1 therapy and 0.4% (95% ci: 0.0% to 0.8%) for anti-PD-L1 therapy. The relative risk for all-grade diarrhea was higher with combination anti-PD-1 and anti-ctla-4 than with anti-PD-1 monotherapy (relative risk: 1.61; 95% ci: 1.14 to 2.29). Anti-PD-1 therapy was discontinued in 4.1% of patients with diarrhea (95% ci: 0.7% to 7.4%) and in 35.7% of those with colitis (95% ci: 0.0% to 81.1%); combination therapy was discontinued in 10.1% of patients with diarrhea (95% ci: 4.8% to 15.4%) and in 39.9% of those with colitis (95% ci: 3.9% to 75.9%). Conclusions: Diarrhea is a relatively frequently encountered gi toxicity when ici therapy is used in lung cancer treatment. Colitis is less frequently encountered, although when it does occur, it often results in therapy discontinuation.

Systematic review with meta-analysis: the impact of Clostridium difficile infection on the short- and long-term risks of colectomy in inflammatory bowel disease.

BACKGROUND: Clostridium difficile infection (CDI) is associated with increased mortality in inflammatory bowel disease (IBD), but the risk of colectomy is variable and has not been adequately studied. AIM: To perform a systematic review and meta-analysis to assess the impact of CDI on colectomy risk in IBD. METHODS: Multiple databases were searched systematically for observational studies reporting colectomy risk in IBD, stratified by the presence of CDI, and the duration of follow-up (short term 3 months, and long term at least 1 year). Weighted summary estimates were calculated using generalised inverse variance with random-effects model. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: Twelve observational studies were identified and included 35 057 IBD patients with CDI, and 929 259 without CDI. CDI did not increase the short-term colectomy risk in IBD patients overall (10 studies) (OR: 1.35; 95% CI: 0.68-2.67), or in patients with ulcerative colitis (nine studies) (OR: 1.20; 95% CI: 0.39-3.76). In contrast, CDI was associated with higher long-term colectomy risk in patients with IBD overall (five studies) (OR: 2.23; 95% CI: 1.18-4.21), and in patients with ulcerative colitis (four studies) (OR: 2.96; 95% CI: 1.19-7.34). The results were stable in subgroups stratified by recruitment period, hospitalisation status and geographical location. All studies were at least of moderate quality. The results were limited in the ability to compare IBD severity and the type of anti-microbial therapy. CONCLUSION: Based on 12 observational studies with at least moderate quality, Clostridium difficile infection appears to increase colectomy risk in IBD in the long- but not short- term.

Toll-like receptor 4-mediated activation of murine mast cells.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are critical for cellular responses to a variety of bacterial, viral, and fungal products. Mast cells are important to host survival in a number of models of bacterial infection and might act as sentinel cells in host defense. We therefore examined the expression of TLRs and associated molecules by murine bone marrow-derived mast cells (BMMCs). BMMCs and the murine mast cell line MC/9 expressed mRNA for TLR2, TLR4, and TLR6 but not TLR5 and for both adapter molecule MD-2 and signaling molecule MyD88 but lacked surface CD14. After activation with the TLR2- and TLR4-dependent stimuli Staphylococcus aureus-derived peptidoglycan and Escherichia coli-derived lipopolysaccharide (LPS), respectively, mast cells produced significant levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). To determine whether mast cells require TLR4 for cellular responses to LPS, mast cells were derived from the bone marrow cells of C3H/HeJ and C57Bl/10ScNCr mice containing a point mutation and a null mutation, respectively, in TLR4. Using these models, we demonstrated that the BMMC IL-6 and TNF-alpha responses to LPS were completely dependent on functional TLR4 with no significant LPS response observed in its absence. These findings have important implications for the mechanism of mast cell responses to pathogens and their products and suggest that different TLR4-expressing cells might have different thresholds for activation with LPS.

Effect of adroxazine, a heterocyclic compound of the adrenals, on the rate of replication of lymphoblastoid cells.

It has been found that the addition of 10(-2)-10(-8) microL/mL of adroxazine, heterocyclic compound of the adrenals, to the tissue culture medium increases the rate at which three strains of lymphoblastoid cells replicate. For example, the addition of 10(-5) micrograms/mL of adroxazine to cultured L5178Y cells decreases their doubling time from approximately 11 to 8 h and addition of 10(-3) micrograms/mL of adroxazine to the tissue culture medium of Huly-16 or Huly-29 cells decreases their doubling time from approximately 43 to 34 and 36 h, respectively. Other concentrations of adroxazine, from 10(-2) to 10(-8) micrograms/mL, cause a less but measurable decrease in doubling time. The effect of adroxazine on the rate of incorporation of [3H]thymidine into acid-precipitable material by lymphoblastoid cells was found to parallel the effect of adroxazine on doubling time. The effect of adroxazine on the length of DNA synthesis and mitosis was calculated from the percent of cells that are labeled with [3H]thymidine during a 20-min interval and the percent of cells in mitosis, respectively. Results showed that adroxazine does not decrease the length of DNA synthesis or mitosis, but markedly decreases the sum of pre- and post-mitotic resting times (TG2 + TG1). Addition of 10(-3) micrograms/mL of adroxazine to the medium decreases the resting times of Huly-16 cells from approximately 20 to 10 h and Huly-29 cells from approximately 12 to 5 h. Addition of 10(-5) micrograms/mL of adroxazine to the medium decreases the resting time of L5178Y cells from 3.3 to 0.1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of leucogenenol, a thymothyroid hormone, with carrier proteins in the thymus.

Leucogenenol a heterocyclic enolic thymothyroid hormone (MW 383) whose concentration in the serum regulates the rate at which already committed cells of the bone marrow develop into functional cells, was found to be associated in the thymus with a carrier protein. The carrier protein for leucogenenol is not precipitated by heating to 80 degrees but following this treatment leucogenenol is precipitated in association with proteins precipitated by acetone and then by saturated ammonium sulfate. On chromatography on Sephacryl G-200 it was found that leucogenenol was associated with proteins of MW approximately 38,000. Leucogenenol is not eluted from the chromatographic column if it is not associated with its carrier proteins. It is suggested that other hormones such as those associated with the reproductive cycle or compounds that result from tissue damage induce the liberation of leucogenenol from its carrier protein in the thymus to the circulation where it is associated as previously described, with a protein of approximately MW 300,000.

Effect of leucogenenol, a thymothyroid hormone, on the growth of immature and neonatally thymectomized rats.

The reports of early investigators that growth is delayed by thymectomy of immature animals have been confirmed. Although growth is delayed by thymectomy, thymectomized animals approach asymptotically with age the same final weight as corresponding intact animals. Treatment with leucogenenol, a thymothyroid hormone, accelerates the rate of growth of immature neonatally thymectomized rats to that of normal rats. However, treatment with leucogenenol does not increase the rate of growth of normal rats. Treatment with leucogenenol does not change levels of growth hormone (GH) or thyroxine (T4) in the serum of either thymectomized or intact immature and adult rats. Neither is the depression in levels of serum leucogenenol that follows thymectomy associated with a change in serum levels of GH or T4. Thus it is apparent that levels of serum leucogenenol do not affect the rate of growth of immature animals by increasing serum levels of GH or T4. By analogy with the finding that treatment with leucogenenol increases the rate at which committed cells of the bone marrow and cells involved in the immune response develop into functional cells, it is suggested that the levels of serum leucogenenol are one of the factors that determine the rate at which types of body cells that make up bone and other body tissues develop from committed precursors.

Effect of leucogenenol, a thymothyroid hormone, on allograft rejection and hemolysin formation.

Recent investigations in this laboratory have established that daily treatment with leucogenenol, an enolic heterocyclic hormone synthesized by the thymus and/or thyroid, induces neonatally thymectomized mice that have accepted a skin allograft to reject this allograft in 7 to 14 days. Also, daily treatment with leucogenenol causes neonatally thymectomized mice to respond to challenge with sheep erythrocytes with the formation of normal titers of hemolysin. These results demonstrate that the hormone leucogenenol induces the development of those cells, absent in neonatally thymectomized mice, that are necessary for a normal immune response.

Effect of tumors on the concentration of leucogenenol in the serum of mice.

It was found that inoculation of several strains of mice with several types of tumor cells resulted, within 24 hr, in a significant decrease in the serum leucogenenol levels of the mice. Serum leucogenenol levels of the mice inoculated with tumors that are rejected become normal or temporarily above normal at approximately the time the tumor is observed to be rejected. Contrariwise, serum leucogenenol levels of mice inoculated with tumors that are not rejected remain at significantly lower than normal levels during the life of the mice. Unlike tumors, skin allografts increase serum leucogenenol levels. When tumors are rejected because of the previous immunization of the mice, serum leucogenenol levels become normal at approximately the time the tumor is observed to be rejected. Excision of the tumor after 1 week of growth, with the consequent recovery of the mice, is accompanied by a recovery of normal serum leucogenenol levels. Also, it was found that injection of mice with a cell-free 0.9% NaCl solution extract of a tumor results in a temporary decrease in serum leucogenenol levels comparable to that observed with the inoculation of a viable tumor which lasts from 24 to 96 hr. It is suggested that the suppression of serum leucogenenol levels is one of the factors responsible for the immunosuppression associated with a growing tumor.

Leucogenenol a thymothyroid hormone.

Thymectomy and, to a lesser extent, thyroidectomy cause a significant decrease in the serum leucogenenol levels of rats. Daily injections of neonatally thymectomized mice with leucogenenol causes the mice to maintain a normal level of neutrophils and lymphocytes in their circulation. The thymus and thyroid are the only tissues in rats and mice that afford radioactive leucogenenol when incubated in a medium containing radioactive D-glucose. It is concluded that the thymus and possibly the thyroid are responsible for the normal biosynthesis of leucogenenol in animals.

Mixed lymphocyte reactivity against normal cells by splenic lymphocytes from tumor-bearing mice : I. Studies of vigorous immune responsiveness induced in f(1) mice by parental strain tumor cells.

The establishment of an intimate connection between autoimmunity and neoplasia would require the demonstration of an experimentally induced, tumor-dependent autoimmune process. For this reason, we have studied cellular immune reactions of mice bearing a transplantable leukemia (L1210). Spleen cells from hybrid BDF(1) mice bearing the L1210 tumor (BDFt) reacted vigorously in mixed lymphocyte culture with mitomycin-treated, normal spleen cells from mice of the parental strain from which the L1210 tumor was derived (DBA/2). Spleen cells from nontumor-bearing BDF(1) mice reacted only weakly with these parental cells. The BDFt cells likewise did not respond when cultured with mitomycin-treated spleen cells from the other parental strain (C57B1/6). The vigorous mixed lymphocyte reaction (MLR) by BDFt cells against normal parental cells of the same strain as the tumor was not due to a double exposure of the reacting cells to histocompatibility antigens shared by tumor cells and normal parental cells. The response of cells from tumor-bearing F(1) mice against normal parental cells seen in these experiments suggests the possibility of the induction of an autoimmune-like process against host lymphocytes by spleen cells from leukemic mice. Theoretically such a phenomenon would considerably reduce an animal's ability to mount an immune attack against malignant cells.

Mixed lymphocyte reactivity against normal cells by splenic lymphocytes from tumor-bearing mice : ii. Studies of autoimmune-like activity in completely syngeneic and semisyngeneic systems.

A possible consequence of an antilymphocytic autoimmune process would be serious impairment of an animal's ability to destroy tumor cells. One measure of autoimmune reactivity of this type would be the demonstration of cellular immune responsiveness by cells from tumor-bearing mice against syngeneic normal cells. These experiments demonstrate that spleen cells from mice bearing a lymphocytic leukemia of identical histocompatability type as the host mounted a vigorous immune response against normal syngeneic cells in a mixed lymphocyte reaction (MLR). Moreover, ascitic cells from leukemic mice responded significantly to normal syngeneic spleen cells in MLR's. The former reactions are usually much more vigorous than the responses of normal to malignant cells. These results are discussed in terms of the relationship between autoimmunity and neoplasia. Alternative explanations necessitated by the dangers involved in the interpretation of the immunology of transplantable tumors are considered.