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.

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.

Enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material.

In vivo studies have shown a major role for the alveolar macrophage in the killing of inhaled bacteria. This contrasted with earlier work which showed a preservation of phagocytic properties but a loss of bactericidal capacity when alveolar macrophages were studied in vitro. Recently, alveolar lining material (ALM) from rats has been shown to enhance the in vitro bactericidal capacity of alveolar macrophages from homologous animals against Staphylococcus aureus. Utilizing a similar system, we have confirmed that rat alveolar macrophages do not kill S. aureus in vitro unless the bacteria have been incubated with rat ALM (R-ALM) before phagocytosis. In addition, human ALM (H-ALM) from 7 of 11 patients assayed showed an enhancement of bactericidal capacity by rat alveolar macrophages which was not significantly different from the results utilizing R-ALM. H-ALM from the other four patients gave results which differed significantly from results with H-ALM from the first seven patients and R-ALM (P less than 0.001). Preliminary results suggest that the factor enhancing the bactericidal capacity of rat alveolar macrophages is present in the lipid fraction of the ALM. Further characterization of the ALM is warranted in an effort to explain the enhancement of the bactericidal capacity of alveolar macrophages by most, but not all, H-ALM tested.

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.

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.

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.

A comparison of prognostic covariates for uveal melanoma.

For 740 selected cases of uveal melanoma from the Armed Forces Institute of Pathology, the following features were determined: the age and sex of the patient, Callender cell type (CT), and largest tumor dimension (LTD). In addition, special morphometric devices were used to measure the standard deviation of nucleolar area (SDNA) and the mean of the largest nucleoli (MLN) from a single routine hematoxylin and eosin-stained section of each tumor. Univariate analysis using the Cox proportional-hazards model revealed that LTD, CT, SDNA, and MLN correlated equally with death from metastatic melanoma (P greater than 10(-6). Age correlated less highly (P less than 0.002), and sex had no relationship to mortality. Multivariate analysis revealed that adding LTD as a prognostic covariate to either CT, SDNA, or MLN yielded a substantial increase in prognostic value. Because MLN can be measured more easily than SDNA and is more reproducible than CT, it can be a useful cytologic index of the malignant potential of uveal melanomas.

Stereologic estimation of nucleolar volume in ocular melanoma: a comparative study of size estimators with prognostic impact.

The aim of this study was to investigate the relationships between one-, two-, and three-dimensional histomorphometric estimators of nucleolar size in ordinary histologic sections of uveal melanomas from 144 patients. In addition, the prognostic value of the various size parameters was studied. The following estimates were obtained: the mean diameter of the 10 largest nucleoli, the mean nucleolar profile area and associated standard deviation of the nucleolar profile area, the volume-weighted mean nucleolar volume (nucleolar vv), and the macroscopic, largest tumor dimension. All histomorphometric parameters were highly intercorrelated (r > .75). The correlation between the largest tumor dimension and the nucleolar vv was rather poor (r = .35). The efficiency of the sampling scheme for estimation of the nucleolar vv was very high; more than 95% of the totally observed variation was contributed by biologic differences between tumors. Single-term Cox analyses demonstrated a highly significant prognostic value of all five investigated, quantitative variables. Evaluation in a multivariate Cox model showed, however, that only the nucleolar vv and the largest tumor dimension were independent prognostic covariates at the chosen level of significance (5%). Unbiased, shape-independent estimates of the nucleolar vv offered superior prediction of clinical outcome, as compared with lower-dimensional, shape-dependent histomorphometric estimators of nucleolar size.

Prognostic value of nucleolar size and size pleomorphism in choroidal melanomas.

Morphometric estimates of nucleolar size have been shown to possess a high prognostic value in patients with uveal melanomas. The authors investigated various quantitative estimators of the mean size and pleomorphism of nucleoli in choroidal melanomas from a consecutive series of 95 Danish patients treated solely by enucleation of the melanoma-bearing eye in the period from 1977 to 1979. The independent prognostic value of the quantitative histopathological variables was evaluated using multivariate Cox analysis. Apart from patient data and information about tumor extent, histological type of melanoma, and largest macroscopic tumor dimension (LTD), the following histomorphometric estimates were obtained: mean diameter of the 10 largest nucleoli (MLN), point-sampled mean nucleolar profile area (nucleolar ao) and the associated standard deviation of nucleolar ao, the volume-weighted mean nucleolar volume (nucleolar vv), and associated variance and relative variance of nucleolar volume (nucleolar Varv(v) and nucleolar CVv(v), respectively). The intra-observer reproducibility of estimates of nucleolar vv was tested in 20 cases and found acceptable (r = 0.84, 2p = 3.6.10(-6)). Correlation analysis indicated that estimates of nucleolar vv and nucleolar Varv(v) are identical in choroidal melanomas, except for a scaling factor. There were no differences of the grouped means of histomorphometric estimates in choroidal melanomas that showed intra- or extra-ocular extension (2p > 0.13). LTD was of the same magnitude in all histological types of melanoma (2p = 0.69). Estimates of nucleolar vv and associated estimates of nucleolar volume pleomorphism were increased in melanomas of the mixed and epitheloid cell type (2p < 0.005). Single factor analyses showed that all quantitative histopathological variables were of prognostic value in the studied patients, in addition to the histological type of tumor. However, using multivariate analysis, only estimates of LTD, MLN, nucleolar vv, and of nucleolar volume pleomorphism had independent prognostic value.

An approach to face-lift surgery.

An approach to the aging face based upon an analysis of surgical principles and dynamics is presented. This approach emphasizes that the face-lift operation should be directed toward areas in which its potential for improvement is greatest, that is, the jowl and neck. Correction of associated manifestations of aging is best accomplished using ancillary procedures specifically designed for rejuvenating these areas rather than by extension of the face-lift operation per se.

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.

Manometric measurement of Eustachian tube ventilatory function.

Although initial manometric studies of Eustachian tube ventilatory function in both normal and abnormal ears suggested that this technique provided an accurate physiologic assessment of ventilatory function, recent studies have questioned the physiologic nature of these tests. In an effort to clarify this controversy, the tubal ventilatory capacity of 51 ears in which Eustachian tube function was clinically normal was assessed manometrically. Similar measurements were made in 18 ears in which Eustachian tube function was clinically normal except for a complaint of aural fullness. This group showed poorer ventilatory function than normal ears, but the most striking result was the inability of over 50% of the normal group to equilibrate negative pressure to a level within the normal range of 0 to -50 mm H2O. It is postulated that Eustachian tube ventilatory function exhibits a range of individual variability such as is characteristic of other biologic systems.

Life-threatening complications of infectious mononucleosis.

Infectious mononucleosis is a common febrile disorder of children and young adults which is generally benign and self-limited. Patients with this disorder, however, may develop life-threatening complications which require prompt recognition and treatment. The clinical features of three such cases are presented and pertinent features of other life-threatening complications are reviewed.

Parapharyngeal neurilemmoma of the hypoglossal nerve.

Although neurilemmomas are uncommon cervical neoplasms, they account for a significant percentage of parapharyngeal space tumors. These neoplasms may originate from any nerve traversing this space, but the vast majority arise from the vagus nerve and sympathetic chain. Satisfactory treatment of neurilemmomas consists of total excision which is best accomplished via an external approach. Immediate nerve grafting is advocated when a segment of cranial nerve must be sacrificed in order to achieve complete tumor removal. A case of a parapharyngeal neurilemmoma arising from the hypoglossal which required treatment in this manner is presented. Electromyographic studies performed 15 months postoperatively demonstrate reinervation of the lingual musculature via the nerve graft.

A simple, efficient, and reproducible method for estimating the malignant potential of uveal melanoma from routine H & E slides.

The malignant potential of 100 intraocular melanomas was assessed by determining the mean of the ten largest nucleoli (MTLN) using a modification of previously described techniques. For each microslide, a five millimeter path through the central portion of the tumor was traversed on a manually controlled mechanical stage. Selected nucleoli in this area were measured at 2000x power using a digital filar micrometer. In their reproducibility and correlation with malignant potential, these measurements proved comparable to standard deviation of nucleolar area (SDNA), which has been well documented as an objective histologic predictor of mortality from intraocular melanoma. This new method for measuring MTLN requires less than 11 minutes per case, compared to an average of 28 minutes for the original method. The measurements of SDNA required approximately 40 minutes per case and a much more elaborate system than that needed for MTLN.