Outcomes of Immune Checkpoint Inhibitor Administration in Hospitalized Patients With Solid Tumor Malignancies.

PURPOSE: More oncologists desire to treat their patients with immune checkpoint inhibitors (ICIs) in the inpatient setting as their use has become more widespread for numerous oncologic indications. This is cost-prohibitive to patients and institutions because of high drug cost and lack of reimbursement in the inpatient setting. We sought to examine current practice of inpatient ICI administration to determine if and in which clinical scenarios it may provide significant clinical benefit and therefore be warranted regardless of cost. METHODS: We conducted a retrospective chart review of adult patients who received at least one dose of an ICI for treatment of an active solid tumor malignancy during hospitalization at a single academic medical center between January 2017 and June 2018. Patient, disease, and admission characteristics including mortality data were examined, and cost analysis was performed. RESULTS: Sixty-five doses of ICIs were administered to 58 patients during the study period. Nearly 40% and 80% of patients died within 30 days and 180 days of ICI administration, respectively. There was a trend toward longer overall survival in patients with good prognostic factors including positive programmed death-ligand 1 (PD-L1) expression or microsatellite instability-high (MSI-H) status. Slightly over 70% of patients were discharged within 7 days of ICI administration. The total cost of inpatient ICI administration over the 18-month study period was $615,016 US dollars. CONCLUSION: Inpatient ICI administration is associated with high costs and poor outcomes in acutely ill hospitalized patients with advanced solid tumor malignancies and therefore should largely be avoided. Careful discharge planning to expedite outpatient treatment after discharge will be paramount in ensuring patients with good prognostic features who will benefit most from ICI therapy can be promptly treated in the outpatient setting as treating very close to discharge in the inpatient setting appears to be unnecessary, regardless of tumor features.

The utility of procalcitonin for diagnosing bacteremia and bacterial pneumonia in hospitalized oncology patients.

PURPOSE: Procalcitonin (PCT) is an inflammatory marker elevated in bacteremia and bacterial pneumonia. We aimed to assess the real-world diagnostic accuracy of PCT in hospitalized patients with malignancy. METHODS: A retrospective cohort of 715 patients with cancer who had PCT measured during 750 admissions was analyzed. Diagnosis of bacteremia was determined using blood culture data. Diagnosis of bacterial pneumonia was based on radiographic infiltrate and/or sputum culture. PCT's performance was assessed using receiver operating characteristic (ROC) curves, sensitivity, and specificity. RESULTS: Patients had bacteremia, bacterial pneumonia, or both during 210 admissions (28%). PCT elevation above 0.5 ng/mL was significantly associated with diagnosed infection in the overall population (p < 0.0001) and in subgroups with solid tumor malignancies (p < 0.0001) and hematologic malignancies (p = 0.008). PCT was associated with infectious status in patients with any metastases, but not those with primary lung cancer, lung metastases, neuroendocrine tumors, febrile neutropenia, or history of bone marrow transplant (BMT). The area under the ROC curve for PCT in the overall population was 0.655. An ideal cutoff of 0.21 ng/mL led to a sensitivity of 60% and specificity of 59%. At cutoffs of 0.5 ng/mL and 0.05 ng/mL, PCT's sensitivity was 39% and 94%, while specificity was 79% and 17%, respectively. CONCLUSION: In this large cohort of hospitalized oncology patients, PCT elevation was associated with diagnosed bacteremia and/or bacterial pneumonia. However, specificity was limited, and PCT elevation was not associated with diagnosed infection in some subpopulations. While PCT may have some diagnostic utility for hospitalized oncology patients, values must be interpreted cautiously and considering clinical context.

Hidden Dangers: A Gastrointestinal Stromal Tumor Concealed Inside of a Meckel's Diverticulum.

Meckel's diverticulum (MD) is one of the most common congenital abnormalities of the gastrointestinal tract, affecting approximately two percent of the population. Rarely, Meckel's diverticula have been found to harbor various tumors, which go unnoticed until later in their course. The clinical presentation varies among each individual, and tumors have often metastasized or caused diverticular rupture at the time of diagnosis. This is a case of a 55-year-old male with a past medical history of alcohol abuse and asthma who presented to the emergency department with abdominal pain. He denied any fever, chills, chest pain, nausea, changes in urinary patterns, recent travel, or sick contacts. He is a non-smoker but has been a heavy drinker for many years. On physical exam, he was found to have diffuse abdominal tenderness with pain greatest in the epigastric region and no bowel sounds. He was afebrile but tachycardic at 112 bpm, hypertensive at 168/98 mmHg, and tachypneic at 38 bpm. Labs showed a markedly elevated white blood cell count, hemoglobin and platelet count, as well as metabolic acidosis and elevated lactate levels. Abdominal CT showed a mechanical small bowel obstruction with unclear etiology. Of note was a 7.2 cm thick-walled collection in the right lower quadrant having no clear communication with any bowel loops. Despite aggressive hydration and supportive care, his abdominal exam continued to worsen, prompting an exploratory laparotomy. During the laparotomy, a perforated MD with frank succus was found. On pathology, the affected segment of the bowel revealed a CD117 and CD34 positive spindle cell gastrointestinal stromal tumor (GIST) with mild cytological atypia, no necrosis, and no regional lymph node involvement. Cultures of peritoneal fluid were positive for Klebsiella oxytoca, and the patient was started on meropenem and doxycycline. The patient showed significant improvement with the appropriate administration of antibiotics and was eventually discharged to follow-up with hematology/oncology as an outpatient for further management and monitoring of his GIST tumor. This case is unique as there are only a few reported cases of patients developing GIST inside of MDs. Despite the high five-year survival rate of typically localized GIST tumors, the complications (such as perforation in the case of our patient) caused by tumor growth inside a MD are detrimental if not diagnosed promptly. Not only does perforation increase the risk of metastasis but also the risk of peritonitis and other complications. This case calls for more research on standardization of care for patients who have MD to prevent malignant transformations as well as potential prophylactic excision of incidental MD findings in adult patients.

Brief assessment of cognitive function in myotonic dystrophy: Multicenter longitudinal study using computer-assisted evaluation.

INTRODUCTION/AIMS: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1. METHODS: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire. RESULTS: Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P < .0001). Executive function performance improved from baseline to 3 months (P < .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance. DISCUSSION: Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.

Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy.

OBJECTIVE: To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS). METHODS: Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes. RESULTS: The cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages. CONCLUSION: MRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy. CLINICALTRIALSGOV IDENTIFIER: NCT01417533.

Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

The Homeobox gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers.

HOXB13, a homeodomain transcription factor, is linked to recurrence following radical prostatectomy. While HOXB13 regulates Androgen Receptor (AR) functions in a context dependent manner, its critical effectors in prostate cancer (PC) metastasis remain largely unknown. To identify HOXB13 transcriptional targets in metastatic PCs, we performed integrative bioinformatics analysis of differentially expressed genes (DEGs) in the proximity of the human prostate tumor-specific AR binding sites. Unsupervised Principal Component Analysis (PCA) led to a focused core HOXB13 target gene-set referred to as HOTPAM9 (HOXB13 Targets separating Primary And Metastatic PCs). HOTPAM9 comprised 7 mitotic kinase genes overexpressed in metastatic PCs, TRPM8, and the heat shock protein HSPB8, whose levels were significantly lower in metastatic PCs compared to the primary disease. The expression of a two-gene set, CIT and HSPB8 with an overall balanced accuracy of 98.8% and a threshold value of 0.2347, was sufficient to classify metastasis. HSPB8 mRNA expression was significantly increased following HOXB13 depletion in multiple metastatic CRPC models. Increased expression of HSPB8 by the microtubule inhibitor Colchicine or by exogenous means suppressed migration of mCRPC cells. Collectively, our results indicate that HOXB13 promotes metastasis of PCs by coordinated regulation of mitotic kinases and blockade of a putative tumor suppressor gene.

Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer.

Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.

Stereotactic radiotherapy for prostate cancer: A review and future directions.

Prostate cancer affects over 200000 men annually in the United States alone. The role of conventionally fractionated external beam radiation therapy (RT) is well established as a treatment option for eligible prostate cancer patients; however, the use of stereotactic body radiotherapy (SBRT) in this setting is less well defined. Within the past decade, there have been a number of studies investigating the feasibility of SBRT as a potential treatment option for prostate cancer patients. SBRT has been well studied in other disease sites, and the shortened treatment course would allow for greater convenience for patients. There may also be implications for toxicity as well as disease control. In this review we present a number of prospective and retrospective trials of SBRT in the treatment of prostate cancer. We focus on factors such as biochemical progression-free survival, prostate specific antigen (PSA) response, and toxicity in order to compare SBRT to established treatment modalities. We also discuss future steps that the clinical community can take to further explore this new treatment approach. We conclude that initial studies examining the use of SBRT in the treatment of prostate cancer have demonstrated impressive rates of biochemical recurrence-free survival and PSA response, while maintaining a relatively favorable acute toxicity profile, though long-term follow-up is needed.

Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor.

Flavanols, mild cognitive impairment, and Alzheimer's dementia.

Alzheimer's disease (AD) is a dementing neurological disorder that results in progressive memory loss and cognitive decline thought to be associated with buildup of amyloid plaques and neurofibrillary tangles in the brain. Vascular Dementia (VaD) is another common dementing disorder characterized by decreased brain perfusion. Together, AD and VaD constitute mixed dementia, an extremely common type of dementia associated with aging. Neuroimaging research suggests that brain vascular atrophy results in mild cognitive impairment (MCI), a possible precursor for AD. Additionally, literature suggests that attention to cardiovascular risk factors such as hypertension could reduce or delay the incidence of mixed dementia. Furthermore, foods and beverages rich in natural antioxidant flavanoids (i.e. epicatechin and catechin) are currently being advocated as possible preventative agents for a number of pathological conditions ranging from coronary heart disease to dementia. Experimental evidence is mounting that oxidative stress is involved in the pathophysiology of AD, and numerous studies are indicating that polyphenolic antioxidants found in fruits and vegetables can be useful in countering this and blocking neuronal death. More specifically, several cocoa studies suggest that daily intake of cocoa flavanols leads to cardiovascular benefits including vasodilatation via a nitric oxide mechanism and increased brain perfusion. The following text will consider an important question that thus arises regarding the potential of flavanols as effective agents for the prevention and delay of the onset of brain vascular atrophy and subsequently MCI and AD. It will also review the molecular mechanisms through which flavanols operate to accomplish their protective effects.

Discriminating sources of PCB contamination in fish on the coastal shelf off San Diego, California (USA).

Management of coastal ecosystems necessitates the evaluation of pollutant loading based on adequate source discrimination. Monitoring of sediments and fish on the shelf off San Diego has shown that some areas on the shelf are contaminated with polychlorinated biphenyls (PCBs). Here, we present an analysis of PCB contamination in fish on the shelf off San Diego designed to discriminate possible sources. The analysis was complicated by the variability of species available for analysis across the shelf, variable affinities of PCBs among species, and non-detects in the data. We utilized survival regression analysis to account for these complications. We also examined spatial patterns of PCBs in bay and offshore sediments and reviewed more than 20 years of influent and effluent data for local wastewater treatment facilities. We conclude that most PCB contamination in shelf sediments and fish is due to the ongoing practice of dumping contaminated sediments dredged from San Diego Bay.

Lipid composition of deep-sea hydrothermal vent tubeworm Riftia pachyptila, crabs Munidopsis subsquamosa and Bythograea thermydron, mussels Bathymodiolus sp. and limpets Lepetodrilus spp.

Lipid composition was determined for hydrothermal vent species collected by the Deep Submergence Vehicle ALVIN from chimneys at 2,500 m depth on the East Pacific Rise. These are the first lipid biomarker studies for most of these species. Lipid content was low and dominated by polar lipid in the vestimentiferan tubeworm Riftia pachyptila, mussels Bathymodiolus sp. and limpets Lepetodrilus spp. The galatheid (Munidopsis subsquamosa) and most brachyuran adult (Bythograea thermydron) crabs were characterized by higher storage lipid (triacylglycerol). Total polyunsaturated fatty acids were similar in R. pachyptila plume and body, but higher in the posterior part of the soft body, which had more docosahexaenoic acid (2-5% of total FA) compared to the anterior and plume (< or =0.3%). Two sulphur-oxidizing bacterial markers, 16:1(n-7)c and 18:1(n-7)c, were high in R. pachyptila and mussel (up to 23%), but lower in both crab species (4-17%). R. pachyptila had greater nonmethylene interrupted diunsaturated fatty acids (8-13%) than all other species (2-8%). R. pachyptila may desaturate and elongate 18:1(n-7)c to obtain essential polyunsaturated fatty acids 20:5(n-3) and 20:4(n-6). The sterol composition of R. pachyptila included similar amounts of cholesterol and desmosterol, whereas the other species had a more diverse sterol composition. These differences in lipids, fatty acids and sterols reflect diverse nutritional strategies and possibly temperature regimes in these species.

Activation of human T cells with NK cell markers by staphylococcal enterotoxin A via IL-12 but not via IL-18.

We have reported recently that mouse liver NK cells and NK1 x 1+ T cells were activated by bacterial superantigens via the IL-12 production from Kupffer cells. In the present study, we examined the effect of staphyloccoccal enterotoxin A (SEA) on human T cells with NK cell markers, CD56 or CD57 (NK-type T cells). After stimulating peripheral blood mononuclear cells (PBMC) with SEA, PBMC produced a large amount of IFN- and acquired a potent antitumour cytotoxicity. The in vitro depletion of either CD56+ TCR NK cells, CD56+ T cells or 57+ T cells from PBMC significantly inhibited the IFN- production from PBMC. When purified NK-type T cells, NK cells and regular T cells were cultured with monocytes and SEA they all produced IFN-, while the IFN- amounts produced by both NK-type T cells were greater than those produced by NK cells. NK cells as well as CD56+ T cells showed cytotoxicity against NK-sensitive K562 cells, whereas both NK-type T cells showed a more potent cytotoxicity against NK-resistant Raji cells than did NK cells. The IFN- production from each population as well as from whole PBMC was greatly inhibited by anti-IL-12 antibody but not by anti-IL-18 antibody. The antitumour cytotoxicity of whole PBMC was also significantly inhibited by anti-IL-12 antibody while the SEA-induced proliferation of PBMC was not affected by anti-IL-12 antibody. Furthermore, SEA-activated NK-type T cells as well as NK cells showed cytotoxicities against vascular endothelial cells. Our findings suggest that human NK-type T cells are thus involved in bacterial superantigen-induced immune response.

Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells.

We investigated the function of CD56+ CD8+ T cells (CD56+ T cells) and CD56- CD57+ CD8+ T cells (CD57+ T cells; natural killer (NK)-type T cells) and compared them with those of normal CD56- CD57- CD8+ T cells (CD8+ T cells) and CD56+ NK cells from healthy volunteers. After the stimulation with immobilized anti-CD3 antibodies, both NK-type T cells produced much larger amounts of interferon-gamma (IFN-gamma) than CD8+ T cells. Both NK-type T cells also acquired a more potent cytotoxicity against NK-sensitive K562 cells than CD8+ T cells while only CD56+ T cells showed a potent cytotoxicity against NK-resistant Raji cells. After the stimulation with a combination of interleukin (IL)-2, IL-12 and IL-15, the IFN-gamma amounts produced were NK cells > or = CD56+ T cells > or = CD57+ T cells > CD8+ T cells. The cytotoxicities against K562 cells were NK cells > CD56+ T cells > or = CD57+ T cells > CD8+ T cells while cytotoxicities against Raji cells were CD56+ T cells > CD57+ T cells > or = CD8+ T cells > or = NK cells. However, the CD3-stimulated proliferation of both NK-type T cells was smaller than that of CD8+ T cells partly because NK-type T cells were susceptible to apoptosis. In addition to NK cells, NK-type T cells but not CD8+ T cells stimulated with cytokines, expressed cytoplasmic perforin and granzyme B. Furthermore, CD3-stimulated IFN-gamma production from peripheral blood mononuclear cells (PBMC) correlated with the proportions of CD57+ T cells in PBMC from donors. Our findings suggest that NK-type T cells play an important role in the T helper 1 responses and the immunological changes associated with ageing.

The mechanism of a defective IFN-gamma response to bacterial toxins in an atopic dermatitis model, NC/Nga mice, and the therapeutic effect of IFN-gamma, IL-12, or IL-18 on dermatitis.

NC/Nga (NC) mice raised under conventional conditions (Conv. NC mice) spontaneously develop dermatitis similar to human atopic dermatitis, whereas NC mice raised under the specific pathogen-free conditions do not develop dermatitis. In the present study, we show that the representative Th1 cytokine, IFN-gamma levels in the sera of NC mice, injected with either staphylococcal enterotoxin B or endotoxin (LPS), to be severalfold lower than those of normal mice. The low IFN-gamma response to staphylococcal enterotoxin B was correlated to the lack of regular Vbeta8(+) T cells and Vbeta8(+) NK T cells, and the low IFN-gamma response to LPS was correlated to an impaired IL-18 production of macrophages. The CD3-stimulated IL-4 production from liver and spleen T cells from Conv. NC mice in vitro was greatly augmented. The serum IL-4 levels of untreated Conv. NC mice also were higher than those of normal mice and specific pathogen-free NC mice. Treatment of Conv. NC mice either with IFN-gamma, IL-12, or IL-18 twice a week from 4 wk of age substantially inhibited the elevation of the serum IgE levels, serum IL-4 levels, and dermatitis, and IL-12 or IL-18 treatment also reduced the in vitro IL-4 production from CD3-stimulated liver T cells. The systemic deficiency in the Th1 response to bacterial stimulation thus leads to a Th2-dominant state and may induce an abnormal cellular immune response in the skin accompanied with an overproduction of IgE and a susceptibility to dermatitis in NC mice.

Decrease of CD56(+)T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma.

CD56(+)T cells and CD56(+)natural killer (NK) cells are abundant in the human liver. The aim of this study was the further characterization of these cells in the liver with or without hepatitis C virus (HCV) infection. Liver mononuclear cells (MNC) were isolated from liver specimens obtained from the patients during abdominal surgery. In addition to a flow cytometric analysis, liver MNC and PBMC were cultured with the immobilized anti-CD3 Ab, IL-2, or a combination of IL-2 and IL-12 and their IFN-gamma production and the antitumor cytotoxicity were assessed. The liver MNC of HCV (-) patients contained 20% CD56(+)T cells whereas the same proportions decreased to 11% in chronic hepatitis livers and to 5% in cirrhotic livers. The proportion of NK cells also decreased in the cirrhotic livers. On the other hand, the populations of these cells in PBMC did not significantly differ among patient groups. The IFN-gamma production and the cytotoxicity against K562 cells, Raji cells, and a hepatocellular carcinoma, HuH-7 cells, greatly decreased in the cirrhotic liver MNC. In contrast, the cytotoxicity in PBMC did not significantly differ among the patient groups and was lower than that in the liver MNC of HCV (-) patients. CD56(+)T cells and NK cells but not regular T cells purified from liver MNC cultured with cytokines showed potent cytotoxicities against HuH-7 cells. These results suggest that a decreased number of CD56(+)T cells and NK cells in cirrhotic livers may be related to their susceptibility to hepatocellular carcinoma.