Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

BACKGROUND: Immune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients. METHODS: We analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded. RESULTS: Overall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR. CONCLUSION: Our results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.

Uranium distribution in rocks by fission-track registration in lexan plastic.

When Lexan plastic is iused to register fission tracks from thermal neutron-induced fission of uranium in rocks, a print of the rock texture is formed on the plastic surface after chemical etching. This print allows positive, rapid location of uranium-bearing phases in the rock and accurate determination of uranium abundances.

Enhancement of electron-phonon coupling in Cs-overlayered intercalated bilayer graphene.

We have performed high-resolution angle-resolved photoemission spectroscopy (ARPES) on cesium (Cs) intercalated bilayer graphene with a Cs overlayer (Cs-C8CsC8). Low-energy electron diffraction shows a (2 × 2) pattern consistent with intercalation of a Cs layer similar to bulk C8Cs, in addition to the signature of a nearly commensurate superstructure created by the Cs overlayer. ARPES results reveal folding of the π bands due to the periodic (2 × 2) potential of the intercalated Cs atoms, together with a free-electron-like state at the [Formula: see text] point. Significant mass renormalization is observed in the band dispersion near the Fermi level, indicative of strong electron-phonon coupling. Based on analysis of the self-energy, we find anisotropic electron-phonon coupling with an estimated strength of [Formula: see text] ± 0.02 in the K-[Formula: see text] direction, and [Formula: see text] in the K-M direction. This coupling is much larger than that of other doped graphenes, and comparable to superconducting bulk GICs. We attribute this large electron-phonon coupling constant to the presence of the Cs overlayer, which highly dopes [Formula: see text] bands, and creates a structure similar to stage-I graphite intercalation compounds.

Labeling of Rh antibodies on solid-phase protein A.

Rh0(D) antibodies which retain immune specificity after radiolabeling were prepared by a procedure which does not require IgG isolation from serum, requires 10-fold less isotope than conventional techniques and yields antibody solutions of defined composition. The method involves radioiodination of IgG on immobilized protein A, depends on employing human red cells reduced in surface cytophilic IgG, and exploits the inability of goat IgG to interact with Staphylococcus aureus protein A. The technique concentrates IgG by affinity adsorption and should prove useful in preparing radiolabeled alloantibodies from dilute human antisera and for red cell autoantibodies.

Superficial and systemic illness related to a hot tub.

In an outbreak of folliculitis in Alaska among bathers in a contaminated hot tub, one person was found in whom follicular lesions were preceded by deep, tender, peripheral nodules. Of nine affected bathers, five showed inflammation of Montgomery's follicles of the breast. Bathing longer in the tub and later in the day was associated with increased risk of disease. This investigation added serotype O-7,8 to the list of pseudomonads associated with hot tub infections.

Recurrent toxin-mediated perineal erythema.

BACKGROUND: Important new diseases due to bacterial toxins functioning as superantigens have been described with increasing frequency within recent years. Toxic shock syndrome, recalcitrant erythematous desquamating disorder, streptococcal toxic shock-like syndrome, and, most recently, mucocutaneous lymph node syndrome (Kawasaki disease) have been etiologically linked with certain staphylococcal and streptococcal toxins. We describe two patients with a novel clinical presentation of toxin-mediated disease, which shares certain clinical features with mucocutaneous lymph node syndrome. OBSERVATIONS: Two otherwise healthy young male adults developed recurrent erysipelaslike perineal erythema, which regularly erupted within 1 to 2 days of the onset of acute pharyngitis. Accompanying signs included mucosal changes and acral erythema with desquamation. Throat cultures obtained during the acute episodes yielded toxin-producing Staphylococcus aureus from one patient and toxin-producing Streptococcus pyogenes from the other. CONCLUSION: The recurrent nature, age predilection, and clinical presentation suggest that our patients display a unique clinical syndrome due to toxin-producing bacteria.

Interactions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with immune responses of rainbow trout.

Chlorinated dioxins, as typified by the most potent isomer, TCDD, are immunosuppressive in mammalian species and can enhance the susceptibility to a number of diseases. In recent years chlorinated dioxins have been detected in fish in many freshwater and marine habitats. Thus far, the effects of these chemicals on the immune responses of fish have not been examined. We studied the influence of TCDD on the defense mechanisms of rainbow trout. Yearling trout were injected intraperitoneally with the vehicle, 0.1, 1.0 or 10 micrograms/kg of TCDD. Interactions with the humoral immune response to sheep red blood cells (SRBC) were assessed by the Jerne plaque assay using head kidney and spleen leukocytes. Serum antibody was measured by complement-mediated lysis of SRBC in a chromium release assay. Effects of TCDD on the cellular immune responses were evaluated by the response of thymic and splenic lymphocytes to Con A and PWM. In addition, the phagocytic activity of peritoneal macrophages was examined in vitro. Trout which received 0.1 or 1.0 micrograms/kg TCDD remained clinically normal, and defense mechanisms were unaltered in these fish. Trout which received 10 micrograms/kg of TCDD became hypophagic and exhibited fin necrosis, ascites and suppression of hematopoiesis. In this treatment group, Con A-induced blastogenesis of thymic and splenic lymphocytes was not significantly changed, however, suppression of the PWM-induced response of splenic lymphocytes occurred. No statistically significant alterations occurred in humoral immune responses, and phagocytic activity of peritoneal macrophages was not decreased. The dose-response curve for various biologic effects of TCDD in the rainbow trout appears different from that in sensitive mouse strains. The 30-day, single-dose, parenteral LD50 for TCDD in the C57BL mouse is 100 micrograms/kg, and TCDD suppresses both cell-mediated and humoral immune responses at 1-2 micrograms/kg in this mouse strain. In the rainbow trout, however, immunosuppression was evident only at doses of TCDD approaching the 80-day, single-dose, parenteral LD50 of 20 micrograms/kg.

Freud's views on early female sexuality in the light of direct child observation.

Freud's writings on early female sexuality are reviewed in order to demonstrate which of his central assumptions are supported and which have been corrected by the direct observation of young children. The study of the emergence of core gender identity in little girls is a key to the modification of Freud's statements on the onset of and crucial factors in the development of femininity. Cognitive functions, learning experiences, and language are believed to be more important than Freud stressed, and penis envy and feelings of inferiority are relegated to a less universal and less necessary place in the onset of femininity. The role of the father is given different emphasis. Direct observation clarifies many aspects of masturbation or early genital self-stimulation in the young female: its onset; its feminine rather than masculine character; its early vicissitudes; its importance relative to other behavior; the impact of the discovery of anatomical difference; one special way it is affected by parental attitude; and how it contrasts with comparable behavior in the young male. Observation refutes Freud's often quoted statement that masturbation is further removed from the nature of women than of men.

The establishment of core gender identity in normal girls. I. (a) introduction; (b) development of the ego capacity to differentiate.

There has been a gradual shift from Freud's point of view that there is no femininity until the phallic phase. Modification of Freud's view on the onset of femininity is furthered by establishing that differences between boys and girls are observable in the preoedipal period and by studying the origin of a girl's sense of femaleness, i.e., her core gender identity. It is not essential whether we call this early development of the girl's sense of her femaleness core gender identity, earliest gender identity,or precursors of gender identity.Several studies confirm it is an essential foundation on which subsequent gender identity is built, Its establishment is normally well under way and sometimes irreversible by age 3 and more firmly secured in the fourth and fifth years. Of the multiple factors-biological (including its expression as instinctual drive), genetic, and experiental-contributing to core gender identity, the ego capacity to differentiate is traced and stressed as a necessary condition. The psychoanalytic and relevant nonpsychoanalytic literature is reviewed. Cognitive functions play a more significant role in core gender identity formation than previously believed and probably are more universally contributory at this early age (before 3) than identification mechanisms, envy of the male genitals, or castration anxiety. Ascription of gender at birth followed by the environmental confirmation impinging on progressively maturating cognitive capacities in the child would then normally be the organizer of gender identity, although definitely not the sole forces molding it.

The establishment of core gender identity in normal girls. II. How meanings are conveyed between parent and child in the first 3 years.

Observations of a normal female child from birth to 3 years are selected to illustrate some of the ways early gender identity is established. These and observations of other normal children suggest that meanings conveyed by parents and identification processes contribute to the establishment of significant beginnings of gender identity before the phallic period and before penis envy, castration anxiety, and the oedipal complex contribute their main influence.

Inhibition of histidyl-tRNA-adenosine triphosphate phosphoribosyltransferase complex formation by histidine and by guanosine tetraphosphate.

Formation of the complex between the first enzyme of histidine biosynthesis from Salmonella typhimurium, ATP phosphoribosyltransferase [1-(5'-phosphoribosyl)-ATP: pyrophosphate phosphoribosyltransferase; EC 2.4.2.17], and histidyl-tRNA is shown to be inhibited by L-histidine and by guanosine-5'-diphosphate-3'-diphosphate in the presence of histidine. Higher histodine levels make guanosine tetraphosphate a more effective inhibitor. Relatively high concentrations of guanosine-5'-triphosphate also inhibit complex formation, but this inhibition is not enhanced by histidine. The possible implications of these observations with respect to the gene regulatory activity of this enzyme are discussed.

Morphologic lesions and acute toxicity in rainbow trout (Salmo gairdneri) treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

To determine effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on growth, mortality, and morphologic lesions in rainbow trout, juvenile Shasta or Wytheville strain fish, obtained from 4 hatcheries, were administered graded single doses of TCDD, 0.1-125 micrograms/kg, ip. TCDD doses of 25 and 125 micrograms/kg caused 85% lethality 2-4 wk after treatment. At these high doses, death occurred before body weight loss could be detected. A lower dose of 5 micrograms/kg caused decreased growth and cumulative mortality of 20% after 11 wk. Stress associated with netting and weighing the fish at weekly intervals significantly shortened the delay period prior to TCDD-induced lethality. Gross and microscopic lesions were evident in rainbow trout treated with 10 micrograms TCDD/kg, but not in fish treated with 1 or 0.1 microgram/kg. Morphologic lesions occurred consistently in epithelial and lymphomyeloid tissues of TCDD-treated fish. Lymphomyeloid lesions included thymic involution, splenic lymphoid depletion, and hypocellularity of hematopoietic tissues in the head kidney and trunk kidney. In association with decreased hematopoiesis, peripheral leukopenia and thrombocytopenia occurred in Shasta strain yearling trout treated with 1 microgram/kg or more TCDD. Regarding epithelial lesions, all 4 hatchery strains treated with 10 micrograms/kg or more TCDD showed multifocal necrosis of gastric cardiac glandular mucosa, 3 of 4 hatchery strains showed vacuolar inclusions in exocrine pancreatic cells, and 2 of 4 hatchery strains showed fin necrosis. The severity and character of lesions in the liver and gastric mucosa varied markedly between hatchery strains of trout. One hatchery strain showed no hepatic lesions, two showed mild hepatocyte lesions, and one exhibited severe diffuse hepatopathy. In this severely affected hatchery strain, hyaline intracytoplasmic inclusions occurred in hepatocytes at 14 and 34 d after TCDD exposure, and bile-duct hyperplasia occurred at 34 d following TCDD exposure. One of 4 hatchery strains showed atrophy of serous gastric glands and 1 of 4 hatchery strains showed hyperplasia of these same glands at 25 and 34 d, respectively, following TCDD treatment. Thus, lymphomyeloid and epithelial tissues are the primary targets for TCDD-induced pathologic lesions in rainbow trout, and the incidence and severity of these lesions is influenced by the strain of trout used and the hatchery from which the trout were obtained.

2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in yellow perch (Perca flavescens).

Growth, mortality and morphologic lesions in juvenile, hatchery-reared yellow perch, Perca flavescens, were studied after treatment with graded single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1-125 micrograms/kg, intraperitoneally). TCDD doses of 25 and 125 micrograms/kg caused 95% mortality by 28 d after treatment, without decreasing body weight. A TCDD dose of 5 micrograms/kg resulted in progressive loss of body weight with cumulative mortality of 80% by 80 d posttreatment. Periodic handling stress did not affect the time course of mortality or cumulative percent lethality in TCDD-treated perch. Fin necrosis, petechial cutaneous hemorrhage, and ascites occurred in perch treated with 5 micrograms/kg or more of TCDD. Thymic atrophy, decreased hematopoiesis in the head kidney, fibrinous pericarditis, focal myocardial necrosis, submucosal gastric edema, and hyperplasia of the epithelium of gill filaments and lamellae occurred in perch dosed with 25 or 125 micrograms/kg. Dose-related splenic lymphoid depletion occurred in perch receiving 5 micrograms/kg or more TCDD, and hepatocyte lipidosis occurred in groups treated with doses of 1 microgram/kg or more TCDD. Thus yellow perch are as responsive to the acute toxic effects of TCDD as some of the more sensitive mammalian species, and neither loss of body weight nor histologic lesions in TCDD-treated perch are sufficient to explain mortality.

Species differences in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and biotransformation in fish.

Rainbow trout, yellow perch, carp, bluegill, largemouth bass, and bullhead were treated with graded doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1, 5, 25, or 125 micrograms/kg) or vehicle, ip. The lethal potency of TCDD tended to be greater in yellow perch, carp, and bullhead than in the other three species (LD50 80 days post-treatment, 3-5 versus 10-16 micrograms/kg, respectively). All species treated with the highest dose of TCDD (125 micrograms/kg) displayed a latency period of 1-4 weeks prior to death; longer latency periods were produced by lower lethal doses. Effects of TCDD treatment on body weight were both species-dependent and dose-dependent. Fin necrosis was observed in all fish species; however, cutaneous hemorrhage was observed only in TCDD-treated perch, carp, and bluegill, and cutaneous hyperpigmentation only in TCDD-treated carp and largemouth bass. Gallbladder bile was analyzed for TCDD and its metabolites 7 days after fish were injected with [14C]TCDD (60 micrograms/kg, ip). At least three TCDD metabolites in addition to the parent compound were found in the gallbladder bile of all six species. In addition, the retention time of the major biliary TCDD metabolite (determined by HPLC) was similar in all species except yellow perch. Beta-Glucuronidase treatment of the bile from largemouth bass and bluegill suggested that at least two of the TCDD metabolites were glucuronide conjugates. Thus, species differences exist in the lethal potency, signs of overt toxicity, and biotransformation of TCDD among freshwater fish.

Inhibition of testicular steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats: evidence that the key lesion occurs prior to or during pregnenolone formation.

The mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment decreases testosterone (T) secretion without significantly altering plasma luteinizing hormone (LH) concentrations was investigated. Testes from sexually mature Sprague-Dawley rats dosed 7 days earlier with 100 micrograms TCDD/kg secreted 30-75% less T than did testes from control rats when perfused in vitro with the LH analog human chorionic gonadotropin (hCG). This decrease confirms that testicular responsiveness to LH, the hormone which regulates T secretion in vivo, is impaired by TCDD treatment. Because TCDD also reduced intratesticular T content, the decrease in T secretion is due to an inhibition of T synthesis rather than to a failure of the secretion process. These effects of TCDD are not secondary to undernutrition, because perfused testes from feed-restricted control rats were fully hCG responsive. TCDD treatment neither increased the hCG-stimulated secretion of any T precursor nor significantly decreased the efficiency with which testes converted the pregnenolone (PREG) they synthesized into T (PREG is the initial steroidogenic intermediate). In addition, TCDD did not inhibit T secretion when steroidogenesis was supported by exogenous PREG at approximately the in vivo rate. We conclude that TCDD does not inhibit the conversion of PREG to T. The inhibition of T biosynthesis must instead result from an inhibition of PREG formation. The finding that TCDD treatment substantially decreased the rate at which hCG-perfused testes secreted PREG and its metabolites (a decrease seen across all hCG concentrations) confirms this conclusion. This inhibition of LH/hCG-stimulated PREG formation by TCDD must be due to a reduction in the activity of the enzyme which converts cholesterol to PREG (cytochrome P450scc), and/or an impairment in the multistep process responsible for mobilizing cholesterol to this enzyme.

Differential binding of IgG anti-D and IgG autoantibodies to reticulocytes and red blood cells.

125I IgG anti-D binding to reticulocytes obtained by density fractionation is reduced relative to that bound to all other red cell (RBC) fractions. Maximum D antigen reactivity occurs following reticulocyte maturation with no detectable change in D reactivity of mature RBC throughout their life span. Reticulocytes have in the range of about 60% of the content of mature RBC. Previously reported increased anti-D agglutinability and binding to old RBC it is not due to an intrinsic increase in D antigen with age, but results from an 'apparent' decrease in anti-D binding to young RBC fractions due to reticulocyte enrichment. IgG RBC autoantibodies obtained by elution from the RBC of eight Coombs-positive blood donors, probably associated with alpha-methyldopa (alpha-MD) administration, showed decreased binding to reticulocytes as determined by 125I protein A (PA). Reticulocytes bound about 70% of the IgG bound to mature RBC, indicating that the membrane antigenic determinant defined by these autoantibodies was incompletely expressed in the reticulocyte. This difference in IgG autoantibody binding between reticulocytes and mature RBC is similar to the decreased D antigen content of reticulocytes and consistent with an autoantibody determinant associated with the Rh complex. Direct testing of density fractionated Coombs-positive RBC in four out of five patients with autoimmune haemolytic anaemia (AIHA) showed reduced quantities of IgG on reticulocytes. The distribution of IgG between reticulocytes and mature RBC may be useful in serologically characterizing patients with AIHA and in identifying subpopulations of patients with this disorder.

Exposure of the Rh0(D) antigen on the surface and cytoplasmic domains of the red cell membrane.

Inside-out (IO) and right-side-out (RO) vesicles derived form human red blood cells were tested for their ability to bind 125I-labelled IgG anti-RHO(D). The binding of anti-RHO(D) to RO vesicles from RHO(D)-positive cells was quantitatively similar to that exhibited by intact cells when compared on a membrane surface area basis. There was no significant binding of labelled antibody to IO vesicles from RhO(D)-positive cells or to either RO or IO vesicles derived from RhO(D)-negative cells. The RhO(D) antigen was immunologically accessible on only the plasma side of the membrane in RhO(D)-positive red cells, as has been shown for blood group antigens defined by carbohydrate determinants. No immunologically reactive RhO(D) antigen was present on either RO or IO vesicles derived from RHO(D)-negative red cells.