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BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

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OBJECTIVE: The entire human genome will be sequenced in September 2000. Facing the exponential increase of data in the GenBank at the National Center for Biotechnology Information, reproductive biologists are being bombarded with massive amounts of information on diverse genes. It is becoming increasingly difficult for individual investigators to sort out the diverse genetic and physiologic information on the localization and function of different genes in the ovary. To alleviate the present situation, we have taken advantage of the accessibility of the Internet and initiated a project that serves the entire ovarian research community. RESULTS AND DISCUSSION: The Ovarian Kaleidoscope database provides information regarding biologic function, expression pattern, and regulation of genes that are expressed in the ovary. In addition, it serves as a gateway to other online information resources relevant to ovarian research by offering results from original papers and data about nucleotide and amino acid sequences, and human and murine mutation phenotypes. All references are linked by hypertext to PubMed and additional links to sequence databases are also included. This information is accessible online and searchable not only by gene name but also by criteria such as the cellular and ovarian function of the gene product, the expression of genes in different ovarian cell types, or their association with specific ovarian phenotypes.

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Food refusal poses difficulties for nurses and care staff and can place older patients with dementia at risk of undernutrition. The dangers of and reasons for food refusal in these patients are explored and the fundamental ethical and legal issues raised in caring for these patients are examined. Practical guidance and solutions are offered through dietetics and speech and language therapy with the aim of helping nurses and care staff, as well as professional carers in palliative care, and explore ways of critically examining and coping with these dilemmas.

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Levels of progesterone (P4), testosterone (T) and estradiol (E2) indicated significant variation among individual echinoids during the annual cycle, reflecting generally the variation in gamete development that can be observed among individuals. Testosterone and E2 levels in both the ovaries and testes were higher during the period of gonadal growth. Levels of all steroids were greatly reduced compared to those levels reported for asteroids. Differences in the levels of P4, T, and estrogens between asteroids and Lytechinus variegatus may be related to differences in gonad morphology and nutrient storage capacity between asteroids and echinoids. It was hypothesized that the low levels of steroids detected in L. variegatus reflect paracrine-like mechanisms in cell signaling as compared to endocrine-like mechanisms proposed to be involved in regulating gonad function in asteroids. Both the ovaries and testes of L. variegatus had the capacity to synthesize T and a variety of 5alpha-reduced androgens including 5alpha-androstane-3beta,17beta-diol and 5alpha-androstane-3alpha,17beta-diol (5alpha-adiols) from androstenedione (AD) in 8 h. Estrogen synthesis was not detected. The sex-specific pattern of accumulation of 5alpha-adiols in the ovaries and testes suggests that the 5alpha-adiols may affect processes related to reproduction in L. variegatus.

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Palliative care professionals have begun to address the issues surrounding the provision of palliative care to non-cancer patients. Yet the situation remains inconsistent and morally unjustifiable. The duty to provide care, non-maleficence, beneficence, protecting the patient's best interests and respecting patient autonomy are key responsibilities which palliative care professionals have for all their patients, regardless of their diagnosis. On the grounds of justice as fairness, equality and equity, the current inconsistencies in the provision of palliative care to non-cancer patients are unfair unequal and inequitable. Professionals can no longer ignore their moral responsibility to address these issues and change their practice to include the provision of care for dying patients regardless of their diagnoses.

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The phylum Microspora contains a diverse group of single-celled, obligate intracellular protozoa sharing a unique organelle, the polar filament, and parasitizing a wide variety of invertebrate and vertebrate animals, including insects, fish, birds, and mammals. Encephalitozoon cuniculi is the classic microsporidial parasite of mammals, and encephalitozoonosis in rabbits and rodents has been and continues to be recognized as a confounding variable in animal-based biomedical research. Although contemporary research colonies are screened for infection with this parasite, E. cuniculi remains a cause of morbidity and mortality in pet and conventionally raised rabbits. In addition, E. cuniculi is a potential pathogen of immature domestic dogs and farm-raised foxes. The recent discovery and identification of Encephalitozoon intestinalis, Encephalitozoon hellem, and Enterocytozoon bieneusi, in addition to E. cuniculi, as opportunistic pathogens of humans have renewed interest in the Microspora. Veterinary pathologists, trained in the comparative anatomy of multiple animal species and infectious disease processes, are in a unique position to contribute to the diagnosis and knowledge of the pathogenesis of these parasitic diseases. This review article covers the life cycle, ultrastructure, and biology of mammalian microsporaidia and the clinical disease and lesions seen in laboratory and domestic animals, particularly as they relate to Encephalitozoon species. Human microsporidial disease and animal models of human infection are also addressed. Often thought of as rabbit pathogens of historical importance, E. cuniculi and the related mammalian microsporidia are emerging as significant opportunistic pathogens of immunocompromised individuals.

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Enteritis is a potential complication of antimicrobial agent use, particularly in certain species of rodents. The organism most frequently implicated in this disease is Clostridium difficile. Anecdotal information suggests that administration of yogurt or other Lactobacillus-containing products in conjunction with antimicrobial agents will prevent or minimize the effects of antibiotic-associated enteritis. We wanted to determine whether a single subcutaneous injection of clindamycin phosphate could induce enteritis in guinea pigs and whether a commercial Lactobacillus preparation would ameliorate the clinical effects of antibiotic administration in these animals. Juvenile male guinea pigs were divided into three treatment groups. Group 1 guinea pigs (n=8) received a single saline injection followed by an oral Lactobacillus preparation twice daily; group 2 (n=8) received a single antibiotic injection followed by an oral Lactobacillus preparation twice daily; group 3 (n=8) received a single antibiotic injection. Attitude, body temperature, body weight, and feed and water consumption were recorded for each guinea pig 7 days prior to and after treatment. Fecal samples were collected and necropsies performed on each guinea pig at the time of euthanasia. C. difficile and other enteric pathogens were not isolated from any group before or after treatment, although some guinea pigs receiving the antibiotic developed enteritis. There were no significant clinical differences between guinea pigs receiving antibiotics with the oral Lactobacillus preparation, and those receiving antibiotics alone. The results of this study suggest that a single injection of clindamycin phosphate can induce enteritis in guinea pigs and that oral administration of a Lactobacillus-containing product is ineffective in preventing clinical disease in guinea pigs administered clindamycin phosphate.

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In the present study we examined the metabolic fate of progesterone (P4) in homogenate and tissue minces of the ovaries and testes of Lytechinus variegatus. P4 was metabolized primarily into 5alpha-reduced metabolites including, 5alpha-pregnane-3,20-dione (DHP), 3beta-hydroxy-5alpha-pregnan-20-one (3beta,20-one), 5alpha-pregnane-3beta,20alpha-diol (3beta,20alpha-diol), 5alpha-pregnane-3beta,20beta-diol (3beta,20beta-diol), and 5alpha-pregnane-3alpha,20alpha-diol (3alpha,20alpha-diol) by both the ovaries and testes. The capacity to metabolize P4 did not differ between the ovaries and testes. However, the relative quantity of Salpha-pregnane-3beta,20zeta-diol synthesized from ovary and testis tissue minces was about 3.3-fold higher than from homogenate preparations. Differences in the synthesis of 3beta,20-one and 3alpha,20alpha-diol in both ovary and testis minces were dependent on reproductive state. This study demonstrates the pathway of P4 conversion in the ovaries and testes of L. variegatus and indicates the rapid conversion of P4 into 5alpha-reduced metabolites in these tissues. Although P4 metabolism is not sex specific, sex-specific responses to P4 metabolites have been demonstrated previously. We hypothesize that the sex-specific responses of the ovaries and the testes to P4 may be associated with receptor-level regulatory processes.

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Lycopene is the predominant carotenoid in tomatoes and tomato-based foods and is also a predominant carotenoid in human serum and tissues. Intake of lycopene-rich foods was recently associated with decreased risk for several chronic diseases. The observation that serum and tissue lycopene is more than 50% cis-lycopene, whereas tomatoes and tomato-based foods contain mainly all-trans-lycopene, has led to the hypothesis that cis-isomers of lycopene are more bioavailable. We tested this hypothesis both in vitro (study 1) and in vivo (study 2). In study 1, bile acid micelles containing crystalline lycopene were prepared. The crystalline lycopene used for these analyses was 54.4% cis-lycopene. The optically clear micelle preparation contained 75.9% cis-lycopene in repeated analyses. In study 2, mesenteric lymph duct cannulated ferrets were used to study the in vivo absorption of lycopene from LycoredTM (an ethyl acetate extract of tomatoes containing 5% lycopene by weight; of which 91% was all-trans lycopene). Before being anesthetized, male ferrets (n = 7) were dosed orally with 40 mg lycopene per kg body weight in soybean oil. Lymph secretions were collected, on ice, for 2 h. The residual stomach and small intestinal contents, mucosa lining, lymph secretion and serum were analyzed by HPLC. Whereas the dose, stomach and intestinal contents contained 6.2-17.5% cis-lycopene, the mesenteric lymph secretions contained significantly more, 77.4%, cis-lycopene (P < 0.01). These studies demonstrate that in ferrets, cis-isomers of lycopene are more bioavailable than trans-lycopene probably because cis-isomers are more soluble in bile acid micelles and may be preferentially incorporated into chylomicrons.

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BACKGROUND AND PURPOSE: The gastrointestinal tract is a common portal of entry for Encephalitozoon cuniculi, one of several microsporidial organisms emerging as opportunistic pathogens in immunocompromised humans. Although most human microsporidial pathogens can be propagated in vitro and in a variety of laboratory animals, an experimental animal system to specifically study intestinal uptake and systemic spread of these organisms does not exist. METHODS: Paired segments of near-term fetal rabbit small intestine were implanted subcutaneously into 25 athymic nude or 10 severe combined immune deficient mice. Five weeks after surgery, 65 xenografts were inoculated intraluminally with E. cuniculi (n = 14), E. intestinalis (n = 27), E. hellem (n = 20), or RK-13 cells (n = 2), or were left uninoculated (n = 2). RESULTS: Intestinal xenograft infection with E. cuniculi (n = 11), E. intestinalis (n = 17), and E. hellem (n = 18) was determined by light microscopy; control xenografts remained uninfected. Extraintestinal infection with E. cuniculi developed in host mouse brain, respiratory tract, spleen, salivary glands, and gastrointestinal tract (3 of 3 mice), and infection with E. intestinalis developed in the liver (8 of 15 mice). CONCLUSION: Intestinal xenografts provide a unique, sterile, and biologically relevant animal model system for studying host enterocyte/parasite interactions, mechanisms of microsporidial pathogenicity, antimicrosporidial chemotherapeutic agents, and immune effector mechanisms. This model provides evidence for persistent graft infection with three Encephalitozoon spp., and for intestinal spread of E. cuniculi and E. intestinalis from infected enterocytes in immunoincompetent mice.

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Recent investigations into the steroid metabolic pathway in the echinoid Lytechinus variegatus demonstrated the capacity of the gonads to convert androstenedione, the classical mammalian precursor to bioactive androgens, into testosterone and a variety of 5 alpha-reduced androgens including 5 alpha-androstane-3 beta, 17 beta-diol and 5 alpha-androstane-3 alpha, 17 beta-diol. The synthesis of these steroids, which requires 5 alpha-reductase activity, varies with sex and reproductive state in L. variegatus, suggesting that these steroids may be involved in reproductive processes. The classical method of castration followed by steroid replacement therapy to determine the biological role of steroids in the gonads of higher vertebrates is not possible in echinoids. Therefore, this study was designed to determine the efficacy of finasteride, a selective 5 alpha-reductase inhibitor in the mammalian prostate gland, on 5 alpha-reductase activity in the gonads of L. variegatus. Finasteride inhibits echinoid 5 alpha-reductase in a dose-dependent manner with IC50 approximately 2.7 microM for both ovaries and testes. These echinoid IC50s are significantly higher than those reported for humans and rats. In addition, oral administration of finasteride to the echinoids appeared to inhibit 5 alpha-reductase with no apparent stress (no spine loss) to the animals. These data suggest that finasteride may be used to selectively and chemically ablate 5 alpha-reduced androgen synthesis in the gonads of L. variegatus.

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Although sex steroids and steroid converting enzymes have been found in echinoids, the relationship between steroids and reproduction has not been demonstrated. On days 0, 4, 8, 16, 32, and 48 of feeding, the gonads of previously starved Lytechinus variegatus were excised and incubated with [3H]androstenedione for 0.5 h to determine if changes in steroidogenic capacity are correlated with gonadal growth. Total rates of androstenedione conversion in the testes and ovaries increased significantly during feeding. In addition, the types and relative quantities of metabolites synthesized varied, suggesting that androstenedione metabolism is influenced by nutritional status. Both testes and ovaries synthesized testosterone, 5alpha-androstane-3alpha,17beta-diol, and 5alpha-androstane-3beta, 17beta-diol (5alpha-adiols), 5alpha-androstanedione, epiandrosterone, and androsterone on all days of feeding. In the testes, the relative quantities of testosterone and 5alpha-adiols increased greatly on day 4 of feeding. In contrast, in the ovaries testosterone synthesis was not detectable on day 4, although the relative quantities of 5alpha-adiols increased threefold. The sex-specific changes in the synthesis of these metabolites reflect a shift in the metabolic pathway indicated by changes in the relative enzyme activity indices for 5alpha-reductase (5alpha-R) (necessary for the synthesis of 5alpha-reduced androgens) and 3alpha/beta-hydroxysteroid dehydrogenase (3alpha/beta-HSDs, necessary for the synthesis of 3alpha- or 3beta-hydroxylated androgens). In both testes and ovaries the relative activities of 5alpha-R and 3alpha/beta-HSD increased on day 4 of feeding. The physiological significance of changes in androstenedione metabolism may be associated with the initiation of biosynthetic processes associated with gametogenesis.

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Sexual mode in colonial animals is expressed at the zooid, colony, and genet level; all three must be characterized to understand sexuality in these animals. I carried out such an examination of the sexual mode of a colonial kamptozoan (entoproct), Barentsia hildegardae, at Friday Harbor, Washington. Calyces never contained both ovaries and testes, and colonies never contained both male and female calyces. Calyces and colonies (including replicate colonies from the same genet) monitored over two years did not change sex. These results suggest that B. hildegardae is comprehensively gonochoric. For comparison, I examined the sexual mode of five other species in the genus Barentsia. Barentsia benedeni, B. conferta, and B. ramosa also appear to be comprehensively gonochoric. Barentsia discreta is hermaphroditic at the colony level, with gonochoric calyces whose sex is environmentally determined, as noted by previous workers. Barentsia aggregata has simultaneously hermaphroditic calyces; this was reported by the authors who described it, but has escaped notice in subsequent reviews of kamptozoan biology. There are thus three contrasting modes of sex within the genus Barentsia. All three modes also occur in colonial cnidarians, and two of them are known in bryozoans, colonial hemichordates, and colonial urochordates. These disparate sexual modes may have evolved as adaptations to differing environmental conditions or population densities.

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A case is reported in which transbronchial lung biopsy using the fiberoptic bronchoscope was complicated by massive, fatal hemorrhage. This previously unreported complication occurred despite normal prothrombin and partial thromboplastin times and platelets of 93,000. Pathological examination revealed that a very small (0.5-mm) vessel was the source of the bleeding. Although severe complications are undoubtedly rare, this report suggests that the transbronchial lung biopsy is not a totally benign procedure. Suggestions are made to prevent future similar occurrences in very ill patients or in patients with coagulative abnormalities or blood dyscrasias.

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