Anti-angiogenesis Revisited: Combination with Immunotherapy in Solid Tumors.

PURPOSE OF REVIEW: Both anti-angiogenesis and immunotherapy are well-established therapeutic options in solid tumors. Here, we review the rationale as well as clinical evidence of combining these two approaches. RECENT FINDINGS: There is strong rationale and substantial preclinical and clinical evidence that anti-angiogenesis plays a pivotal role in overcoming immunotherapy resistance. The combination of an anti-angiogenic agent and a checkpoint inhibitor offers a more robust treatment option in many clinical trials in a wide variety of solid tumor types. Combination of anti-angiogenesis and immunotherapy has emerged as a standard of care in some tumor types and the indication is expected to expand to more tumor types in the years to come.

The distribution of strongylid egg and lungworm (Dictyocaulus eckerti) larval counts in adult female farmed red deer (Cervus elaphus), and the implications for parasite control.

Whilst healthy adult farmed red deer show little clinical indication of parasite infection, they may still be maintaining infection levels on the farm through low-level shedding of nematode eggs and lungworm larvae. This work was undertaken to establish the long-term distribution of parasite counts, to determine whether the higher counts seen in previous trials are repeatable across the same animals. All adult female red deer on a New Zealand North Island property were faecal sampled (n = 209), weighed, and body condition scored (BCS) on five sampling occasions from March - August 2021. Faecal samples were processed by modified Baermanns to recover, identify, and enumerate lungworm 1st stage larvae (FLC), and nematode faecal egg counts (FEC) were determined by mini-FLOTAC. Between animal variation for FEC was significant (p < 0.001); whilst many counts were low to zero, a few individuals were consistently shedding higher egg counts. Younger animals tended to have higher egg counts (p = 0.003), but there was no association between FEC and BCS (p = 0.22), and FEC and liveweight (p = 0.58). Modelling of the data indicated that 50% of the egg output resulted from 21% of the animals. Additionally, there was no significant association between the higher egg counts and the gastrointestinal nematode classification; 'long tails' (likely Oesophagostomum sp.) p = 0.76, and the Ostertagiinae complex p = 0.75. Lungworm counts tended to be very low (0 - 26 lpg); consistent with previous trials and literature in farmed adult deer. However, between animal differences were statistically significant (p < 0.001) indicating some animals were passing more larvae than others, and poorer conditioned animals (BCS 2.5) were significantly associated with higher larval count (p = 0.03). There was no relationship between larval count and age (p = 0.62) and larval count and liveweight (p = 0.22). Modelling indicates that 50% of pasture larval contamination was contributed by 15% of the animals. There was no correlation between nematode egg count and lungworm larvae count (p = 0.22). Adult deer may play an important role as a source of infection for young deer, therefore, an improved understanding of the distribution of infection is needed to improve parasite control.

A model for the development of the free-living stages of Ostertagia leptospicularis, used in conjunction with on-farm egg count data, to estimate sources of pasture contamination on New Zealand red deer (Cervus elaphus) farms.

Farmed red deer face challenges from nematode parasites, primarily the pulmonary species Dictyocaulus eckerti and the complex of Ostertagiinae nematodes in the abomasum. Previous investigations on New Zealand deer farms identified limited seasonality in faecal egg and larval output in all stock classes, however, this does not indicate the key times of year those eggs develop into infective-stage larvae, and subsequently contribute to infection risk. A simple temperature-driven model was developed for the free-living stages of a representative deer-specific Ostertagiinae species; Ostertagia leptospicularis. The model was then validated using development data generated from seasonal plot trials. Using faecal egg counts and animal numbers from the previous monitoring study, and local weather data from each of the sampling farms, the relative contribution of each stock class to infective third-stage larvae population on pasture was estimated for each month of the year (2018-2019). The mixed-age adult females were the primary source of infective larvae on most of the sampled farms, principally due to their numerical dominance (i.e., venison breeding farms). The frequent anthelmintic use in the youngest stock class (< 12 months old) on some farms limited their output of eggs and hence their contribution to pasture infestation with infective larvae. However, the trends of larval development on pasture differed between the farms (due to local climate), and between the sampling years (2018-2019). Therefore, calendar-based application of anthelmintics to older stock is not recommended, as contribution to pasture contamination is multifactorial. The study provides a better understanding of deer parasite epidemiology on which to base improved management practices.

Seasonal output of gastrointestinal nematode eggs and lungworm larvae in farmed wapiti and red deer of New Zealand.

Gastrointestinal nematode parasites and lungworm are significant animal health issues for farmed wapiti and red deer (Cervus elaphus). Chronic infection with gastrointestinal nematodes, coupled with sporadic, often pathogenic, outbreaks of the lungworm Dictyocaulus eckerti in young deer has resulted in many farmers relying heavily on anthelmintic treatments. An improved understanding of the epidemiology of the parasites infecting farmed deer, including the sources and seasonality of pasture contamination on the farm, is essential to the development of more integrated and sustainable control programs. The numbers of strongyle nematode eggs and lungworm larvae shed by different stock classes (red and/ or wapiti mixed-age stags, mixed-age red hinds, rising 2-year-old red stags and mix-sex rising 1-year olds) were monitored monthly, across six farms located in different regions of New Zealand, from January 2018 to early 2020. Every month, 10 fresh on-pasture faecal samples were collected from each stock class and couriered overnight to the laboratory. Baermann apparatus to recover lungworm 1st-stage larvae were set up immediately on sample arrival. Faecal samples for nematode faecal egg count were stored at 4 °C until the number of strongyle eggs were counted by mini-FLOTAC. Additional information, including stocking density, grazing systems, and anthelmintic treatments, were also noted every collection month. Results indicate a relatively consistent proportion of animals within each stock class shedding low numbers of both gastrointestinal nematode eggs (about 75 %) and lungworm larvae (about 50 %) all year round. There was little apparent seasonality and few differences between farms (location). Further, the average number of eggs/larvae shed was also relatively constant across seasons and locations, within each stock class. Interestingly, there was little correlation between lungworm larval counts and egg counts suggesting that the same animals were not consistently shedding both parasites. The data indicate that in the presence of regular anthelmintic treatments to young deer (< 1 year old), the adult stock groups constitute a potentially significant source of pasture contamination, and hence future infection. However, these data do not incorporate the seasonal effects of weather on egg/larval development, nor the number of animals of each stock class on the farms. Incorporation of these variables will be necessary to identify the sources and timing of subsequent infection. This work is currently underway.

Faecal egg counts and nemabiome metabarcoding highlight the genomic complexity of equine cyathostomin communities and provide insight into their dynamics in a Scottish native pony herd.

Understanding the composition of gastrointestinal nematode communities may help to mitigate or exploit parasite adaptations within their host. We have used nemabiome deep amplicon sequencing of internal transcribed spacer-2 (ITS-2) ribosomal DNA to describe the temporal and host species composition of gastrointestinal nematode communities following sampling of six Scottish ponies across 57 months. In the absence of parasite control, each horse showed seasonal trends of increases and decreases in faecal egg counts, consistent with the epidemiology of equine strongylid parasites, however, the composition of parasites within individuals changed over time. Sixteen presumptive strongylid species were identified in each of the horses, 13 of which were distributed in a complex clade together with small numbers of amplicon sequences which could not be classified beyond the Cyathostominae subfamily level. Egg shedding of seven trichostrongylid species, which had previously been identified in co-grazed Soay sheep, was identified during the early spring. Faecal egg counts and the percentage of amplicon sequences assigned to each gastrointestinal nematode species were combined to describe their relative abundance across both host and time. Significant differences in species diversity between horses and between months were observed, being greatest from March to May and least from October to December. The magnitude of the individual horse effect varied between months and, conversely, the magnitude of the seasonal effect varied between individual horses. The most abundant gastrointestinal nematode in each of the horses was Cylicostephanus longibursatus (46.6% overall), while the abundance of the other strongylid species varied between horses and relative to each other. Patent C. longibursatus infections over the winter months might represent a genetic adaptation towards longer adult worm survival, or a lower rate of developmental arrest in the autumn. This study provides insight into highly complex phylogenetic relationships between closely related cyathostomin species; and describes the dynamics of egg shedding and pasture contamination of co-infecting equine gastrointestinal nematode communities. The results could be applied to determine how climatic and management factors affect the equilibrium between hosts and their parasites, and to inform the development of sustainable gastrointestinal nematode control strategies for different host species.

Building a National Reassessment Process for Oncology Drugs: Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration through a Simulated Reassessment Exercise.

The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.

Molecular confirmation of Hymenolepis hibernia in field mice (Apodemus sylvaticus) from St Kilda has potential to resolve a host-parasite relationship.

Insular wildlife populations provide opportunities to examine biological questions in systems that are relatively closed and potentially tractable, striking examples being the long-term studies of ecology and evolution in the red deer and feral sheep populations on the Hebridean islands of Rum and St Kilda. In the case of parasitology, Understanding of parasitic infections insular wildlife populations in conjunction with knowledge of their origins has the potential to add a fresh perspective to disease control in humans and domestic animals. In the case of parasitology, understanding infections of insular wildlife populations, in conjunction with knowledge of their origins, has the potential to add a fresh perspective to disease control in humans and domestic animals. With this in mind, gross and molecular examination for the presence of cyclophyllidean tapeworms was performed on the viscera and rectal contents of 17 preserved specimens of Apodemus sylvaticus field mice and on the naturally voided faeces of a further four mice on the remote archipelago of St Kilda. Molecular speciation of hexacanth embryos extracted from the faeces of two mice, using nucleotide sequence analysis of the ribosomal cytochrome c-oxidase subunit-1, confirmed infection with Hymenolepis hibernia. Phylogenetic analysis showed that these were genetically distinct from Hymenolepis diminuta, previously reported in the insular A. sylvaticus mice, and from other published H. hibernia haplotypes. There was insufficient hymenolepidid tapeworm phylogeographic variation to resolve the origins of the co-evolved St Kilda mice, primarily due to a lack of published H. hibernia Cox-1 sequence data across the parasite's geographical range. Nevertheless, the Maximum Likelihood haplotype tree shows the potential for molecular parasitology to resolve a host-parasite relationship once more data become available. Morphological diagnostic features of zoonotic H. hibernia eggs are also described.

Lattice calculation of non-gaussian density perturbations from the massless preheating inflationary model.

If light scalar fields are present at the end of inflation, their nonequilibrium dynamics such as parametric resonance or a phase transition can produce non-Gaussian density perturbations. We show how these perturbations can be calculated using nonlinear lattice field theory simulations and the separate universe approximation. In the massless preheating model, we find that some parameter values are excluded while others lead to acceptable but observable levels of non-Gaussianity. This shows that preheating can be an important factor in assessing the viability of inflationary models.

Follow-up after primary therapy for endometrial cancer: a systematic review.

OBJECTIVE: To determine the optimum follow-up of women who are clinically disease-free following potentially curative treatment for endometrial cancer. METHODS: A systematic search of MEDLINE, EMBASE and the Cochrane Library databases (1980 to October 2005) was conducted. Data were pooled across trials to determine overall estimates of recurrence patterns. RESULTS: Sixteen non-comparative retrospective studies were identified. The overall risk of recurrence was 13% for all patients and 3% or less for patients at low risk. Approximately 70% of all recurrences were symptomatic, and 68% to 100% of recurrences occurred within approximately the first 3 years of follow-up. No reliable differences in survival were detected between patients with symptomatic or asymptomatic recurrences nor were differences in patient outcomes reported by type of follow-up strategy employed. Detection of asymptomatic recurrences ranged from 5% to 33% of patients with physical examination, 0% to 4% with vaginal vault cytology, 0% to 14% with chest X-ray, 4% to 13% with abdominal ultrasound, 5% to 21% with abdominal/pelvic CT scan, and 15% in selected patients with CA 125. CONCLUSIONS: There is limited evidence to inform whether intensive follow-up schedules with multiple routine diagnostic interventions result in survival benefits any more or less than non-intensive follow-up schedules without multiple routine diagnostic interventions. Routine testing seems to be of limited benefit for patients at low risk of disease. Most recurrences tend to occur in high risk patients within 3 years, and most recurrences involve symptoms. The most appropriate follow-up strategy is likely one based upon the risk of recurrence and the natural history of the disease. Counseling on the potential symptoms of recurrence is extremely important because the majority of patients with recurrences were symptomatic. A proposed routine follow-up schedule is offered.