Real-World Outcomes of Aggressive B-Cell Non-Hodgkin Lymphoma in People Living with HIV (PLWH) Treated in Australia: An Australasian Lymphoma Alliance Study

Background Modern antiretroviral therapy (ART) has reduced HIV associated morbidity and mortality, and allowed a similar treatment approach of aggressive lymphomas in PLWH to that of their HIV negative counterparts. Australia is an ethnically diverse country with a low HIV prevalence and an excellent population-wide ART coverage and adherence in PLWH. We aimed to describe the real-world Australian experience in managing PLWH diagnosed with diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL), and compare our treatment approach and outcomes against international data. Methods This was a retrospective, multicenter study conducted by the Australasian Lymphoma Alliance across 6 centers in 5 states. HIV positive patients with biopsy proven BL and DLBCL, diagnosed between 1st January 2009 and 31st December 2019 were identified through each institution's database. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate. Results 44 patients (24 DLBCL, 20 BL) were included in the analysis. The median age was 52 years (range 32-78). The median follow-up was 1.8 years (range 0.1-13.1). 36 (82%) patients presented with advanced stage (III-IV) disease. 28 (64%) were defined as high-risk based on disease specific IPI scoring systems. The mean CD4 count was 334 cells/μL at diagnosis and 10 (23%) patients had a CD4 count of <100 cells/μL. 23 (52%) had a HIV viral load <50 copies/ml. 12 (27%) were diagnosed with HIV at the time of lymphoma diagnosis (Mean CD4 count 191 cells/μL, mean viral load 665,612 copies/ml). 41 (93%) patients received chemotherapy with curative intent and 39 (88%) received Rituximab. 37 (84%) were given concurrent ART and chemo(immuno)therapy. 11 (55%) of BL patients were treated with CODOX-M/IVAC or HyperCVAD followed by 6 (30%) with Da-EPOCH. 14 (58%) of DLBCL patients received CHOP-based therapy with 11 (45%) receiving more intensive regimens (Da-EPOCH, HyperCVAD or CODOX-M/IVAC). In the whole cohort, median number of chemotherapy cycles delivered was 6, 6, 4 and 3 for CHOP, Da-EPOCH, CODOX-M/IVAC and HyperCVAD respectively. CR rates after first-line curative intent therapy were 75% and 83% in BL and DLBCL respectively. All treatment response assessments were made by positron emission tomography. Grade 3-4 toxicity was significant higher in patients receiving intensive chemotherapy (77% vs 29%, p=0.015). Total treatment related mortality was 5% (2 died of bacterial sepsis). The 2-year OS was 77% (95% CI 61-88); 67% for BL (95% CI 46-88) and 81% for DLBCL (95% CI 53-90)]. 2-year PFS was 67% for BL (95% CI 40-83) and 77% for DLBCL (95% CI 53-89). An initial drop of mean CD4 count post treatment was observed (334 to 214 cells/μL), followed by a rise after 6 and 12 months (290 and 431 cells/μL respectively) (fig 1). At 6 months post chemotherapy, 83% of patients had a HIV viral load of <50 copies/ml with 40% and 83% achieving a CD4 count of >350 cells/μL and >200 cells/μL respectively. Conclusions A significant proportion of PLWH still present with aggressive lymphoma as an AIDS-defining event prior to HIV diagnosis, despite high levels of health education and healthcare availability. Our results appear equivalent to those for non-HIV patients with acceptable toxicity. Current Australian practice favors treating aggressive lymphomas in PLWH similarly to the HIV negative population, with the addition of concurrent ART. CD4+ T-cell-related immune reconstitution appears to recover within 6 months post-therapy. The OS of this cohort appears similar to the HIV negative population and published cohort studies (Coutinho AIDS 2013, Evens Blood 2019, Alderuccio Blood Adv 2021). Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ku: Genor Biopharma: Consultancy; Antegene: Consultancy; Roche: Consultancy.

Elucidating the Characteristics of Two Tumor Cell Populations in Small Cell Variant of Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma

The small cell variant of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (SC-ALCL) is a subtype defined as comprising two distinct tumor cell populations in immunohistochemistry: small cells staining negative or weakly positive for ALK and CD30 protein; and large cells staining strongly positive for those proteins. Although the constitution of these two different cell populations might contribute to the poor prognosis, detailed characterization of each population by molecular-based approaches has not been done due to the difficulty of cell separation from solid tumor sample. In this paper, we have analyzed the characterization of each tumor cell population using the patient sample from SC-ALCL leukemic phase obtained from peripheral blood by molecular-based approaches. Flow cytometric analysis revealed two distinct abnormal populations. The major population comprising 74% of total leukocytes was positive for CD3 and CD8, and negative for CD4, CD5, CD25 and CD30. The minor population comprising 5% of total leukocytes was positive for CD25, CD30, CD11b and CD13. Fluorescent in situ hybridization with ALK break-apart probes and RT-PCR analysis confirmed that most of the cells including both populations were rearranged with NPM-ALK gene. To elucidate the cause underlying the distinct levels of ALK protein expression in each population, we separated those tumor cells by CD30-PE antibody and a magnetic bead separation kit, extracted DNA and RNA from each population, and compared NPM-ALK mRNA expression levels by droplet digital polymerase chain reaction. The expression level of NPM-ALK mRNA in the CD30-negative population was ten-fold less than that in the CD30-positive population (Table). This result indicated that the two tumor cell populations expressed the distinct level of NPM-ALK mRNA, although both populations possessed NPM-ALK fusion gene. To assess the effectiveness of various chemotherapies in each tumor cell population, we monitored each population in peripheral blood by flow cytometric analysis (small cell; CD30-5-8+, large cell; CD30+) over time. Intriguingly, CD30-negative population behaved as chemo-resistant cells in clinical course, however alectinib, a second-generation ALK-inhibitor, eradicated both populations inducing first complete remission. This study revealed two definitive features regarding the small CD30-negative population of SC-ALCL, with a lower expression level of NPM-ALK mRNA transcripts and chemoresistance. The cause of distinct ALK staining levels in immunohistochemistry was revealed depending on the distinct expression level of NPM-ALK mRNA transcripts. Finally, since both populations were sensitive to ALK-inhibitor, early administration of ALK-inhibitor might be the reasonable option for SC-ALCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A comparison of COVID-19 inpatients by HIV status

COVID-19 in-hospital morbidity and mortality in people living with HIV (PLWH) were compared to HIV-negative COVID-19 patients within a New York City metropolitan health system, the hardest hit region in the United States early in the pandemic. A total of 10,202 inpatients were diagnosed with COVID-19, of which 99 were PLWH. PLWH were younger (58.3 years (SD = 12.42) versus 64.32 years (SD = 16.77), p < 0.001) and had a higher prevalence of men (73.7% versus 57.9%, p = 0.002) and Blacks (43.4% versus 21.7%, p < 0.001) than the HIV-negative population. PLWH had a higher prevalence of malignancies (18% versus 7%, p = < 0.001), chronic liver disease (12% versus 3%, p < 0.001), and end-stage renal disease (11% versus 4%, p = 0.007). Use of a ventilator, admission to the ICU, and in-hospital mortality were not different. Of the 99 PLWH, 12 were virally unsuppressed and 9 had CD4% < 14. Two of the 12 virally unsuppressed patients and 4/9 patients with CD4% < 14 died. Ninety-one of the 99 PLWH were on treatment for HIV, and 5 of the 8 not on treatment died. Among PLWH with prior values, absolute CD4 count decreased an average of 192 cells/mm3 at the time of COVID-19 diagnosis ( p < 0.001). Hospitalized patients with HIV and COVID-19 coinfection did not have worse outcomes than the general population. Among PLWH, those with CD4%<14 or not on treatment for HIV had higher mortality rates. Those PLWH who received IL-6 inhibitors had lower mortality rates. PLWH given antifungal medications, hydroxychloroquine, antibiotics (including azithromycin), steroids, and vasopressors had higher mortality rates.

Does Chytridiomycosis Affect Tree Frog Attachment?

The pandemic disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), is a major threat to amphibian biodiversity. For most species, the exact mechanisms of chytridiomycosis that lead to negative population dynamics remain uncertain, though mounting evidence suggests that sublethal effects could be an important driver. In this review, we propose that tree frog attachment is a promising case to study the sublethal effects of a Bd infection on amphibians. A synthesis of the current knowledge on the functional morphology of the adhesive toe pads of tree frogs, on the underlying mechanisms of tree frog attachment, and on the epidermal pathology of chytridiomycosis substantiates the hypothesis that Bd-induced epidermal alterations have the potential to disrupt tree frog attachment. We highlight a series of (biomechanical) experiments to test this hypothesis and to shed some light on the sublethal disease mechanisms of chytridiomycosis. The knowledge generated from such an approach could contribute to future research on Bd epidemiology and ultimately to the conservation of the biodiversity of arboreal anurans.

Impact of dendritic cell vaccines added to neoadjuvant CT on pathological complete responses in early breast cancer patients according to PD-L1 expression.

585 Background: Breast cancer (BC) in early stages exhibit a naïve and competent immune system that translates into a more prominent TIL infiltration and higher PD-L1 expression as compared to the advanced BC scenario were immunoescape and exhaustion are more prevalent. Expression of PD-L1 has been related to a better pCR when immune checkpoint inhibitors (IPI) have been added to neaodjuvant chemotherapy (NACT) in triple negative BC (TNBC). Our prior results shown dendritic cells vaccines (DCV) increased pCR in both TNBC and luminal B subtypes, with an absolute gain of 20% (p = 0.03) and a safe tolerance. Methods: Eighty-three HER2 negative BC patients with untreated stage II-III were included: 39 patients from the NCT01431196 trial that combine NACT with autologous DCV and 44 patients from a historic control group treated with the same NACT alone. NACT consists of dose dense Epirubicin plus Cyclophosphamide for 4 cycles sequenced to Docetaxel for 4 cycles. PD-L1 expression was measured in the membrane of tumoral cells with monoclonal rabbit anti PD-L1 28.8 pharmaDX (DAKO, Agilent Technologies) in FFPE samples at diagnosis. Primary endpoint was pathologic complete response (pCR) stratified by PD-L1 expression (positive or negative), while secondary endpoints were event-free survival (EFS) and overall survival (OS), also stratified by PD-L1 expression. Results: Both cohorts were well balanced in most of the features. Thirty-three percent of the tumors in the experimental group were PD-L1 positive, whereas 50% of them in the CG expressed PD-L1 (p = 0.06). Pathological CR was observed in 50% of the PD-L1 positive population, in contrast to a 2.8% in the PD-L1 negative in the NACT cohort (p < 0.01) as compared to the patients assigned to the DCV group (33.4% in PD-L1 positive vs 23.1% in PD-L1 negative population; p = 0.16). Among PD-L1 positive population, more pCR were seen in the CG than in the DCV group (50% vs 33.4%; p = 0.06). Within the PD-L1 negative population, more pCR were observed in the DCV group than in the CG (23.1% vs 2.8%; p < 0.05). With a median follow-up of 7 years, no significant differences were observed between the different subgroups neither in EFS (HR = 1.7; 0.42-6.8; p = 0.19) nor in OS (HR = 2.5; 0.56-11, p = 0.43). At 7 years, 20% and 14.4% of the patients relapsed according to the PD-L1 positive versus negative status respectively, and 10.78% versus 13.33% were dead. Conclusions: The benefit of DCV seems to be outstanding in the PD-L1 negative tumors that have a basal immune appropriate milieu. PD-L1 expression implies a more suppressed niche in which DCV are not able to stimulate antigen presentation and cell cytotoxic activity. PD-L1 positive population reach higher responses with both NACT±DCV than PD-L1 negative group, although the benefit seem to be higher in the NACT alone cohort. Further studies combining DVC+IPI together with NACT are needed. Clinical trial information: NCT01431196.

Impacts of forest fires on the number of hunting fauna populations in Irkutsk region

Using the statistical data for 2004-2018, the dynamics of forest fires and the number of hunting and fishing fauna in Irkutsk region and in one of its specially protected natural area - Olkhon district as part of the Baikal national Park were studied. Against the background of the positive dynamics of forest fire indicators, the dependence of the number of animals on their family, species and fires in adjacent areas and the region as a whole was established. The linear correlations confirmed the positive impact of fires on the population of deer (Cervidae), canids (Canidae), cats (Felidae), bears (Ursidae) and pheasants (Phasianidae), determined by the migration of animals from mountainous areas. The unstable and negative population dynamics was revealed for the Kunya family (Mustelidae).

Payments for Conservation of Animal Genetic Resources in Agriculture: One Size Fits All?

Local livestock breeds in Slovenia have been eligible for financial incentives in the form of a fixed payment per livestock unit (LU) since 2002. The scheme has however not been successful in reversing the erosion of animal genetic resources (AnGR). This paper investigates an alternative, whereby incentive payments would better reflect breeders’ actual opportunity costs. The paper contributes to the limited existing body of knowledge related to the use of tender mechanisms in the design of the payments for agrobiodiversity conservation schemes (PACS), particularly for AnGR. Empirical findings draw on the results of a stated preference survey involving 301 farmers in Slovenia, engaging, or being potentially able to engage, in the rearing of local pig, sheep and goat breeds. Interval and logistic regression model results suggest that willingness to accept (WTA) conservation support significantly differs from actual payment levels. The estimated WTA was found to be 27% lower for the local sheep and goat breeds and 5% higher for the local pig breed, suggesting that differentiated incentive payments would provide a more cost-effective alternative. Additional analysis of breeders’ preferences and motives for engaging in local livestock breed production further informs understanding regarding AnGR conservation policy and the importance of accompanying actions to reverse negative population trends. These include reducing administrative barriers and enhancing the market valorisation of local breeds.

Slow life history leaves endangered snake vulnerable to illegal collecting

Global wildlife trade is a multibillion-dollar industry and a significant driver of vertebrate extinction risk. Yet, few studies have quantified the impact of wild harvesting for the illicit pet trade on populations. Long-lived species, by virtue of their slow life history characteristics, may be unable to sustain even low levels of collecting. Here, we assessed the impact of illegal collecting on populations of endangered broad-headed snakes (Hoplocephalus bungaroides) at gated (protected) and ungated (unprotected) sites. Because broad-headed snakes are long-lived, grow slowly and reproduce infrequently, populations are likely vulnerable to increases in adult mortality. Long-term data revealed that annual survival rates of snakes were significantly lower in the ungated population than the gated population, consistent with the hypothesis of human removal of snakes for the pet trade. Population viability analysis showed that the ungated population has a strongly negative population growth rate and is only prevented from ultimate extinction by dispersal of small numbers of individuals from the gated population. Sensitivity analyses showed that the removal of a small number of adult females was sufficient to impose negative population growth and suggests that threatened species with slow life histories are likely to be especially vulnerable to illegal collecting.

Country-level structural stigma, identity concealment, and day-to-day discrimination as determinants of transgender people’s life satisfaction

Purpose Discriminatory laws, policies, and population attitudes, surrounding transgender people vary greatly across countries, from equal protection under the law and full acceptance to lack of legal recognition and open bias. The consequences of this substantial between-country variation on transgender people’s health and well-being is poorly understood. We therefore examined the association between structural stigma and transgender people’s life satisfaction across 28 countries. Methods Data from transgender participants (n = 6771) in the 2012 EU-LGBT-survey regarding identity concealment, day-to-day discrimination, and life satisfaction were assessed. Structural stigma was measured using publicly available data regarding each country’s discriminatory laws, policies, and population attitudes towards transgender people. Results Multilevel models showed that country-level structural stigma was associated with lower life satisfaction, an association largely explained by higher levels of identity concealment in higher-structural-stigma countries. Yet identity concealment was also associated with lower day-to-day discrimination and therefore protected against even lower life satisfaction. Conclusion The results emphasize the importance of changing discriminatory legislation and negative population attitudes to improve transgender people’s life satisfaction, and also highlight targets for intervention at interpersonal and individual levels.