Pancreatic INI1-deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab-paclitaxel following immediate progression on FOLFIRINOX: a case report.

INTRODUCTION: INI1-deficient undifferentiated rhabdoid carcinoma is a rare pancreatic carcinoma for which the optimal treatment is unknown. Pancreatic ductal adenocarcinoma, the most common histology of pancreas cancer, is treated with combination chemotherapy in the advanced setting, a strategy supported by strong evidence in well powered studies. In patients with excellent performance status, first-line treatment usually consists of the three-drug regimen FOLFIRINOX, with the combination of gemcitabine with nab-paclitaxel, typically less toxic than the three-drug regimen, reserved for second-line therapy. Given the lack of published reports describing treatment outcomes for patients with rare forms of pancreatic cancer, the same treatment approach used for pancreatic ductal adenocarcinoma is typically employed. OBSERVATION: This case describes a patient with metastatic pancreatic INI1-deficient undifferentiated rhabdoid carcinoma who was primarily resistant to FOLFIRINOX therapy but who then achieved an immediate, marked and sustained response to gemcitabine with nab-paclitaxel. CONCLUSION: Given the lack of data informing on optimal management of INI1-deficient pancreatic undifferentiated rhabdoid carcinoma, and the exceptional response achieved by gemcitabine with nab-paclitaxel, this case report highlights a surprising and potentially informative anecdote. Additional studies are needed to confirm responses observed in this report which when taken together may strongly influence first-line therapy choice for this rare malignancy. Given the difficult in acquiring sufficient numbers of these rare histologies in any one institution, multi-institution collaboration in studying outcomes of rare pancreatic malignancies is likely essential.

Association of Viral Persistence and Atherosclerosis in Adults With Treated HIV Infection.

Importance: Persons living with HIV (PLWH) have increased risk for cardiovascular disease, and inflammation is thought to contribute to this excess risk. Production of HIV during otherwise effective antiretroviral therapy (ART) has been associated with inflammation. Objective: To determine whether higher levels of viral persistence are associated with atherosclerosis as assessed by changes in carotid artery intima-media thickness (IMT) over time. Design, Setting, and Participants: In this cohort study, intima-media thickness, a validated marker of atherosclerosis, was assessed over time in a cohort of treated PLWH with viral suppression. Cell-associated HIV DNA and RNA and change in IMT, adjusted for demographics, cardiovascular risk factors, and HIV-related factors, were examined, as well as which factors were associated with viral persistence. One hundred fifty-two PLWH with undetectable viral loads for at least 6 months before study enrollment were recruited from HIV clinics affiliated with 2 hospitals in San Francisco, California, from January 1, 2003, to December 31, 2012. Data were analyzed from February 7, 2018, to May 12, 2020. Exposures: Cell-associated HIV RNA and DNA were measured using enriched CD4+ T cells from cryopreserved peripheral blood mononuclear cells. Main Outcomes and Measures: Carotid IMT was measured at baseline and the last visit, with a mean (SD) follow-up of 4.2 (2.7) years, using high-resolution B mode ultrasonography. The main study outcomes were baseline IMT, annual IMT progression, and incident plaque, defined as a focal region of carotid IMT of greater than 1.5 mm. Results: The analysis included 152 PLWH (140 [92.1%] male; median age, 48.5 [interquartile range {IQR}, 43.3-53.7] years). Older age, smoking, medications for hypertension, higher low-density lipoprotein levels, and higher interleukin 6 levels were associated with higher baseline mean IMT, whereas cell-associated HIV DNA (estimate, -0.07% [95% CI, -6.1% to 6.4%]; P = .98), and HIV RNA levels (estimate, -0.8% [95% CI, -5.9% to 4.4%]; P = .75) were not. Levels of HIV RNA (0.017 [95% CI, 0.000-0.034] mm/y; P = .047) and HIV DNA (0.022 [95% CI, 0.001-0.044] mm/y; P = .042) were significantly associated with annual carotid artery IMT progression in unadjusted models only. Both HIV RNA (incidence risk ratio [IRR], 3.05 [95% CI, 1.49-6.27] per IQR; P = .002) and HIV DNA (IRR, 3.15 [95% CI, 1.51-6.57] per IQR; P = .002) were significantly associated with incident plaque, which remained significant after adjusting for demographics, cardiovascular risk factors, and HIV-related factors (IRR for HIV RNA, 4.05 [95% CI, 1.44-11.36] per IQR [P = .008]; IRR for HIV DNA, 3.35 [95% CI, 1.22-9.19] per IQR [P = .02]). Higher C-reactive protein levels were associated with higher cell-associated HIV RNA (estimate, 20.7% [95% CI, 0.9%-44.4%] per doubling; P = .04), whereas higher soluble CD14 levels were associated with HIV DNA (estimate, 18.6% [95% CI, 3.5%-35.8%] per 10% increase; P = .01). Higher soluble CD163 levels were associated with a higher HIV RNA:DNA ratio (difference, 63.8% [95% CI, 3.5%-159.4%]; P = .04). Conclusions and Relevance: These findings suggest that measurements of viral persistence in treated HIV disease are independently associated with incident carotid plaque development. The size and transcriptional activity of the HIV reservoir may be important contributors to HIV-associated atherosclerosis.

Plasma tissue factor and immune activation are associated with carotid intima-media thickness progression in treated HIV infection.

OBJECTIVES: We evaluated the roles of biomarkers of immune activation with carotid intima-media thickness (CIMT) progression in treated HIV infection. DESIGN: Longitudinal observational study of 118 treated and virologically suppressed individuals. METHODS: We measured biomarkers of immune activation at baseline using cryopreserved samples. CIMT was measured at baseline and longitudinally using high-resolution ultrasound. Linear regression was used to estimate biomarker associations with CIMT progression, and logistic regression was used to model plaque progression. RESULTS: The median duration of follow-up was 2.0 years. The median annual rate of change in mean CIMT was 6.0%. Rates of progression were more rapid in the bifurcation (5.6%/year, P = 0.006) and internal (6.5%/year, P = 0.0008) than common CIMT (4.3%/year). Incident plaque occurred in 13 of the 52 individuals without baseline plaque. In multivariable adjusted analysis, plasma tissue factor and monocyte chemoattractant protein-1 were associated with more rapid common CIMT progression (0.058 mm/year, P = 0.0004 and 0.067 mm/year, P = 0.017; all estimates per doubling). CD8 T-cell count and percentage of HLA-DRCD38CD8 T cells were associated with more rapid internal CIMT progression (0.10 mm/year, P = 0.008 and 0.054 mm/year, P = 0.045). CD8 T-cell count was also associated with 0.068 mm/year more rapid mean CIMT progression (P = 0.011). Each 10% increase in CD4 T-cell count at baseline was associated with a 34% reduced odds of plaque progression (P = 0.018). CONCLUSION: Residual immune activation and plasma tissue factor are independently associated with CIMT progression in treated HIV infection. Interventions targeting coagulation and inflammatory pathways to reduce cardiovascular disease risk in HIV merit additional investigations.

MicroRNA biomarkers associated with type 1 myocardial infarction in HIV-positive individuals.

OBJECTIVE: Individuals with HIV suffer a higher burden of cardiovascular diseases. Traditional cardiovascular risk scores consistently underestimate cardiovascular risk in this population. Subsets of microRNAs (miRNAs) are differentially expressed among individuals with cardiovascular disease and individuals infected with HIV. However, no study has clarified whether specific miRNAs may be biomarkers for cardiovascular disease in individuals with HIV. DESIGN/METHODS: We compared the miRNA expression profiles of 34 HIV-positive individuals who had experienced clinically adjudicated type I myocardial infarctions (MI) with the profiles of 76 HIV-positive controls matched by traditional cardiovascular risk factors and HIV-specific measures. Using the elastic net algorithm, we selected miRNAs most strongly associated with incident MI and then used conditional Cox proportional hazards regression and cross-validation to evaluate miRNAs and their association with incident MI. We evaluated whether miRNA markers would improve risk classification relative to the Framingham Risk Score. RESULTS: Higher miR-125a-5p and miR-139-5p expression levels were each associated with increased risk of developing MI after adjustment for Framingham Risk Score and HIV-related factors (hazard ratio 2.43, P = 0.018; hazard ratio 2.13, P = 0.048, respectively). Compared with the Framingham Risk Score alone, adding expression levels of miR-125a-5p or miR-139-5p resulted in an integrated discrimination improvement of 10.1 or 5.8%, respectively. CONCLUSION: MiR-125a-5p and miR-139-5p, transcripts known to be differentially expressed in HIV-positive individuals, may serve as unique biomarkers predictive of cardiovascular disease in these patients and may help clarify processes because of HIV infection that contribute to cardiovascular disorders in this population.

Carnitine Is Associated With Atherosclerotic Risk and Myocardial Infarction in HIV -Infected Adults.

Background People living with HIV ( PLWH ) have an increased risk of myocardial infarction ( MI ). Changes in the gut microbiota that occur with chronic HIV infection could play a role in HIV -associated atherosclerosis. Choline, carnitine, betaine, and trimethylamine N-oxide are small molecules that are, in part, metabolized or produced by the gut microbiome. We hypothesized that these metabolites would be associated with carotid artery intima-media thickness and MI in PLWH . Methods and Results Carotid artery intima-media thickness was measured at baseline and at a median interval of 4 years in 162 PLWH from the SCOPE (Study of the Consequences of the Protease Inhibitor Era) cohort in San Francisco, CA . Separately, 105 PLWH (36 cases with type I adjudicated MI and 69 controls without MI ) were selected from the Center for AIDS Research Network of Integrated Clinical Systems, a multicenter clinic-based cohort. Controls were matched by demographics, CD 4 cell count, and duration of viral suppression. In the SCOPE cohort, higher carnitine levels had a significant association with presence of carotid plaque and greater baseline and progression of mean carotid artery intima-media thickness after adjusting for traditional cardiovascular disease risk factors. In the treated and suppressed subgroup, these associations with carnitine remained significant after adjustment for cardiovascular disease risk factors. In the Center for AIDS Research Network of Integrated Clinical Systems cohort, the risk of MI was significantly increased in subjects with carnitine levels in the highest quartile after adjustment for cardiovascular disease risk factors. Conclusions In PLWH , including the treated and suppressed subgroup, carnitine is independently associated with carotid artery intima-media thickness, carotid plaque, and MI in 2 separate cohorts. These results emphasize the potential role of gut microbiota in HIV -associated atherosclerosis and MI , especially in relation to carnitine metabolism.