Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.

What is integrative oncology and can it help my patients?

Integrative oncology lends itself to the comprehensive practice of gynecologic oncology with multiple tools and interventions that can impact on QoL and survival. However, there remains a paucity of well-designed, well-powered randomized control trials on various CAM modalities for gynecologic cancer patients. The reasons for the lack of level 1 evidence include the nascent state of integrative medicine as a science, the limitations on CAM funding, the relative lack of integration of CAM practitioners into the oncology community, and absence of strict regulation of herbs and supplements by the US FDA. The use of CAM as adjunctive therapies will likely continue given the patient-driven trends to date, and given the evidence for at least safety and potentially efficacy, our patients deserve our willingness to use all possible approaches to improving their outcomes. Continued evolution of our ability to specifically measure and describe QoL will further our ability to hone in on domains most important to patients and their survival and allow practitioners to make patient-specific recommendations. Multimodal programs that include physical activity, stress management, and diet have the potential to address demonstrated deficits in PWB and FWB in ovarian cancer patients which suggests a model of collaborative gynecologic oncology care). Integrative oncology represents a holistic approach to patient care whose goal is maximization of patient quantity and quality of life. Patients can achieve this optimal outcome through the synergy of conventional care, integrative modalities, lifestyle modifications, and supportive care. Refer to Table 4 for a listing of integrated medicine Internet resources.

A TRIM5alpha-independent post-entry restriction to HIV-1 infection of macaque cells that is dependent on the path of entry.

The replication of human immunodeficiency type-1 (HIV-1) is restricted in macaque cells, in part due to host factors that provide intrinsic immunity after entry. Here we show that a rhesus macaque epithelial cell line engineered to express human CD4, sMAGI cells, has at least two post-entry restrictions to HIV-1 replication: one that is dependent on a previously described post-entry restriction factor of macaque cells, TRIM5alpha, and another that is primarily TRIM5alpha-independent. The TRIM5alpha restriction, which was observed with particles that had an HIV-1 core pseudotyped with VSV-G envelope, is saturable and can be completely abrogated by introducing TRIM5alpha-specific siRNA into the cells. A similar TRIM5alpha-dependent restriction was observed when sMAGI cells expressing human CCR5 were infected with an R5-HIV-1. In contrast, even when viruses enter sMAGI cells using CD4 and an endogenous rhesus coreceptor at levels sufficient to saturate TRIM5alpha, they do not productively infect the sMAGI cells. Nor does treatment of sMAGI cells with TRIM5alpha-specific siRNA relieve this post-entry restriction; this was true whether the HIV-1 core was pseudotyped with SIV envelope or an R5-HIV-1 envelope. Together these data suggest that there is an alternate restriction to replication, here called Lv3, that is encountered by viruses that enter via interaction with CD4 and an endogenous rhesus coreceptor. Thus, these findings suggest that post-entry events are dependent upon the mechanism by which HIV-1 enters the cell.

Characterization of virus infectivity and cell-free capsid assembly of SIVMneCL8.

We have previously described a cell-free system that reconstitutes immature capsid assembly of Gag polypeptides from viruses belonging to three major primate lentiviral lineages, including HIV-1, HIV-2 and SIVagm. Studies described here examine a member of the SIVmac/Mne lineage, SIVMneCL8, using assays for virus production and infectivity as well as cellular events in capsid formation. We report that SIVMneCL8, a molecular clone with properties typical of transmitted viral variants, is less infectious per unit p27 Gag than another member of the SIVmac/Mne lineage, SIVmac239. SIVMneCL8 Gag polypeptides are arrested at an early stage of capsid assembly in the cell-free system. Additionally, SIVMneCL8 Gag polypeptides associate minimally with the host factor human HP68. This is the first report of a primate lentivirus that does not complete capsid assembly in the cell-free system.