Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

K and mixed K+O adlayers on Rh(110).

The evolution of the structure of the adlayers and the substrate during adsorption of K and coadsorption of K and O on Rh(110) is studied by scanning tunneling microscopy and low-energy electron diffraction. The K adsorption at temperature above 450 K leads to consecutive (1x4), (1x3), and (1x2) missing-row reconstructions for coverage up to 0.12 ML, which revert back to (1x3) and (1x4) with increasing coverage up to 0.21 ML. The coadsorption of different oxygen amount at T>450 K and eventually following reduction-reoxidation cycles led to a wealth of coadsorbate structures, all involving substrate missing-row-type reconstructions, some including segmentation of Rh rows along the [110] direction. The presence of K stabilizes the (1x2) missing-row reconstruction, which facilitates the formation of a great variety of very open (10x2)-type reconstructions at high oxygen coverage, not observed in the single adsorbate systems.

HLA-B allele frequencies in Côte d'Ivoire defined by direct DNA sequencing: identification of HLA-B*1405, B*4410, and B*5302.

Direct automated DNA sequencing was used to analyze exons 2 and 3 of HLA-B alleles present in forty-four unrelated individuals residing in the village of Adiopodoume, Côte d'Ivoire (Ivory Coast). Of the 23 HLA-B alleles observed, the most frequently detected allele was HLA-B*5301 (22.7%), which is believed to confer resistance to severe Plasmodium falciparum malaria. B*4501 (9.1%), B*1503 (8.0%), B*0705 (5.7%), B*1510 (5.7%) and B*3501 (5.7%) occurred frequently in the population. A second allele of B53 was identified; B*5302 contains a single amino acid variation at residue 171 (Y-->H). Two additional novel alleles, B* 1405 (a single amino acid variant of B*1402) and B*4410 (a five amino acid variant of B*4403) were characterized.

Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses.

PURPOSE: This trial sought to determine, for the first time, the validity in human vaccinations of using two different recombinant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen. PATIENTS AND METHODS: Eighteen patients with advanced tumors expressing carcinoembryonic antigen (CEA) were randomized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations, or avipox-CEA (three times) followed by one rV-CEA vaccination. Subsequent vaccinations in both cohorts were with avipox-CEA. Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production. RESULTS: rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses. Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin (IL)-2 were given with subsequent vaccinations. The treatment was extremely well tolerated. Limited clinical activity was seen using vaccines alone in this patient population. Antibody production against CEA was also observed in some of the treated patients. CONCLUSION: rV-CEA was more effective in its role as a primer of the immune system; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors. Future trials should use rV-CEA first followed by avipox-CEA. Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity. T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease. Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses.

Detection of four novel alleles: DRB1*1130, DRB1*13072, DRB1*1315 and DRB1*1331.

Four new DR52-associated DRB1 alleles are described. One allele, DRB1*1130, is a hybrid between a DRB3*02 allele and a DRB1*11011 allele. The other alleles, DRB1*13072, DRB1*1315, and DRB1*1331, are simple reshufflings of known polymorphic motifs.

Novel HLA-A and HLA-B alleles.

Nine novel HLA-A and HLA-B alleles are described: A*2609, A*6803, A*6806, B*1539, B*1540, B*2712, B*4103, B*5109, and B*5603. Most appear to have arisen by gene conversion events. B*5603 appears to have arisen by a reciprocal recombination event joining exon 2 of a B*55/ *56 allele with exon 3 of a B*15 allele. Serologically, the antigen encoded by this allele types with broad B22- and Bw6-specific alloantisera. Also unique, the antigen encoded by B*2712 does not react with B27-specific alloantisera but does react with Bw6-specific alloantisera.

Novel HLA-B alleles, B*8201, B*3515 and B*5106, add to the complexity of serologic identification of HLA types.

Three class I alleles, B*8201, B*3515 and B*5106, have been described using DNA and cDNA sequencing. The B*8201 allele is most structurally related to B*5602, differing from it by 14 nucleotide substitutions resulting in 5 amino acid differences. The other two alleles, B*3515 and B*5106, differ from their most closely related HLA-B alleles by 2-3 nucleotide substitutions resulting in 1-2 amino acid substitutions, respectively. The majority of nucleotide substitutions marking these new alleles are observed in other HLA-B alleles suggesting that gene conversion and/or reciprocal recombination have created this diversity. All of the amino acid substitutions are predicted to alter the antigen binding site of the HLA-B molecule. The newly defined HLA-B allelic products were originally defined by their unusual serologic reactivity patterns. The B*8201 allelic product is serologically typed as a B "blank" or as a variant of B22 or B45. These patterns and the serologic reactivity of the other newly described allelic products are consistent with the protein sequence homology among specific HLA-B molecules. While serology remains a powerful tool for detecting HLA diversity, alleles generated by events resulting in the sharing of HLA sequence polymorphisms among alleles at a locus will continue to create complexity in the interpretation of typing results.

Prospective payment for home care.

Prospective pay models propose to make one payment to cover an entire episode of care, rather than making one payment per visit. What elements must be considered in developing such a system? Is the new Congress likely to enact such a plan--and if so, what does that mean for the home care industry?

Highlights of the first national homecare agency & hospice inventory.

Automation of home care will certainly speed documentation and free time for more proactive duties. It will also facilitate data collection, which is important for identifying trends, utilization rates, and data sets for further data collection.

Prospective payment still only a concept, but....

The Medicare home health PPS demonstrations are now being conducted, after a lengthy and checkered past. They are leading toward a payment method that should avoid many of the former reimbursement problems.

The home medical equipment industry: a home care perspective.

The home medical equipment industry, under fire from the media and consumer affairs organizations, is aligning itself with the home care industry in an attempt to change its image. Until the medical equipment industry is able to take care of some problems, however, the home care industry should be wary of such an alliance.

Public programs for the elderly ... can we afford them?

Is America draining its resources and short-changing the future of younger generations by funding programs for the elderly? A closer look explodes some of the myths surrounding this country's Social Security system.

Case management and the payor: where are we and where do we go from here?

Over the past 20 years, increasing numbers of states have sought to control the costs of their home care programs by establishing case management systems. These payor-directed case management systems duplicate the activities of the caregiver agency and have proven to be quite costly. It is generally assumed that case management will continue to be an essential component of public home care programs, including any future federal long-term care program. However, there is reason to believe that cost considerations and other factors will lead to a much-reduced payor case management role.