Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand ...1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors’ outcomes in patients with R/M HNSCC.
NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes.
High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively).
Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.
•PD-1/PD-L1 axis inhibitors have become the standard of care for R/M HNSCC.•Low response rates dictate the need to identify resistance mechanisms and develop biomarkers for patient selection.•The associations of immune cell density with treatment outcomes were investigated in nivolumab-treated R/M HNSCC cases.•Increased B-cell infiltration led to prolonged PFS and improved PD-L1-based patient selection.•The synchronous assessment of B-cell infiltration and PD-L1 expression could guide therapeutic decisions in R/M HNSCC.
Gallic acid (GA) and quercetin (QU) are two important bioactive molecules with increased biomedical interest. Cellulose acetate (CA) is a polymer derived from cellulose and is used in various ...applications. In this work, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR) were used to study the thermal behavior of electrospun CA membranes loaded with quercetin or gallic acid. It was found that gallic acid and quercetin depress the thermochemical transition (simultaneous softening and decomposition) of CA, in a mechanism similar to that of the glass transition depression of amorphous polymers by plasticizers. The extensive hydrogen bonding, besides the well-known effect of constraining polymer’s softening by keeping macromolecules close to each other, has a secondary effect on the thermochemical transition, i.e., it weakens chemical bonds and, inevitably, facilitates decomposition. This second effect of hydrogen bonding can provide an explanation for an unexpected observation of this study: CA membranes loaded with quercetin or gallic acid soften at lower temperatures; however, at the same time, they decompose to a higher extent than pure CA. Besides optimization of CA processing, the fundamental understanding of the thermochemical transition depression could lead to the design of more sustainable processes for biomass recycling and conversion.
While early stages of melanoma are usually cured by surgery, metastatic melanomas are difficult to treat because the widely available options have low response rates. Careful and precise diagnosis ...and staging are essential to determine patient's risk and to select appropriate treatments. Fortunately, the recent progress in immunotherapy is very encouraging. In this context, it is important to characterize the intratumoral infiltration of immune cells in each patient, which is however not done routinely due to the lack of standardized methods. In this study, we used Fourier transform infrared (FTIR) imaging combined with multivariate statistical analyses to investigate non-metastatic and metastatic lymph nodes from melanoma patients. Our results show that the different cell types have different infrared spectral features allowing automated identification of these cell types. High recognition rates were obtained using a supervised partial least square discriminant analysis (PLS-DA) model. Melanoma cells were recognized with 87.1% sensitivity and 85.7% specificity, showing that FTIR spectroscopy has similar detection power as immunohistochemistry. Besides, FTIR imaging could also distinguish lymphocyte subpopulations (B and T cells). Finally, we investigated the changes in lymphocytes due to the presence of metastases. Interestingly, specific features of spectra of lymphocytes present in metastatic or tumor-free lymph nodes could be evidenced by PCA. A PLS-DA model was capable of predicting whether lymphocytes originated from invaded or non-invaded lymph nodes. These data demonstrate that FTIR imaging is capable to distinguish known and also novel biological features in human tissues, with potential practical relevance for histopathological diagnosis and biomarker assessment.
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•FTIR imaging allows automated cell type identification in lymph node sections.•Non-metastatic and metastatic lymph node lymphocytes have different FTIR spectra.•FTIR recognizes metastatic melanoma cells with 87% sensitivity and 86% specificity.•FTIR imaging distinguishes lymphocyte subpopulations (B and T cells).
A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod—a Toll-like receptor 8 (TLR8) ...agonist that stimulates robust innate immune responses—combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.
Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6–12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.
The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P=0.923, HR=1.22) or progression-free survival (PFS; log rank one-sided P=0.943, HR=1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.
The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.
Clinicaltrials.gov, NCT 01666444.
Molecular aspects of multiple myeloma Kastrinakis, N. G.; Gorgoulis, V. G.; Foukas, P. G. ...
Annals of oncology,
10/2000, Letnik:
11, Številka:
10
Journal Article
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Multiple myeloma (MM) is a B-cell neoplasm characterized by bone marrow infiltration with malignant plasma cells, which synthesize and secrete monoclonal immunoglobulin (Ig) fragments. Despite the ...considerable progress in the understanding of MM biology, the molecular basis of the disease remains elusive. The initial transformation is thought to occur in a post-germinal center B-lineage cell, carrying a somatically hypermutated Ig heavy chain (IGH) gene. This plasmablastic precursor cell colonizes the bone marrow, propagates clonally and differentiates into a slowly proliferating myeloma cell population, all under the influence of specific cell adhesion molecules and cytokines. Production of interleukin-6 by stromal cells, osteoblasts and, in some cases, neoplastic cells is an essential element of myeloma cell growth, with the cytokine stimulus being delivered intracellularly via the Jack-STAT and ras signaling pathways. While karyotypic changes have been identified in up to 50% of MM patients, recent molecular cytogenetic techniques have revealed chromosomal abnormalities in the vast majority of examined cases. Translocations mostly involve illegal switch rearrangements of the IGH locus with various partner genes (CCND1, FGFR3, c-maf). Such events have been assigned a critical role in MM development. Mutations in coding and regulatory regions, as well as aberrant expression patterns of several oncogenes (c-myc, ras) and tumor suppressor genes (p16, p15) have been reported. Key regulators of programmed cell death (BCL-2, Fas), tumor expansion (metallo-proteinases) and drug responsiveness (topoisomerase II alpha) have also been implicated in the pathogenesis of this hematologic malignancy. A tumorigenic role for human herpesvirus 8 (HHV8) was postulated recently, following the detection of viral sequences in bone marrow dendritic cells of MM patients. However, since several research groups were unable to confirm this observation, the role of HHV8 remains unclear. Translation of the advances in MM molecular biology into novel therapeutic strategies is essential in order to improve disease prognosis.
Hepatic tuberculosis as a part of disseminated tuberculosis is seen in 50–80% of cases. Isolated hepatic tuberculosis is very uncommon even in countries with high prevalence of tuberculosis. It can ...occur as a primary case or due to reactivation of an old tubercular focus. We report a case of a 59-year-old Caucasian woman who presented with persistent right upper quadrant pain and a hepatic lesion on an abdominal CT. She had a history of pulmonary tuberculosis 15 years ago with localised lung tuberculosis treated with lobectomy and antituberculous drugs.
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