Eribulin promotes proliferation of CD8+ T cells and potentiates T cell-mediated anti-tumor activity against triple-negative breast cancer cells.

PURPOSE: Chemotherapeutic agents exert immunomodulatory effects on triple-negative breast cancer (TNBC) cells and immune cells. Eribulin favorably affects the immunological status of patients with breast cancer. However, the effects of eribulin on the immune cells remain unexplored. The aim of this study was to investigate the effects of eribulin on immune cells. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy donors and mouse splenocytes were stimulated with anti-CD3 and anti-CD28 antibodies. The effects of eribulin and paclitaxel on cell proliferation and differentiation status were analyzed using flow cytometry. RNA sequencing was performed to assess alterations in gene expression in CD8+ T cells following eribulin and paclitaxel treatment. Using TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157), the anti-tumor activity of CD3/CD28-stimulated T cells combined with eribulin or paclitaxel was evaluated. RESULTS: Eribulin did not affect CD3/CD28-stimulated PBMCs proliferation. However, eribulin significantly decreased the CD4/CD8 ratio in T cells, indicating that eribulin facilitates CD8+ T cell proliferation. Furthermore, eribulin significantly increased the frequency of less differentiated CD45RA+, CCR7+, and TCF1+ subsets of CD8+ T cells. RNA sequencing revealed that eribulin enhanced the expression of gene sets related to cell proliferation and immune responses. Moreover, eribulin augmented the anti-tumor effects of CD3/CD28-stimulated T cells against TNBC cells. These results were not observed in experiments using paclitaxel. CONCLUSIONS: Eribulin promoted CD8+ T cell proliferation, repressed effector T cell differentiation, and harnessed T cell-mediated anti-tumor effects. These mechanisms may be one of the cues that eribulin can improve the immunological status of tumor-bearing hosts.

Neutrophil-to-Lymphocyte Ratio Is Associated With the Proportion of Poorly Differentiated Components in Papillary Thyroid Carcinoma.

INTRODUCTION: Diagnosis of poorly differentiated thyroid cancer (PDTC) requires ≥ 50% of poorly differentiated components (PDC) in Japan. However, the optimal cutoff percentage of PDC for PDTC diagnosis remains controversial. Although high neutrophil-to-lymphocyte ratio (NLR) correlates with the aggressiveness of papillary thyroid cancer (PTC), whether NLR is associated with the proportion of PDC in PTC remains unstudied. MATERIALS AND METHODS: Patients with the pure PTC (n = 664), PTC with < 50% PDC (n = 19), or PTC with ≥ 50% PDC (n = 26) who underwent surgery were retrospectively analyzed. Twelve-year disease-specific survival and preoperative NLR were compared among these groups. RESULTS: Twenty seven patients died from thyroid cancer. The PTC with ≥ 50% PDC group (80.7%) showed significantly worse 12-year disease-specific survival than the pure PTC group (97.2%) (P < 0.001); however, the < 50% PDC group (94.7%) did not (P = 0.91). The PTC with ≥ 50% PDC group had a significantly higher NLR than the pure PTC (P < 0.001) and the PTC with < 50% PDC groups (P < 0.001), whereas there was no significant difference in the NLR between the pure PTC and the PTC with < 50% PDC groups (P = 0.48). CONCLUSIONS: PTC with ≥ 50% PDC is more aggressive than either pure PTC or PTC with < 50% PDC, and NLR potentially reflects the PDC proportion. These results support the validity of 50% PDC as a cut-off for PDTC diagnosis and indicate the utility of NLR as a biomarker for PDC proportion.

Multimodal Intralesional Therapy for Reshaping the Myeloid Compartment of Tumors Resistant to Anti-PD-L1 Therapy via IRF8 Expression.

Intralesional therapy is a promising approach for remodeling the immunosuppressive tumor microenvironment while minimizing systemic toxicities. A combinatorial in situ immunomodulation (ISIM) regimen with intratumoral administration of Fms-like tyrosine kinase 3 ligand (Flt3L), local irradiation, and TLR3/CD40 stimulation induces and activates conventional type 1 dendritic cells in the tumor microenvironment and elicits de novo adaptive T cell immunity in poorly T cell-inflamed tumors. However, the impact of ISIM on myeloid-derived suppressor cells (MDSCs), which may promote treatment resistance, remains unknown. In this study, we examined changes in the frequencies and heterogeneity of CD11b+Ly-6CloLy-6G+ polymorphonuclear (PMN)-MDSCs and CD11b+Ly-6ChiLy-6G- monocytic (M)-MDSCs in ISIM-treated tumors using mouse models of triple-negative breast cancer. We found that ISIM treatment decreased intratumoral PMN-MDSCs, but not M-MDSCs. Although the frequency of M-MDSCs remained unchanged, ISIM caused a substantial reduction of CX3CR1+ M-MDSCs that express F4/80. Importantly, these ISIM-induced changes in tumor-residing MDSCs were not observed in Batf3-/- mice. ISIM upregulated PD-L1 expression in both M-MDSCs and PMN-MDSCs and synergized with anti-PD-L1 therapy. Furthermore, ISIM increased the expression of IFN regulatory factor 8 (IRF8) in myeloid cells, a known negative regulator of MDSCs, indicating a potential mechanism by which ISIM decreases PMN-MDSC levels. Accordingly, ISIM-mediated reduction of PMN-MDSCs was not observed in mice with conditional deletion of IRF8 in myeloid cells. Altogether, these findings suggest that ISIM holds promise as a multimodal intralesional therapy to alter both lymphoid and myeloid compartments of highly aggressive poorly T cell-inflamed, myeloid-enriched tumors resistant to anti-PD-L1 therapy.

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells.

The use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 agonists vaccination and an increased frequency of circulating antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for the antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, in vivo depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination. These findings indicate that the vaccine-primed CX3CR1+ subset is dispensable for antitumor CD8+ T cell responses, but can be used as a blood-based T-cell biomarker for effective priming of CD8+ T cells as post-differentiated T cells. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.

Skeletal muscle loss during neoadjuvant chemotherapy predicts poor prognosis in patients with breast cancer.

BACKGROUND: The skeletal muscle index (SMI), which is calculated as the ratio of skeletal muscle area at the third lumbar vertebral level divided by height squared, has been considered a prognostic factor in patients with breast cancer. However, the prognostic impact of changes in SMI during treatment remains unclear. This study aimed to evaluate the influence of SMI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS: We reviewed patients with breast cancer who underwent NAC and subsequent surgery for breast cancer between 2010 and 2017. The rate of SMI change during NAC was calculated, and the association between SMI changes and prognosis was retrospectively analyzed. RESULTS: In total, 141 patients were evaluated. 48 (34.0%), 53 (37.6%), and 40 (28.4%) patients exhibited increased (≥ 3%), maintained (- 3% <, < 3%), and decreased (- 3% ≥) SMI during NAC, respectively. The decreased SMI group showed significantly poorer disease-free survival than the maintained and increased SMI groups (hazard ratio [HR] 8.29, p <  0.001 for the decreased vs. increased SMI groups; HR 3.49, p <  0.001 for the decreased vs. maintained SMI groups). Moreover, decreased SMI was an independent risk factor for disease-free survival in multivariate analysis (HR 3.68, p <  0.01). CONCLUSIONS: Skeletal muscle loss during NAC predicts poor prognosis. Our results underscore the importance of monitoring and maintaining skeletal muscle mass during NAC.

A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells.

In vivo expansion of adoptively transferred CD8+ T cells is a critical determinant of successful adoptive T cell therapy. Emerging evidence indicates Batf3-dependent conventional type 1 dendritic cells (cDC1s) rarely found within the tumor myeloid compartment are crucial for effector T cell recruitment to the tumor microenvironment. However, the role of cDC1s in expansion of tumor-specific CD8+ T cells remains unclear. In this article, we addressed the role of cDC1s and their costimulatory molecules, CD40, CD70, and CD80/CD86, in expansion and antitumor efficacy of adoptively transferred in vitro-primed CD8+ T cells recognizing nonmutated tumor-associated self-antigens. We found that TLR/CD40-mediated expansion and antitumor efficacy of adoptively transferred tumor-specific CD8+ T cells were abrogated in Batf3-/- mice. Further mechanistic studies using mixed bone marrow chimeric mice identified that CD40 and CD70 but not CD80/CD86 signaling in cDC1s played a critical role in expansion and antitumor efficacy of adoptively transferred CD8+ T cells. Moreover, induction and activation of cDC1s by administration of FMS-like tyrosine kinase 3 ligand (Flt3L) and TLR/CD40 agonists augmented expansion of adoptively transferred CD8+ T cells, delayed tumor growth, and improved survival. These findings reveal a key role for CD40 and CD70 signaling in cDC1s and have major implications for the design of new vaccination strategies with adoptive T cell therapy.

Surgical resection of the primary tumor prevents an undesirable locoregional condition and improves the quality of life in patients with anaplastic thyroid cancer.

PURPOSE: Anaplastic thyroid cancer (ATC) is a highly aggressive tumor that invades surrounding tissues and rapidly metastasizes throughout the body. Growth of the primary tumor in the neck often causes serious conditions that decrease the quality of life (QOL) of patients. The objective of this study was to investigate the role of surgical resection in improving the QOL of patients with ATC. METHODS: This was a retrospective review of 62 patients with ATC treated at Shinshu University Hospital between January 2001 and June 2019. RESULTS: Fourteen patients underwent R0/R1 resection. Thirteen of the 14 patients received postoperative radiation, and 4 received chemotherapy. The mean survival period was 15.4 ± 18.2 (range, 2-75) months. Distant metastases appeared within 3.2 ± 2.3 months postoperatively in 12 patients. A permanent tracheostomy was required in six patients; however, eight patients did not show airway obstruction until death. Daily treatment for exudate or bleeding from tumors that eroded in the neck, which deteriorated the QOL, was unnecessary in 12 patients. CONCLUSIONS: As surgical resection can improve the QOL in patients with ATC, thyroid surgeons should promptly and carefully evaluate the resectability of the tumor and favor resection as much as possible.

HDAC6 inhibition enhances the anti-tumor effect of eribulin through tubulin acetylation in triple-negative breast cancer cells.

PURPOSE: Improved prognosis for triple-negative breast cancer (TNBC) has plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC. METHODS: The effect of eribulin in combination with an HDAC inhibitor was tested in three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by Western blotting for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin. RESULTS: The simultaneous administration of low concentrations (0.2 µM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5 µM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5 µM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Immunohistochemical analyses revealed that the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC. CONCLUSIONS: HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.

Multicenter retrospective study on the use of Curebest™ 95GC Breast for estrogen receptor-positive and node-negative early breast cancer.

BACKGROUND: The benefits of postoperative chemotherapy in patients with estrogen receptor (ER)-positive breast cancer remain unclear. The use of tumor grade, Ki-67, or ER expression failed to provide an accurate prognosis of the risk of relapse after surgery in patients. This study aimed to evaluate whether a multigene assay Curebest™ 95GC Breast (95GC) can identify the risk of recurrence and provide more insights into the requirements for chemotherapy in patients. METHODS: This single-arm retrospective multicenter joint study included patients with ER-positive, node-negative breast cancer who were treated at five facilities in Japan and had received endocrine therapy alone as adjuvant therapy. The primary lesion specimens obtained during surgery were analyzed using the 95GC breast cancer multigene assay. Based on the 95GC results, patients were classified into low-risk (95GC-L) and high-risk (95GC-H) groups. RESULTS: The 10-year relapse-free survival rates were 88.4 and 59.6% for the 95GC-L and 95GC-H groups, respectively. Histologic grade, Ki-67, and PAM50 exhibited a significant relationship with the 95GC results. The segregation into 95GC-L and 95GC-H groups within established clinical factors can identify subgroups of patients using histologic grade or PAM50 classification with good prognosis without receiving chemotherapy. CONCLUSIONS: Based on the results of our retrospective study, 95GC could be used to evaluate the long-term prognosis of ER-positive, node-negative breast cancer. Even though further prospective validation is necessary, the inclusion of 95GC in clinical practice could help to select optimal treatments for breast cancer patients and identify those who do not benefit from the addition of chemotherapy, thus avoiding unnecessary treatment.

Prognostic significance of neutrophil-to-lymphocyte ratio for long-term outcomes in patients with poorly differentiated thyroid cancer.

Poorly differentiated thyroid cancer (PDTC) is a distinct but rare type of thyroid cancer with intermediate biological behavior between differentiated and anaplastic thyroid cancers. PDTC was first defined in 2005 in Japan, but the diagnostic criteria changed in 2015, requiring the tumor to have more than 50% of poorly differentiated components for diagnosis. Because only six years have passed since the PDTC definition change, prognostic factors for long-term survival who meet the latest criteria have not been determined. Neutrophil-to-lymphocyte ratio (NLR) is a prognostic marker in various solid malignancies. However, its impact on PDTC remains unclear. This study aimed to evaluate the significance of NLR as a prognostic factor for patients with PDTC diagnosed based on the latest criteria. In total, 28 PDTC cases (4.4%) of 637 thyroid cancer patients who underwent surgery between 2002 and 2012 were retrospectively analyzed. The median follow-up period was 120 months (range, 7-216 months). Of the 13 deaths (46.4%), 9 patients (32.1%) died from PDTC. The median preoperative NLR was 2.7 (0.67-8.62), and the NLR cut-off value determined by the receiver operating characteristic curve was 2.88. Patients with a high NLR (>2.88) showed significantly worse disease-specific survival (hazard ratio [HR] 4.67, p = 0.036) and overall survival (HR 4.94, p = 0.007) than those with a low NLR (≤2.88). Multivariate analysis revealed that a high NLR independently predicted a worse prognosis (HR 6.06, p = 0.0087). In conclusion, NLR is a useful prognostic marker for patients with PDTC.

Neoadjuvant chemotherapy-induced decrease of prognostic nutrition index predicts poor prognosis in patients with breast cancer.

BACKGROUND: The prognostic nutritional index (PNI), which is an easily calculated nutritional index, is significantly associated with patient outcomes in various solid malignancies. This study aimed to evaluate the prognostic impact of PNI changes in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). METHODS: We reviewed patients with breast cancer who underwent NAC and a subsequent surgery for breast cancer between 2005 and 2016. PNI before and after NAC were calculated using the following formula: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count/mm3. The relationship between PNI and prognosis was retrospectively analyzed. RESULTS: In total, 191 patients were evaluated. There was no significant difference in disease-free survival (DFS) between the pre-NAC PNI high group and the pre-NAC PNI low group (cutoff: 53.1). However, PNI decreased in 181 patients (94.7%) after NAC and the mean PNI also significantly decreased after NAC from 52.6 ± 3.8 pre-NAC to 46.5 ± 4.4 post-NAC (p < 0.01). The mean ΔPNI, which was calculated as pre-NAC PNI minus post-NAC PNI, was 5.4. The high ΔPNI group showed significantly poorer DFS than the low ΔPNI group (cut off: 5.26) (p = 0.015). Moreover, high ΔPNI was an independent risk factor of DFS on multivariate analysis (p = 0.042). CONCLUSIONS: High decrease of PNI during NAC predicts poor prognosis. Thus, maintaining the nutritional status during NAC may result in better treatment outcomes in patients with breast cancer.

Comparative efficacy and safety of tyrosine kinase inhibitors for thyroid cancer: a systematic review and meta-analysis.

The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

[A Case of Arteritis That Developed after Pegfilgrastim Administration during Chemotherapy for Breast Cancer].

A 61-year-old woman presented with metastatic breast cancer in her right lung 4 years and 11 months after the operation for her right breast cancer(HER2 enriched type). Chemotherapy(pertuzumab plus trastuzumab plus docetaxel)were ad- ministered. On day 2 of cycle 2, pegfilgrastim was administered because her neutrophils decreased to 54 cells/mL on day 8 of cycle 1. On day 9 of cycle 2, she developed left neck and chest pain. Moreover, she developed a fever of 39°C on day 14 and visited our hospital. Her WBC and CRP increased to 18,300 cells/mL and 25.48mg/dL, respectively. Computed tomography revealed an increased CT value of the panniculus, around the aorta and left pleural effusion. Ultrasonography of the neck showed a marginal hypoechoic area around the left carotid artery, which corresponded with the pain. Arteritis induced by PFG was suspected. The neck pain and fever almost completely improved 19 days later, and cycle 3 was performed 28 days after cycle 2. To our knowledge, the present case is the second report of arteritis that was suspected to be associated with PFG.

A Case of Adenomyoepithelioma of the Breast Showing Strong Uptake of 18 F-Fluorodeoxyglucose on a Positron Emission Tomography.

An adenomyoepithelioma of the breast is a rare tumor characterized by biphasic proliferation of both epithelial and myoepithelial cells. This tumor is generally considered as a benign neoplasm, and there are few reports describing the imaging features of this tumor through 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Here, we report a case of an adenomyoepithelioma that showed strong uptake of FDG on PET similar to that observed with a malignant tumor. A 73-year-old woman presented to our hospital with a 3.5-cm, mobile, and elastic hard tumor in the upper area of the left breast. Although the findings of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging suggested that the tumor was malignant, it was diagnosed as an adenomyoepithelioma by core needle biopsy. An invasive ductal carcinoma, 0.5-cm in size, was detected in the medial upper area of the ipsilateral breast during an examination. Although FDG-PET demonstrated no lymph node or distant metastases from the invasive ductal carcinoma, strong uptake of FDG was detected in the adenomyoepithelioma. Breast conserving surgery and sentinel lymph node biopsy for the invasive ductal carcinoma together with resection of the adenomyoepithelioma was performed. A diagnosis of adenomyoepithelioma was confirmed through histologic examination of the resected specimen. This case indicates that some adenomyoepitheliomas may show a strong uptake of FDG on PET, which resembles a malignant tumor.

[A Case of Retroperitoneal Abscess Due to Acute Appendicitis during Neo-Adjuvant Chemotherapy for Breast Cancer].

When acute appendicitis occurs in patients treated with chemotherapy, neutropenia and abdominal complaints caused by chemotherapy can contribute to the diagnostic difficulty, masking the increase in white blood cell(WBC)counts and physical findings of acute appendicitis. A 43-year-old premenopausal woman who was diagnosed with stage IIIA left breast cancer was scheduled for neoadjuvant chemotherapy includingfluorouracil plus epirubicin plus cyclophosphamide(FEC), followed by docetaxel and trastuzumab(DOC plus HER). The patient developed fever and lower abdominal pain on day 17 of DOC plus HER cycle 1, and was diagnosed with acute gastroenteritis in the emergency room. These symptoms were almost improved 4 days later, and then cycle 2 was performed as scheduled. WBC counts decreased to 1,530 cells/mL due to DOCinduced myelosuppression on day 8 of cycle 2 when the patient developed lower abdominal pain again. However, WBC counts increased to 21,680 cells/mL on day 13 of cycle 2. Computed tomography scans revealed an intraperitoneal abscess due to acute appendicitis, and consequently urgent operation was performed. It is necessary to understand that patients with acute appendicitis duringchemotherapy can present less clinical findings.

Clinical and immunological relevance of SLAMF6 expression in the tumor microenvironment of breast cancer and melanoma.

Compelling evidence shows that the frequency of T cells in the tumor microenvironment correlates with prognosis as well as response to immunotherapy. However, considerable heterogeneity exists within tumor-infiltrating T cells, and significance of their genomic and transcriptomic landscape on clinical outcomes remains to be elucidated. Signaling lymphocyte activation molecule 6 (SLAMF6) is expressed on intra-tumoral progenitor-exhausted T cells, which exhibit the capacity to proliferate, self-renew and produce terminally-exhausted T cells in pre-clinical models and patients. Here, we investigated the impact of SLAMF6 expression on prognosis in two immunologically different tumor types using publicly available databases. Our findings demonstrate that high SLAMF6 expression is associated with better prognosis, expression of TCF7 (encoding T-cell factor 1), and increased gene signatures associated with conventional type 1 dendritic cells and effector function of T cells in melanoma and breast cancer. Single-cell profiling of breast cancer tumor microenvironment reveals SLAMF6 expression overlaps CD8 T cells with a T-effector signature, which includes subsets expressing TCF7, memory and effector-related genes, analogous to progenitor-exhausted T cells. These findings illustrate the significance of SLAMF6 in the tumor as a marker for better effector responses, and provide insights into the predictive and prognostic determinants for cancer patients.

Generation, Transcriptomic States, and Clinical Relevance of CX3CR1+ CD8 T Cells in Melanoma.

Recent progress in single-cell profiling technologies has revealed significant phenotypic and transcriptional heterogeneity in tumor-infiltrating CD8+ T cells. However, the transition between the different states of intratumoral antigen-specific CD8+ T cells remains elusive. Here, we sought to examine the generation, transcriptomic states, and the clinical relevance of melanoma-infiltrating CD8+ T cells expressing a chemokine receptor and T-cell differentiation marker, CX3C chemokine receptor 1 (CX3CR1). Analysis of single-cell datasets revealed distinct human melanoma-infiltrating CD8+ T-cell clusters expressing genes associated with effector T-cell function but with distinguishing expression of CX3CR1 or PDCD1. No obvious impact of CX3CR1 expression in melanoma on the response to immune checkpoint inhibitor therapy was observed while increased pretreatment and on-treatment frequency of a CD8+ T-cell cluster expressing high levels of exhaustion markers was associated with poor response to the treatment. Adoptively transferred antigen-specific CX3CR1- CD8+ T cells differentiated into the CX3CR1+ subset in mice treated with FTY720, which inhibits lymphocyte egress from secondary lymphoid tissues, suggesting the intratumoral generation of CX3CR1+ CD8+ T cells rather than their trafficking from secondary lymphoid organs. Furthermore, analysis of adoptively transferred antigen-specific CD8+ T cells, in which the Cx3cr1 gene was replaced with a marker gene confirmed that CX3CR1+ CD8+ T cells could directly differentiate from the intratumoral CX3CR1- subset. These findings highlight that tumor antigen-specific CX3CR1- CD8+ T cells can fully differentiate outside the secondary lymphoid organs and generate CX3CR1+ CD8+ T cells in the tumor microenvironment, which are distinct from CD8+ T cells that express markers of exhaustion. SIGNIFICANCE: Intratumoral T cells are composed of heterogeneous subpopulations with various phenotypic and transcriptional states. This study illustrates the intratumoral generation of antigen-specific CX3CR1+ CD8+ T cells that exhibit distinct transcriptomic signatures and clinical relevance from CD8+ T cells expressing markers of exhaustion.

CA19-9 producing locally advanced papillary thyroid carcinoma: a case report.

BACKGROUND: CA19-9 is a tumor marker for gastrointestinal and biliary-pancreatic adenocarcinomas; however, its association with thyroid cancer is unknown. Here, we report a case of CA19-9 producing locally advanced papillary thyroid carcinoma (PTC). CASE PRESENTATION: A 66-year-old woman who was identified with a thyroid tumor after a close examination of an elevated serum CA19-9 level, which was detected at health screening, was referred to our hospital. Ultrasonography revealed a 34 × 31 mm hypoechoic lesion in the lower pole of the left thyroid lobe. Computed tomography revealed a solid thyroid tumor with tracheal invasion without any distant metastases. Bronchoscopy revealed tumor exposure into the tracheal lumen on the left side of the trachea. Fine-needle aspiration cytology led to a diagnosis of papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy, tracheal sleeve resection with end-to-end anastomosis, and lymph node dissection in the left cervical and superior mediastinal regions (D3c) with a reversed T-shaped upper sternotomy down to the third intercostal level. Histopathological analysis confirmed the diagnosis of PTC with tracheal invasion and no lymph node metastases (pT4a Ex2 N0). Immunohistochemical staining showed the expression of CA19-9 in cancer cells. Postoperatively, the serum CA19-9 level of the patient decreased to within the normal range. CONCLUSIONS: Some PTCs produce CA19-9, although less frequently. When elevated serum CA19-9 levels are observed, PTC should be included in the differential diagnosis for further investigation.

The Advantage of Using an Optical See-Through Head-Mounted Display in Ultrasonography-Guided Needle Biopsy Procedures: A Prospective Randomized Study.

An optical see-through head-mounted display (OST-HMD) can potentially improve the safety and accuracy of ultrasonography (US)-guided fine-needle aspiration. We aimed to evaluate the usefulness of an OST-HMD in US-guided needle-puncture procedures. We conducted a prospective randomized controlled study in which we compared the accuracy and safety of the US-guided needle puncture procedure and the stress on the practitioner when using OST-HMD versus standard US display (SUD). Inexperienced medical students were enrolled and randomly divided into two groups. A breast phantom was used to evaluate the required time and accuracy of the US-guided needle puncture. Practitioner stress was quantified using a visual analog scale (VAS). When the procedure was performed for the first time, the time required to reach the target lesion at a shallow depth was significantly shorter in the OST-HMD group (39.8 ± 39.9 s) than in the SUD group (71.0 ± 81.0 s) (p = 0.01). Using the OST-HMD significantly reduced the unintentional puncture of a non-target lesion (p = 0.01). Furthermore, the stress felt by the practitioners when capturing the image of the target lesion (p < 0.001), inserting and advancing the needle more deeply (p < 0.001), and puncturing the target lesion (p < 0.001) was significantly reduced in the OST-HMD group compared with that in the SUD group. Use of OST-HMD may improve the accuracy and safety of US-guided needle puncture procedures and may reduce practitioner stress during the procedure.