Publications by authors named "Yoshihiko Hirohashi"

168 Publications

Prediction of treatment response from the microenvironment of tumor immunity in cervical cancer patients treated with chemoradiotherapy.

Med Mol Morphol 2021 May 8. Epub 2021 May 8.

Department of Radiology, Sapporo Medical University School of Medicine, S1 W16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive chemoradiotherapy. We retrospectively analyzed the expression of CD8, FoxP3, HLA-1, PD-L1, and XRCC4 in 100 cases of cervical cancer. The observed tumor immune microenvironments were also classified into three types: inflamed, excluded, and cold type. Less FoxP3+ T cells and cold-type tumor were found to be poor prognostic factors in addition to non-SCC, large pre-treatment tumor volume, and three or less cycles of concurrent chemotherapy based on multivariate analysis. Cold-type tumors had significantly worse prognoses than the other two types, whereas inflamed- and excluded-type tumors showed similar 5-year disease-specific survival (P < 0.001; 0% vs. 60.3% vs. 72.3%). Radiotherapy could overcome the inhibitory immune microenvironment that occurs in excluded type. Individualized combination therapy adapted to pre-treatment tumor immunity may be necessary to improve radiotherapy outcomes in cervical cancer.
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http://dx.doi.org/10.1007/s00795-021-00290-wDOI Listing
May 2021

IL-13 modulates ∆Np63 levels causing altered expression of barrier- and inflammation-related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis.

Immun Inflamm Dis 2021 Apr 1. Epub 2021 Apr 1.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Background: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53-like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified.

Objective: In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD-associated molecules regulated by ΔNp63 in keratinocytes.

Methods: The immunohistochemical expression profiles of ΔNp63 and AD-related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD-related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method.

Results: In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier-related proteins including filaggrin, caspase-14, claudin-1, and claudin-4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL-1β and IL-33, pro-inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL-13 exposure increased the thickness of the three-dimensional culture of keratinocytes. IL-13 interfered with ΔNp63 downregulation during calcium-induced keratinocyte differentiation. IL-13 modulated some barrier-related and inflammation-related molecules, which were regulated by ΔNp63.

Conclusions: We have shown that ΔNp63 modulated AD-related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL-4/IL-13. IL-13-ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.
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http://dx.doi.org/10.1002/iid3.427DOI Listing
April 2021

Neuregulin-1-β1 and γ-secretase play a critical role in sphere-formation and cell survival of urothelial carcinoma cancer stem-like cells.

Biochem Biophys Res Commun 2021 05 19;552:128-135. Epub 2021 Mar 19.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan. Electronic address:

Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1 cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-β1 were preferentially expressed in ALDH1 cells compared with ALDH1 cells; however, siRNA experiments revealed that NRG1-β1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-β1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-β1 remain elusive.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.038DOI Listing
May 2021

Epithelioid granulomatous lesions express abundant programmed death ligand-1 (PD-L1): a discussion of adverse events in anti-PD-1 antibody-based cancer immunotherapy.

Hum Vaccin Immunother 2021 Jul 11;17(7):1940-1942. Epub 2021 Feb 11.

Department of Pathology, Sapporo Medical University, School of Medicine, Sapporo, Japan.

The immune system is often called a double-edged sword, due to the inextricable link between cancer immunity and allergy/autoimmunity. Intriguingly, a growing number of cases have been reported in which PD-1 blockade triggers the exacerbation of tuberculosis (TB), an organ-invasive granulomatous disease caused by bacterial infection. As a result, the exacerbation of TB is now considered a severe adverse effect of nivolumab and pembrolizumab. In this letter, we report the strong expression of PD-L1 in epithelioid granulomatous lesions in tuberculosis, sarcoidosis, Crohn's disease, and foreign body granuloma. In addition, we discussed the exacerbation of tuberculosis after anti-PD-1 antibody-based cancer immunotherapy.
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http://dx.doi.org/10.1080/21645515.2020.1870364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189068PMC
July 2021

Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.

Cancer Sci 2021 Mar 18;112(3):1320-1325. Epub 2021 Jan 18.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
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http://dx.doi.org/10.1111/cas.14773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935803PMC
March 2021

Spatiotemporal metabolic dynamics of the photosensitizer talaporfin sodium in carcinoma and sarcoma.

Cancer Sci 2021 Feb 4;112(2):550-562. Epub 2020 Dec 4.

Graduate School of Photonic Science, Chitose Institute for Science and Technology, Sapporo, Japan.

Photodynamic therapy (PDT) using the photosensitizer talaporfin sodium (talaporfin) is a new mode of treatment for cancer. However, the metabolic mechanism of talaporfin has not been clarified. Thus, we investigated the uptake, transportation, and elimination mechanisms of talaporfin in carcinoma and sarcoma. The results showed that talaporfin co-localized in early endosomes and lysosomes. Talaporfin uptake was via clathrin- and caveolae-dependent endocytosis and a high amount of intracellular ATP was essential. Inhibition of lysosomal enzymes maintained intracellular talaporfin levels. Inhibition of K-Ras signaling reduced talaporfin uptake in carcinoma and sarcoma cell lines. Talaporfin was taken up by clathrin- and caveolae-dependent endocytosis, translocated from early endosomes to lysosomes, and finally degraded by lysosomes. We also demonstrated that ATP is essential for the uptake of talaporfin and that activation of K-Ras is involved as a regulatory mechanism. These results provide new insights into the metabolism of talaporfin in cancer cells for the enhancement of PDT for carcinoma and sarcoma.
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http://dx.doi.org/10.1111/cas.14735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894003PMC
February 2021

Non-bacterial cystitis with increased expression of programmed death-ligand 1 in the urothelium: An unusual immune-related adverse event during treatment with pembrolizumab for lung adenocarcinoma.

IJU Case Rep 2020 Nov 12;3(6):266-269. Epub 2020 Aug 12.

Department of Pathology School of Medicine Sapporo Medical University Sapporo Japan.

Introduction: Immune checkpoint inhibitors are now a standard therapeutic option for lung adenocarcinoma. However, Immune checkpoint inhibitors often induce various immune-related adverse events.

Case Presentation: The patient was a 78-year-old woman with lung adenocarcinoma who had a partial response to pembrolizumab. During treatment, she complained of pollakiuria and nocturia with painful micturition. Histological analysis revealed infiltration of CD8-positive and/or TIA-1 cytotoxic granule-associated RNA binding protein-positive lymphocytes and programmed death-ligand 1 expression in the urothelium. A diagnosis of immune-related adverse event cystitis was made based on these clinical and pathological findings. The patient's subjective symptoms and findings on cystoscopy improved dramatically after treatment with prednisolone.

Conclusion: Immune checkpoint inhibitors-induced cystitis is extremely rare. This report is the first to include an immunohistochemical analysis of the urothelial epithelium in immune-related adverse event cystitis and describes an instructive case.
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http://dx.doi.org/10.1002/iju5.12211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609190PMC
November 2020

Association between cancer immunity and treatment results in uterine cervical cancer patients treated with radiotherapy.

Jpn J Clin Oncol 2020 Oct;50(11):1290-1297

Department of Radiology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Objective: To evaluate proteins related to tumor immune response and treatment outcome from radiotherapy for uterine cervical cancer patients.

Methods: We performed a retrospective immunohistochemical staining of 81 patients with uterine cervical cancer who underwent definitive radiotherapy. We examined the expression of programmed death ligand 1, human leukocyte antigen class I, tumor-infiltrating CD8+, and forkhead box P3+ (FoxP3+) T cells in tumor tissues.

Results: In biopsy specimen, patients with a higher number of CD8+ T cells and FoxP3+ T cells had a better disease-specific survival than patients with a lower number of CD8+ T cells and FoxP3+ cells (P = 0.018 and P = 0.009). Multivariate analysis showed that equivalent dose in 2 Gy fractions (EQD2) of the minimum dose to 90% of the high-risk clinical target volume, FoxP3+ T cells and expression of human leukocyte antigen class I were significant prognostic factors. When the EQD2 is 70 Gy or more, a higher local control rate is obtained regardless of the number of CD8- or FoxP3-positive cells. When EQD2 is <70 Gy, the number of CD8-positive cells has a significant impact on treatment outcome: the recurrence rate (local recurrence rate + distant metastasis rate) was 46.2% in the group with a CD8 value of 230 or higher, whereas the recurrence rate was 75.7% in the group with a CD8 value of less than 230.

Conclusion: The combination of CD8 or FoxP3 with EQD2 can be potentially useful to predict the treatment results of radiotherapy for cervical cancer, leading to individualized optimal selection of treatment for cervical cancer.
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http://dx.doi.org/10.1093/jjco/hyaa149DOI Listing
October 2020

Development of an artificial antibody specific for HLA/peptide complex derived from cancer stem-like cell/cancer-initiating cell antigen DNAJB8.

Br J Cancer 2020 10 5;123(9):1387-1394. Epub 2020 Aug 5.

Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.

Background: Peptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8.

Methods: We screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8_143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed.

Results: scFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex (K = 2.96 × 10 M and 5.04 × 10 M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8).

Conclusion: We isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.
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http://dx.doi.org/10.1038/s41416-020-1017-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592043PMC
October 2020

Borderline Microenvironment Fibrosis Is a Novel Poor Prognostic Marker of Oral Squamous Cell Carcinoma.

Anticancer Res 2020 Aug;40(8):4319-4326

Department of Pathology, Sapporo Medical University School of Medicine, Hokkaido, Japan.

Background/aim: The tumor microenvironment (TME) balances tumor growth and suppression through humoral factors and cell-cell interactions. In oral squamous cell carcinoma (OSCC), TMEs have been associated with prognosis of cancer patients and are evaluated by microscopy; however, these methods of evaluation vary among studies.

Materials And Methods: To evaluate the TME, borderline microenvironment fibrosis (bMF) was evaluated histologically in 236 OSCC cases and used to determine the clinicopathological status.

Results: bMF was observed in 47% (110 in 236 cases) of OSCC cases and associated with higher T category, N category, stage, histological grade and mode of invasion. bMF-positive was related to overall survival (OS) and progression-free survival (PFS). Multivariate analysis revealed that bMF-positive was an independent factor for OS in all cases [n=226; HR=1.683 (1.018-2.781); p=0.042], especially in T1+T2 cases [n=186; HR=1.926 (1.079-3.440); p=0.024], and PFS in all cases [n=226; HR=2.254 (1.397-3.637); p=0.001].

Conclusion: bMF may act as a novel biomarker for OSCC.
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http://dx.doi.org/10.21873/anticanres.14434DOI Listing
August 2020

Fatal fulminant hepatitis induced by combined ipilimumab and nivolumab therapy despite favorable histologic response and confirmed by autopsy in a patient with clear cell renal cell carcinoma.

Immunol Med 2020 Jul 7:1-6. Epub 2020 Jul 7.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Effective management of immune-related adverse events in patients receiving immunotherapy for cancer is problematic. In this report, we present the case of a 58-year-old man with advanced clear cell renal cell carcinoma who responded well to a combination of ipilimumab and nivolumab. However, after two courses of treatment, he developed fulminant hepatitis and died. An autopsy confirmed that the primary lesion in the left kidney was more than 99% necrotic with only six small residual tumor lesions. These lesions were infiltrated by large numbers of CD8-positive/TIA-1-positive lymphocytes. However, a metastatic lesion in the right kidney harbored few lymphocytes. Furthermore, the tumor cells in the metastatic lesion and one of the residual lesions showed decreased expression of HLA class I molecules, which are a prerequisite for cytotoxic T-lymphocyte-mediated immunotherapy in tumor cells. In this patient, more than 80% of hepatocytes were destroyed and the parenchyma was infiltrated with CD8-positive/TIA-1-positive lymphocytes. The patient had polyuria, which was attributed to neurohypophysitis caused by the infiltration of CD8-positive/TIA-1-positive lymphocytes. We believe that this is an instructive case for immuno-oncologists.
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http://dx.doi.org/10.1080/25785826.2020.1788229DOI Listing
July 2020

Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma.

Cancer Sci 2020 Aug 30;111(8):3071-3081. Epub 2020 Jun 30.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.
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http://dx.doi.org/10.1111/cas.14524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419050PMC
August 2020

Less correlation between mismatch repair proteins deficiency and decreased expression of HLA class I molecules in endometrial carcinoma: a different propensity from colorectal cancer.

Med Mol Morphol 2021 Mar 14;54(1):14-22. Epub 2020 May 14.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.
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http://dx.doi.org/10.1007/s00795-020-00254-6DOI Listing
March 2021

Abscopal effect following nivolumab induction in a patient with metastatic renal cell carcinoma-unique pathological features of the primary specimen: A case report.

Exp Ther Med 2020 Mar 3;19(3):1903-1907. Epub 2020 Jan 3.

Department of Urology, Kushiro City General Hospital, Kushiro 085-0822, Japan.

The case of a patient with metastatic renal cell carcinoma who exhibited the abscopal effect following treatment by anti-programmed death-1 (PD-1) antibody is presented. A 40-year-old woman was diagnosed with an 8.2-cm renal tumor without distant metastases, and radical nephrectomy was subsequently performed. Pathological examination revealed a clear cell renal cell carcinoma. At 3 months after surgery, the patient developed one lung metastasis. Following treatment with interferon and three types of tyrosine kinase inhibitors, anti-PD1 antibody (nivolumab) was started. During the treatment, para-aortic/supraclavicular lymph nodes and several lung lesions remained, although other lesions decreased markedly. The patient was subsequently treated by palliative radiotherapy to the para-aortic and supraclavicular lymph nodes for pain control. After the radiotherapy, the lung lesions previously refractory to nivolumab started to decrease, probably due to an abscopal effect. Additionally, the laboratory data and Karnofsky Performance Status improved. Histological re-examination of the primary lesion revealed heterogeneity of the immunological microenvironment, which may be associated with the heterogeneity of treatment sensitivity.
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http://dx.doi.org/10.3892/etm.2020.8423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027149PMC
March 2020

Association between radiotherapy-induced alteration of programmed death ligand 1 and survival in patients with uterine cervical cancer undergoing preoperative radiotherapy.

Strahlenther Onkol 2020 Aug 17;196(8):725-735. Epub 2020 Jan 17.

Department of Radiology, Sapporo Medical University School of Medicine, S1W16, Chuo-Ku, 060-8543, Sapporo, Hokkaido, Japan.

Purpose: To evaluate radiotherapy-induced changes in the expression of programmed death ligand 1 (PD-L1), programmed death 1 (PD-1), and human leukocyte antigen class I (HLA-1) in patients with uterine cervical cancer, as well as infiltration of CD8+ and Forkhead box P3+ (FoxP3+) T lymphocytes into tumor tissue and the prognostic value of these parameters.

Materials And Methods: We performed immunohistochemical analysis of pre-radiotherapy biopsies and corresponding post-radiotherapy resected tissues in 104 uterine cervical cancer patients undergoing preoperative chemoradiotherapy or radiotherapy alone. We scored the expression of various proteins to distinguish positive from negative samples.

Results: PD-L1-expressing tumor cells (PD-L1 TC) increased significantly after chemoradiotherapy (p = 0.043). CD8+ T cell infiltration (p = 0.002) and FoxP3+ T cell infiltration (p = 0.003) decreased significantly after chemoradiotherapy. Expression of PD‑1, PD-L1-expressing immune cells (PD-L1 IC), and HLA‑1 did not change after chemoradiotherapy. In biopsy specimens obtained before chemoradiotherapy or radiotherapy, greater infiltration of CD8+ T cells (p = 0.001) and FoxP3+ T cells (p = 0.003) were significant predictors of better overall survival (OS). In surgical specimens obtained after chemoradiotherapy or radiotherapy, greater infiltration of PD-L1 TC was the only significant predictor of better OS (p < 0.001) and was related to a significantly lower probability of out-of-field recurrence (p = 0.005).

Conclusion: Chemoradiotherapy induced an immunologic shift that increased PD-L1 TC. Chemoradiotherapy has immunological effects that can influence the results of treatment for uterine cervical cancer.
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http://dx.doi.org/10.1007/s00066-019-01571-1DOI Listing
August 2020

Peptide vaccinations elicited strong immune responses that were reboosted by anti-PD1 therapy in a patient with myxofibrosarcoma.

Cancer Immunol Immunother 2020 Feb 18;69(2):189-197. Epub 2019 Dec 18.

Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.

Peptide-based immunotherapy does not usually elicit strong immunological and clinical responses in patients with end-stage cancer, including sarcoma. Here we report a myxofibrosarcoma patient who showed a strong clinical response to peptide vaccinations and whose immune responses were reboosted by anti-PD1 therapy combined with peptide vaccinations. The 46-year-old man showed a strong response to the peptide vaccinations (papillomavirus binding factor peptide, survivin-2B peptide, incomplete Freund's adjuvant, and polyethylene glycol-conjugated interferon-alpha 2a) and subsequent wide necrosis and massive infiltration of CD8+ T cells in a recurrent tumor. The patient's immune responses weakened after surgical resection; however, they were reboosted following the administration of nivolumab combined with peptide vaccinations. Thus, anti-PD1 therapy combined with peptide vaccinations might be beneficial, as suggested by the observations in this sarcoma patient.
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http://dx.doi.org/10.1007/s00262-019-02455-0DOI Listing
February 2020

Osteosarcoma-initiating cells show high aerobic glycolysis and attenuation of oxidative phosphorylation mediated by LIN28B.

Cancer Sci 2020 Jan 29;111(1):36-46. Epub 2019 Nov 29.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Osteosarcoma (OS) is a highly malignant bone tumor and the prognosis for non-responders to chemotherapy remains poor. Previous studies have shown that human sarcomas contain sarcoma-initiating cells (SIC), which have the characteristics of high tumorigenesis and resistance to chemotherapy. In the present study, we characterized SIC of a novel OS cell line, screened for SIC-related genes, and tried to regulate the proliferation of OS by metabolic interference. Initially, we established a new human OS cell line (OS13) and isolated clones showing higher tumorigenesis as SIC (OS ) and counterpart clones. OS cells showed chemoresistance and their metabolism highly depended on aerobic glycolysis and suppressed oxidative phosphorylation. Using RNA-sequencing, we identified LIN28B as a SIC-related gene highly expressed in OS cells. mRNA of LIN28B was expressed in sarcoma cell lines including OS13, but its expression was not detectable in normal organs other than the testis and placenta. LIN28B protein was also detected in various sarcoma tissues. Knockdown of LIN28B in OS13 cells reduced tumorigenesis, decreased chemoresistance, and reversed oxidative phosphorylation function. Combination therapy consisting of a glycolysis inhibitor and low-dose chemotherapy had antitumor effects. In conclusion, manipulation of glycolysis combined with chemotherapy might be a good adjuvant treatment for OS. Development of immunotherapy targeting LIN28B, a so-called cancer/testis antigen, might be a good approach.
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http://dx.doi.org/10.1111/cas.14229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942429PMC
January 2020

Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma.

Cancer Sci 2019 Aug 23;110(8):2378-2385. Epub 2019 Jul 23.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-β (IFNβ); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFNβ. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFNβ (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFNβ group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFNβ in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFNβ did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFNβ vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).
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http://dx.doi.org/10.1111/cas.14106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676125PMC
August 2019

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series.

Cancer Sci 2019 Aug 11;110(8):2386-2395. Epub 2019 Jul 11.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN-2B), a 9-mer antigenic peptide encoded by survivin, and an SVN-2B peptide vaccine-based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN-2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN-2B peptide vaccination and 6 who had not, as negative controls. The expression of immune-related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme-linked immunospot assay. Histological analysis revealed dense infiltration of CD8 T cells in some lesions in patients who had received the SVN-2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN-2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor-specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.
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http://dx.doi.org/10.1111/cas.14099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676134PMC
August 2019

[PD-L1-Mediated Immune Escape Mechanism of Cancer Stem-Like Cells].

Gan To Kagaku Ryoho 2019 May;46(5):850-854

Dept. of Pathology, Sapporo Medical University School of Medicine.

Immune checkpoint inhibitors(ICIs)have provided great success in cancer treatment field, and immunotherapies using ICIs have become standard therapy for several cancers. Cancer stem-like cells(CSCs)are defined by their higher tumorigenicity and resistance to chemotherapy and radiotherapy, thus they are supposed to be responsible for recurrence and distant metastasis. Therefore, control of CSCs is a key factor to improve patients' prognosis. In this review article, we summarize the expression of PD-L1, a molecular target of ICIs, in CSCs, and discuss the possibility of CSC-targeting immunotherapy using ICIs.
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May 2019

ABCG2 expression is related to low 5-ALA photodynamic diagnosis (PDD) efficacy and cancer stem cell phenotype, and suppression of ABCG2 improves the efficacy of PDD.

PLoS One 2019 13;14(5):e0216503. Epub 2019 May 13.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

Photodynamic diagnosis/therapy (PDD/PDT) are novel modalities for the diagnosis and treatment of cancer. The photosensitizer protoporphyrin IX is metabolized from 5-aminolevulinic acid (5-ALA) intracellularly, and PDD/PDT using 5-ALA have been approved in dermatologic malignancies and gliomas. However, the molecular mechanism that defines the efficacy of PDD/PDT is unknown. In this study, we analyzed the functions of ATP-binding cassette (ABC) transporters in PDD using 5-ALA. Most of the human gastrointestinal cancer line cells examined showed a homogenous staining pattern with 5-ALA, except for the pancreatic cancer line PANC-1, which showed heterogeneous staining. To analyze this heterogeneous staining pattern, single cell clones were established from PANC-1 cells and the expression of ABC transporters was assessed. Among the ABC transporter genes examined, ABCG2 showed an inverse correlation with the rate of 5-ALA-positive staining. PANC-1 clone #2 cells showed the highest level of ABCG2 expression and the lowest level of 5-ALA staining, with only a 0.6% positive rate. Knockdown of the ABCG2 gene by small interfering RNAs increased the positive rate of 5-ALA staining in PANC-1 wild-type and clone cells. Interestingly, PANC-1 clone #2 cells showed the high sphere-forming ability and tumor-formation ability, indicating that the cells contained high numbers of cancer stem cells (CSCs). Knockdown or inhibition of ABCG2 increased the rate of 5-ALA staining, but did not decrease sphere-forming ability. These results indicate that gastrointestinal cancer cell lines expressing high levels of ABCG2 are enriched with CSCs and show low rates of 5-ALA staining, but 5-ALA staining rates can be improved by inhibition of ABCG2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216503PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513434PMC
January 2020

Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report.

J Immunother Cancer 2019 04 3;7(1):97. Epub 2019 Apr 3.

Department of Pathology, Sapporo Medical University, School of Medicine, South 1, West 17, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan.

Background: Immune checkpoint inhibitors (ICIs) have provided more options in the treatment of lung cancer. However, ICIs can cause several unfavorable reactions generally referred to as immune-related adverse effects.

Case Presentation: In this report, we present the case of a 52-year-old woman with successful regression of pleomorphic carcinoma of the lung following nivolumab therapy. She developed purpura fulminans (PF) ultimately resulting in amputation of both lower extremities. Blood tests revealed thrombocytopenia with increased serum soluble IL-2 receptor, ferritin, and triglyceride levels suggesting hemophagocytic lymphohistiocytosis (HLH). In addition, serum A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 activity was decreased, suggesting thrombotic thrombocytopenic purpura (TTP). Further detailed analysis revealed severe hypercytokinemia including increased levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF.

Conclusion: The severe systemic inflammatory reaction and impaired peripheral circulation in this patient was attributed to excessive immunological effect induced by nivolumab resulting in cytokine release syndrome (CRS). This is the first report of a patient with multiple pathological conditions including HLH, TTP-like condition, and PF presumably arising from ICI-induced CRS. Further accumulating thoroughly investigated cases would lead to better understanding of the disease and development of reliable cancer immunotherapy.
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http://dx.doi.org/10.1186/s40425-019-0582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448268PMC
April 2019

Upstream Position of Proline Defines Peptide-HLA Class I Repertoire Formation and CD8 T Cell Responses.

J Immunol 2019 05 1;202(10):2849-2855. Epub 2019 Apr 1.

Department of Pathology, Sapporo Medical University, Sapporo, Hokkaido 060-8556, Japan.

Cytotoxic CD8 T lymphocytes (CTLs) recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Difficulty in predicting HLA class I ligands is attributed to the complexity of the Ag processing pathway across the cytosol and the endoplasmic reticulum. By means of HLA ligandome analysis using mass spectrometry, we collected natural HLA class I ligands on a large scale and analyzed the source-protein sequences flanking the ligands. This comprehensive analysis revealed that the frequency of proline at amino acid positions 1-3 upstream of the ligands was selectively decreased. The depleted proline signature was the strongest among all the upstream and downstream profiles. Experiments using live cells demonstrated that the presence of proline at upstream positions 1-3 attenuated CTL responses against a model epitope. Other experiments, in which N-terminal-flanking Ag precursors were confined in the endoplasmic reticulum, demonstrated an inability to remove upstream prolines regardless of their positions, suggesting a need for synergistic action across cellular compartments for making the proline signature. Our results highlight, to our knowledge, a unique role and position of proline for inhibiting downstream epitope presentation, which provides a rule for defining natural peptide-HLA class I repertoire formation and CTL responses.
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http://dx.doi.org/10.4049/jimmunol.1900029DOI Listing
May 2019

Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma.

Exp Mol Pathol 2019 02 30;106:78-88. Epub 2018 Nov 30.

Departments of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo 060-8556, Japan; CREST, Japan Science and Technology Agency, Tokyo 102-0076, Japan. Electronic address:

Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.
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http://dx.doi.org/10.1016/j.yexmp.2018.11.013DOI Listing
February 2019

Occult ovarian clear-cell carcinoma diagnosed as primary adenocarcinoma of the lung: A case report of a diagnostic pitfall for clinicians and pathologists.

Respir Med Case Rep 2018 18;25:306-308. Epub 2018 Oct 18.

Department of Pathology, Sapporo Medical University, School of Medicine, Sapporo, Hokkaido, 060-8556, Japan.

We present a case of ovarian clear-cell carcinoma that was initially diagnosed as adenocarcinoma of lung origin. This is an instructive diagnostic pitfall for clinicians and pathologists because of the unusual clinical course, small biopsy material, and noteworthy immunophenotype of the carcinoma. Imaging analysis identified only lung and liver lesions. In addition, the biopsy specimen from the lung was TTF-1 negative and napsin A positive, which is still possible for cancer of lung origin. Postmortem examination found that the cancer should be classified as ovarian clear-cell carcinoma distinguished by positive staining for napsin A and paired-box gene 8 (PAX8). Although PAX8 may not be usually investigated when tumoral lesions are identified in only the lung and liver, it is important to keep the necessity of PAX8 in mind to excluding carcinoma of Müllerian, renal, or thyroid origin.
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http://dx.doi.org/10.1016/j.rmcr.2018.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205346PMC
October 2018

Development of a T-cell receptor multimer with high avidity for detecting a naturally presented tumor-associated antigen on osteosarcoma cells.

Cancer Sci 2019 Jan 1;110(1):40-51. Epub 2018 Dec 1.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.

For efficacy of peptide vaccination immunotherapy for patients with cancer, endogenous expression of the target peptide/human leukocyte antigen (HLA) on cancer cells is required. However, it is difficult to evaluate the expression status of a peptide/HLA complex because of the lack of a soluble T-cell receptor (TCR) that reacts with tumor-associated antigen (TAA) with high avidity. In the present study, we developed two soluble TCR-multimers that were each directed to TAA, survivin-2B (SVN-2B) and PBF in the context of HLA-A24 (SVN-2B TCR-multimer and PBF TCR-multimer, respectively), from CTL clones that were established from peptide-vaccinated patients. Both TCR multimers could recognize cognate peptide-pulsed antigen-presenting cells, C1R-A24 cells, in a CD8-independent method. Moreover, the PBF TCR-multimer successfully recognized a PBF peptide naturally presented on HLA-A24 PBF osteosarcoma cells. Taken together, the results indicated that a TCR-multimer might be useful for detection of a TAA-derived peptide presented by HLA in patients receiving immunotherapy.
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http://dx.doi.org/10.1111/cas.13854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317924PMC
January 2019

Differential bronchial epithelial response regulated by ΔNp63: a functional understanding of the epithelial shedding found in asthma.

Lab Invest 2019 02 25;99(2):158-168. Epub 2018 Sep 25.

Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8556, Japan.

Bronchial epithelial cells serve as a physical barrier at the forefront of the immune system. Barrier disruption and an excessive immune response of the bronchial epithelium contribute to the pathophysiology of asthma, a chronic bronchial inflammatory disease. The purpose of this study was to investigate the functional significance of ΔNp63, a p53-like transcription factor expressed by the basal bronchial epithelium. The immunohistochemical expression profile of ΔNp63 was evaluated in human bronchial tissue derived from asthma patients. The role of ΔNp63 in apoptosis inhibition and production of soluble mediators was investigated in vitro with cultured BEAS-2B bronchial epithelial cells using molecular biological analysis. In healthy bronchial tissue, ΔNp63-positive basal epithelial cells were covered with differentiated ΔNp63-negative cells but in the asthmatic airway, ΔNp63-positive cells were directly exposed to the bronchial lumen due to severe epithelial shedding. ΔNp63 regulated bronchial apoptosis in response to Toll-like receptor 3 stimulation. On the other hand, expression of ΔNp63 was modulated by stimulation with trypsin and SLIGKV, protease-activated receptor 2 ligands. Further phenotypic analysis revealed that ΔNp63 controlled the transcriptional expression and protein release of some epithelium-derived proinflammatory cytokines and endogenous protease inhibitors. We conclude that ΔNp63 modulates the bronchial epithelial response to viral infection. At the same time, ΔNp63 expression is influenced by proteases, which are abundant in house dust mites. Therefore, the ΔNp63 axis would be intimately involved in these two major triggers of asthma exacerbations, viral infection and protease overload.
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http://dx.doi.org/10.1038/s41374-018-0132-6DOI Listing
February 2019

Influence of PD-L1 expression in immune cells on the response to radiation therapy in patients with oropharyngeal squamous cell carcinoma.

Radiother Oncol 2018 11 21;129(2):409-414. Epub 2018 Sep 21.

Department of Radiology, Sapporo Medical University School of Medicine, Japan. Electronic address:

Background And Purpose: To investigate influences of proteins involved with tumor immunity on outcomes of radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC).

Material And Methods: We performed immunohistochemical staining to examine expressions of p16 and proteins involved with tumor immunity in 92 OPSCC patients treated with radiotherapy.

Results: Patients with abundant infiltrating CD8-positive cells had the significantly better overall survival (OS) rate than patients with fewer CD8-positive cells (p = 0.026). Patients with higher PD-L1 expression in tumor cells (TC 1-3) had a better outcome than those with low PD-L1 expression in tumor cells (TC 0) for both OS (p = 0.019) and progression-free survival (PFS) rate (p = 0.032). Patients with high PD-L1 expression in infiltrating immune cells (IC 3) showed significantly better OS (p = 0.009) and PFS (p = 0.011) than those with low PD-L1 expression (IC 0-2). Patients with p16-negative and IC 3 showed similar OS to patients with p16-positive and IC 0-2. P16-positive tumors had a significantly higher CD8-positive cell infiltration and PD-L1 expression in tumor cells than p16-negative tumors.

Conclusions: In addition to tumor p16 expression, PD-L1 expression in TC and IC can be useful for predicting the response of OPSCC to radiotherapy.
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http://dx.doi.org/10.1016/j.radonc.2018.08.023DOI Listing
November 2018

Case report: Long-term survival of a pancreatic cancer patient immunized with an SVN-2B peptide vaccine.

Cancer Immunol Immunother 2018 Oct 1;67(10):1603-1609. Epub 2018 Aug 1.

Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, S1, W16, Chuo-ku, Sapporo, 060-8543, Japan.

A 62-year-old woman who underwent surgery to treat pancreatic cancer provided written, informed consent to undergo adjuvant therapy with gemcitabine, tegafur, and uracil. However, this was stopped after only 14 days due to Grade 4 neutropenia. She was then started on vaccine therapy with Survivin 2B peptide (SVN-2B) including IFA and INF-α. Although metastatic lung tumors were identified and resected at 82 months after surgery, the patient has remained free of new or relapsed disease for 12 years thereafter. Tetramer and ELISPOT assays revealed the continuous circulation of SVN-2B-restricted cytotoxic T-lymphocytes (CTLs) in her peripheral blood, and CTL clones had specific activity for SVN-2B at 12 years after surgery. The adverse effects of the peptide vaccination were tolerable and comprised low-grade headache, nausea, and fatigue. A prognosis beyond 10 years in the face of pancreatic cancer with distant metastasis is extremely rare. This experience might indicate the value of cancer vaccination therapy.
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http://dx.doi.org/10.1007/s00262-018-2217-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182403PMC
October 2018

LpMab-23-recognizing cancer-type podoplanin is a novel predictor for a poor prognosis of early stage tongue cancer.

Oncotarget 2018 Apr 20;9(30):21156-21165. Epub 2018 Apr 20.

Department of Oral Surgery, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8543, Japan.

Purpose: We report that the reactivity of a novel monoclonal antibody LpMab-23 for human cancer-type podoplanin (PDPN) is a predictor for a poor prognosis of tongue cancer.

Patients And Methods: The association between LpMab-23-recognizing cancer-type PDPN expression and clinical/pathological features were analyzed on 60 patients with stage I and II tongue cancer treated with transoral resection of the primary tumor.

Results: In the mode of invasion, the LpMab-23-dull/negative cases were significantly larger in cases with low-grade malignancies and without late cervical lymph node metastasis, than in cases with high-grade malignancies and the metastasis. In the high-grade malignant cases, LpMab-23-positive cases were significantly larger than LpMab-23-dull/negative cases. The Kaplan-Meier curves of the five-year metastasis-free survival rate (MFS) were significantly lower in the LpMab-23 positive patients than in LpMab-23 dull/negative patients. The LpMab-23-dull/negative cases showed the highest MFS in all of the clinical/pathological features and particularly, the MFS of the LpMab-23 positive cases decreased to less than 60% in the first year. In the Cox proportional hazard regression models a comparison of the numbers of LpMab-23 dull/negative with positive cases showed the highest hazard ratio with statistical significance in all of the clinical/pathological features.

Conclusions: LpMab-23 positive cases may be considered to present a useful predictor of poor prognosis for early stage tongue cancer.
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http://dx.doi.org/10.18632/oncotarget.24986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940393PMC
April 2018