Abstract only
8548
Background: Since any surgery for malignant pleural mesothelioma (MPM) are cytoreductive, effective chemotherapy is a prerequisite for surgery. In this context, we give ...neo-adjuvant chemotherapy (NAC) to all surgical candidates. Methods: Hyogo College of Medicine MPM Surgery Program mandates all surgical candidates to receive NAC, and only patients with stable disease (SD) or better response proceeds to surgery. The program comprised NAC followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation until 2012, and NAC followed by pleurectomy/decortication (P/D) and postoperative chemotherapy thereafter. Eligibility criteria are histologically confirmed non-sarcomatoid MPM, clinically resectable stage (T1-3N0-1M0), performance status 0–1, and no major comorbidity. Results: From December 2006 to December 2018, 225 patients were enrolled. Of 225, 24 patients (10.7%, Group A) did not proceed to surgery because of progressive disease (n=23) or serious adverse events (n=2). Of the remaining 201 patients with partial response (n=38, 16.9%) or stable disease (n=163, 72.4%), 19 refused surgery (Group B), 16 received exploratory thoracotomy (Group C), and 165 completed surgery (Group D, EPP58, P/D107). Surgical mortality rates at 30 and 90 days were 1.1% (n=2) and 2.8% (n=5), and surgical morbidity (≧grade 3) was 26.0% (n=47). Median survival time and survival rates of each group were shown in the table. Briefly, 2-yr survival competed among Group B,C and D, whereas 5-yr survival rapidly dropped in Group B and C. Conclusions: Approximately 90% of MPM patients with surgical intent successfully underwent either of EPP or P/D after effective chemotherapy with acceptable surgical mortality and morbidity. Comparison of patients who refused or accepted surgery suggested that surgery contributed to long-term survival. Table: see text
Abstract only
e14041
Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers. There is a demand for less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T ...cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells, tumor mutation burden and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P < 0.05, P < 0.05, P < 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P < 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. TCR repertoire was proportional to TMB. Clones found in multiple patients were more frequent in indel than in SNP. Conclusions: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy.
Introduction
The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage ...patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group.
Methods
Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery pleurectomy decortication
n
= 57 (64.1%), extrapleural pneumonectomy
n
= 32 (35.9%) at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models.
Results
Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3-year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3-year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (
p
= 0.015).
Conclusions
Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy.
Abstract
OBJECTIVES
Impact of pleurectomy/decortication (P/D) on quality of life (QOL) is not widely reported. We investigated QOL and lung function after P/D.
METHODS
A single-centre, retrospective ...cohort study was performed among patients who underwent P/D for malignant mesothelioma between June 2014 and June 2018 at Hyogo College of Medicine. Data at 4 points before and 3, 6 and 12 months on QOL and lung function were evaluated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function tests.
RESULTS
Forty-five out of 65 patients completed SF-36. Physical function and role physical decreased from 78 to 65 and 69 to 41 and did not recover. Body pain decreased from 74 to 52. It increased to 62 at 12 months but was lower than before. General health perceptions, vitality and social function decreased from 56 to 49, 50 to 47 and 63 to 50, respectively, but returned to baseline. Role emotional decreased from 75 to 54, then once increased to 63, but decreased again to 58. Mental health tended to improve from 58 to 70. Thirty-eight patients out of 45 completed pulmonary function tests. Forced vital capacity and forced expiratory volume in 1 s decreased from 98% to 61% and 93% to 67% and did not increase. Right-sided surgery or complications was the risk factors of poor lung function but no significant risk factors in QOL.
CONCLUSIONS
This study suggests that P/D had an impact on QOL. Despite the lack of recovery in lung function QOL in mental aspects tended to improve, suggesting that pulmonary function tests alone are limited in assessing QOL.
Malignant pleural mesothelioma (MPM) is a high-grade malignant tumour.
We performed multimodality therapy comprising preoperative chemotherapy, extrapleural pneumonectomy (EPP), and radiation therapy for patients with malignant pleural mesothelioma (MPM). Although ...multimodality therapy resulted in good prognosis, further improvement is required. Therefore, herein, we analysed the prognostic factors using surgical specimens and searched for suitable molecular targets to improve the prognosis after multidisciplinary treatment.
Forty-six patients with MPM underwent multimodality therapy. Paraffin-embedded surgical samples were used for immunohistochemistry to evaluate the expression of phosphorylated (p-) AKT, extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and S6 ribosomal protein (S6RP).
On univariate and multivariate analyses, significant differences were observed according to the histological type, pathological stage, and p-mTOR expression rate.
The prognosis of MPM is affected by p-mTOR expression, suggesting that molecular-targeted treatment might be used during multimodal therapy for MPM.
Abstract
Background: Programmed death 1 (PD-1) blockade with Nivolumab are effective in patients with malignant pleural mesothelioma (MPM), however; successful predictive biomarker has not been ...available. Unlike invasive test with tumor biopsy, peripheral blood is safe and easily obtainable source of biomarkers. We have previously reported that T cell receptor (TCR) diversity of CD8+PD-1+ T cells were effective to predict response to anti-PD-1 antibody treatment in non-small cell lung cancer (NSCLC) patients (AACR2019: Abstract nr 2230). In this study, Next generation sequence(NGS)-based TCR α and β repertoires were examined with peripheral CD8+PD-1+ T cells isolated from 11 patients with MPM and treatment responses were evaluated 2 months after anti-PD-1 antibody treatment.
Methods: Peripheral blood mononuclear cells were collected from 11 MPM patients enrolled in this study before administration of anti-PD-1 antibody (Nivolumab). NGS-based TCR α and β repertoire analysis were performed with CD8+PD-1+ T cells isolated with FACS sorting by Repertoire Genesis Inc. TCR diversity was statistically evaluated by Shannon, Simpson and Diversity Evenness 50 (DE50) indices. CT scan was performed during week 8 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine.
Results: Three of 11 (27.3%) MPM patients responded to anti-PD-1 treatment. There were good correlation of all diversity indices between TCRα and TCRβ. TCRβ diversity was significantly higher among responders than non-responders based on DE50 (0.0019 ± 0.00032 vs 0.0011 ± 0.00042, P < 0.05). Also, responders exhibited a clear trend to have higher TCR diversity of CD8+PD-1+ T cells in terms of Shannon, normalized Shannon and Simpson indices.
Conclusion: Like NSCLC patients, PD-1 blockade was more effective in MPM patients who had higher levels of TCR diversity in peripheral CD8+PD-1+ T cells. This result suggested the TCR diversity of peripheral CD8+PD-1+ T cells has potential to predict response to immune checkpoint inhibitors in various tumor patient. Further clinical study would be needed to verify effectiveness of this biomarker.
Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Ryo Takahashi, Takashi Yokoi, Hiroshi Kodama, Yoshie Inao, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Aki Kobayashi, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Koichiro Yamakado, Takashi Kijima, Seiki Hasegawa. Effective prediction of treatment responders with anti-PD-1 antibody in malignant pleural mesothelioma by diversity of peripheral CD8+PD-1+ T cell subpopulation abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4478.
Evaluation of tumor markers may facilitate follow-up of malignant pleural mesothelioma (MPM). We aimed was to evaluate the value of tumor markers for monitoring and predicting recurrence in patients ...with MPM.
In total, 152 patients who underwent curative-intent surgery after induction chemotherapy for MPM between July 2004 and December 2017 were retrospectively reviewed. Preoperative and postoperative (≤3 months after surgery) levels of soluble mesothelin-related peptide (SMRP), cytokeratin 19 fragment (Cyfra21-1), and tissue polypeptide antigen (TPA) and rates of recurrence and non-recurrence were evaluated. Factors associated with recurrence-free survival (RFS) were assessed using the Kaplan-Meier method and Cox proportional hazards model.
Of the 152 patients, the positive rates of preoperative SMRP, Cyfra21-1, and TPA, levels were 26.7%, 8.6%, 9.6%, respectively; the respective postoperative levels were 4.0%, 6.3%, and 6.5%; the respective levels in patients with recurrence were 39.3%, 31.4%, 28.6%; the respective levels in patients with no recurrence were 3.7%, 0.0%, 3.8%. Nearly half (45.2%) of the patients with recurrence exhibited an increase in one or more tumor marker levels. Multivariate analysis revealed that the preoperative positive rates of one or more of the three tumor markers (hazard ratio: 1.8, 95% confidence interval: 1.1-2.8; P=0.02) were independent significant predictors of recurrence.
The positive rates of SMRP, Cyfra21-1, and TPA in recurrence-free patients were extremely low, with high specificity. Preoperative levels of SMRP, Cyfra21-1, and TPA, which identified patients with a high risk for recurrence, could improve management of patients with MPM.
Abstract
Background:
The prognosis of Malignant pleural mesothelioma (MPM) is very poor, the new drug for MPM is need. IL-6 in serum with MPM patients is high, IL-6/Stat3 pathway is activated. We ...investigated that Stat3 is the potential target for the treatment of MPM.
Methods:
Cell viability was assayed with Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) were seeded into 96-wellplates. After the treatment with Stat3 inhibitor (BBI-608). Cell Counting Kit-8 solution was added to each well of the plate and measured the absorbance using a microplate reader. The levels of phosphorylated Stat3 (p-Stat3) were measured in cell lysates using an InstantOne ELISA assays (eBioscience). The translocated p-Stat3, c-Myc were analyzed by Confocal immunofluorescent. In vivo study, H226 cells were injected into the subcutaneous over the flank region of nude mice. Mice were randomly assigned into four groups (5 mice each group) 1) vehicle control 2) treated with BBI-608 3) Radiation 4) BBI608/RT. Tumor is measured twice per week.
Results:
BBI-608 inhibited MPM cell lines (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) viability in a dose-dependent manner. The level of p-Stat3 was decreased 90% by BBI-608 10μM treatment in H226. Untreated H226, p-stat3 was observed in cytoplasma and localized in the nucleus. As compared with untreated cells, p-stat3, c-Myc were decrease in cytoplasma and was not localized in the nucleus with BBI-608 treated cells. BBI-608 suppressed tumor growth (p<0.05) and completely suppressed tumor growth with radiation in mouse model.
Conclusion:
In this study, we have shown that BBI-608 inhibited the proliferation of all MPM cell (epithelial, biphasic, sarcomatoid) lines and inhibited Stat3 phosphorylation and blocked the translocation to the nucleus. We also demonstrated that BBBI-608 completely suppressed tumor growth with radiation in mouse model. Furthermore, Stat3 inhibitor with Radiation Therapy (START) is promising in MPM therapy.
Citation Format: Seiji Matsumoto, Hiroshi Doi, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa. Stat3 inhibitor (BBI-608) with radiation therapy is promising in malignant pleural mesothelioma. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2488.
Acute pancreatitis is an aseptic inflammation caused by pathologically activated pancreatic enzymes and inflammatory mediators produced secondarily by neutrophils and other inflammatory cells and is ...one of the most difficult diseases to treat. This study aimed to investigate the role of neutrophils in pancreatitis by examining tissue dynamics.
We created a model of caerulein-induced pancreatitis in 12-week-old male granulocyte colony-stimulating factor knockout mice (G-CSF-KO) and wild-type littermate control mice (six intraperitoneal injections of caerulein 80 μg/kg body weight at hourly intervals for 2 days). Mice were sacrificed 0, 3, 6, 12, 24, 36, 48, 72, and 168 h after caerulein administration and examined histologically.
The survival rate after one week of caerulein administration was 100 % in the control mice, whereas it was significantly lower (10 %) in the G-CSF-KO mice. Histological examination revealed significant hemorrhage and inflammatory cell migration in the G-CSF-KO mice, indicating prolonged inflammation.
Prolonged inflammation was observed in the G-CSF-KO mice. Tissue cleanup by neutrophils during the acute phase of inflammation may influence healing through the chronic phase.
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