Publications by authors named "Takahiro Karasaki"

38 Publications

Lung autotransplantation for bronchial necrosis after radiotherapy: a case report.

Surg Case Rep 2021 Apr 1;7(1):79. Epub 2021 Apr 1.

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Bronchial necrosis is a rare but fatal complication after radiation therapy. Because of the anatomical complexity and rarity of this condition, determining the most appropriate management for individual patients is extremely challenging. Lung autotransplantation is a surgical technique that has been applied to hilar neoplastic lesions to preserve pulmonary function and avoid pneumonectomy. We herein report a case of bronchial necrosis secondary to radiotherapy that was treated with lung autotransplantation.

Case Presentation: A 46-year-old man developed broad necrosis and infection of the right bronchus secondary to previous stereotactic body-radiation therapy. This treatment was supplied close to a right hilar metastatic pulmonary tumor derived from a mediastinal malignant germ cell tumor that had been surgically resected with the left phrenic nerve. The bronchial necrosis accompanied by infection with Aspergillus fumigatus was progressive despite antibiotics and repetitive bronchoscopic debridement. Because of the patient's critical condition and limited pulmonary function, right lung autotransplantation with preservation of the right basal segment was selected. An omental flap was placed around the bronchial anastomosis to prevent later complications. The postoperative course involved multiple complications including contralateral pneumonia and delayed wound healing at the bronchial anastomosis with resultant stenosis, the latter of which was overcome by placement of a silicone stent. The patient was discharged 5 months postoperatively. Three months after discharge, however, the patient developed hemoptysis and died of bronchopulmonary arterial fistula formation.

Conclusions: We experienced an extremely challenging case of bronchial necrosis secondary to radiotherapy. The condition was managed with lung autotransplantation and omental wrapping; however, the treatment success was temporary and the patient eventually died of bronchopulmonary arterial fistula formation. This technique seems to be a feasible option for locally advanced refractory bronchial necrosis, although later complications can still be fatal.
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http://dx.doi.org/10.1186/s40792-021-01164-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017021PMC
April 2021

Respiratory strength and pectoralis muscle mass as measures of sarcopenia: Relation to outcomes in resected non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 Nov 19. Epub 2020 Nov 19.

Department of Thoracic Surgery, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Objectives: Physical biomarkers to stratify patients with lung cancer into subtypes predictive of outcome beyond tumor-related characteristics are underexplored. This study was designed to investigate the clinical utility of preoperative sarcopenia based on respiratory strength and pectoralis muscle mass to predict the risk of death.

Methods: This retrospective study included 346 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. Respiratory strength and muscle mass were assessed by peak expiratory flow rate and pectoralis muscle index (pectoralis muscle area/body mass index) using preoperative spirometry and chest axial images, respectively. Sarcopenia cutoff points were defined by gender-specific medians of peak expiratory flow rates and pectoralis muscle indices. Survival was compared between patients with sarcopenia and patients without.

Results: Sarcopenia was present in 98 patients (28.3%) and was significantly associated with advancing age (P < .001). Patients with sarcopenia exhibited worse 5-year overall survival compared with patients without sarcopenia (69.9% vs 87.2%, P < .001). Multivariate analysis revealed that sarcopenia was an independent adverse prognostic factor (hazard ratio, 1.88; 95% confidence interval, 1.09-3.24; P = .023) after adjustment for gender, age, smoking status, coronary heart disease, diffusing capacity for carbon monoxide, neutrophil-to-lymphocyte ratio, albumin, histologic type, and pathologic stage.

Conclusions: Preoperative sarcopenia as identified by the criteria of low respiratory strength and reduced pectoralis muscle mass is significantly associated with poor overall survival. This may help to develop more individualized management strategies and optimize longitudinal care for patients.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.133DOI Listing
November 2020

Integrative immunogenomic analysis of gastric cancer dictates novel immunological classification and the functional status of tumor-infiltrating cells.

Clin Transl Immunology 2020 17;9(10):e1194. Epub 2020 Oct 17.

Department of Immunotherapeutics The University of Tokyo Hospital Tokyo Japan.

Objectives: A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer.

Methods: We performed whole-exome sequencing (WES), RNA-Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA-Seq data of 45 patients who received pembrolizumab (Kim . 2018; : 1449-1458) were also analysed.

Results: Immunogram analysis of cancer-immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T-cell signature, while cold tumors had an exclusion signature. tumor-infiltrating lymphocyte analysis documented T-cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T-cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti-PD-1 therapy and have the potential to be a biomarker for the treatment of gastric cancer.

Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different.
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http://dx.doi.org/10.1002/cti2.1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568758PMC
October 2020

Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.

J Immunother Cancer 2020 09;8(2)

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Background: Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.

Methods: NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×10) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.

Results: Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0-479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%-20.4%) and 68.0% (46.5%-85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.

Conclusions: Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.

Trial Registration Number: UMIN000006128.
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http://dx.doi.org/10.1136/jitc-2020-001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511646PMC
September 2020

Prognostic significance of low pectoralis muscle mass on preoperative chest computed tomography in localized non-small cell lung cancer after curative-intent surgery.

Lung Cancer 2020 09 7;147:71-76. Epub 2020 Jul 7.

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Objectives: The impact of sarcopenia on the outcome in patients following resection of non-small cell lung cancer is yet to be fully determined. This study aimed to evaluate the clinical utility of a computed tomography-based pectoralis muscle assessment, which reflects sarcopenia, to predict the risk of postoperative outcomes.

Materials And Methods: This retrospective study included 347 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. The pectoralis muscle index (pectoralis muscle area/body mass index) was assessed at the level of the fourth thoracic vertebra on chest axial images. The primary outcomes were compared between the lowest gender-specific quintile (sarcopenia) and the other quintiles according to the index. The prognostic significance of low pectoralis muscle index was calculated by the Cox proportional hazards regression model. A propensity score matching analysis was performed to adjust the differences in clinical characteristics.

Results: Sixty-nine patients were identified with sarcopenia according to the lowest gender-specific quintile of pectoralis muscle index. Patients with sarcopenia exhibited worse 5-year overall survival rate compared with patients without sarcopenia (64.2 % vs. 86.7 %, P < 0.001). Even in stage I non-small cell lung cancer, the rate of 5-year overall survival in the sarcopenia group was lower than that in the non-sarcopenia group (74.2 % vs. 92.4 %, P = 0.001). Multivariate analysis revealed that low pectoralis muscle index was independently associated with adverse overall survival (hazard ratio: 2.09, 95 % confidence interval: 1.20-3.62, P = 0.009). After propensity score matching, the prognostic impact of sarcopenia based on low pectoralis muscle index was also robust for overall survival (hazard ratio: 3.23, 95 % confidence interval: 1.38-7.60, P = 0.007).

Conclusions: Low pectoralis muscle index was significantly associated with poor long-term outcomes in patients with localized non-small cell lung cancer after curative surgery. This may help assist preoperative risk stratification and longitudinal management after surgery.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.008DOI Listing
September 2020

Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma.

J Immunother Cancer 2020 05;8(1)

Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.

Background: There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.

Methods: A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine and promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.

Results: As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAgHLA) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAgHLA) in HR-deficient HGSC.

Conclusions: Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.
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http://dx.doi.org/10.1136/jitc-2019-000375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254153PMC
May 2020

Different immunological effects of the molecular targeted agents sunitinib, everolimus and temsirolimus in patients with renal cell carcinoma.

Int J Oncol 2020 04 4;56(4):999-1013. Epub 2020 Feb 4.

Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113‑8655, Japan.

Treatment with molecular targeted agents together with immune checkpoint inhibitors will most likely improve the efficacy of current cancer immunotherapy. Because molecular targeted agents not only directly affect cancer cells, but also influence immune cells and modulate the tumor microenvironment, a better understanding of the overall immunological effects of these drugs will contribute to the rational design of combination therapies. Therefore, this study performed extensive immune monitoring of patients' peripheral blood mononuclear cells (PBMCs) to investigate the immunological effects of the molecular targeted agents sunitinib, everolimus and temsirolimus, which have been widely used for the treatment of renal cell carcinoma (RCC). Immunophenotyping and functional analysis of PBMCs revealed that these molecular targeted agents exerted different immunological effects on patients with RCC. Sunitinib decreased the percentage of early‑stage myeloid‑derived suppressor cells (eMDSCs) and increased natural killer cells, but did not affect the phenotypes and effector functions of CD4+ or CD8+ T cells. Everolimus decreased effector regulatory T cells, but also decreased IL‑2‑producing CD4+ T cells and increased dysfunctional CD8+ T cells. Conversely, temsirolimus decreased programmed cell death protein 1+CD8+ T cells and eMDSCs, but increased interferon‑γ and tumor necrosis factor‑α double producers at the same time as decreasing dysfunctional CD8+ T cells, albeit not significantly. In conclusion, although everolimus and temsirolimus are mTOR inhibitors, their effects on overall T‑cell functions are very different. Therefore, although it may increase the risk of immune‑related toxicity, temsirolimus is expected to offer the best outcome when combined with other immunomodulators for the development of cancer immunotherapy.
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http://dx.doi.org/10.3892/ijo.2020.4975DOI Listing
April 2020

Salvage stereotactic body radiotherapy for post-operative oligo-recurrence of non-small cell lung cancer: A single-institution analysis of 59 patients.

Oncol Lett 2020 Apr 17;19(4):2695-2704. Epub 2020 Feb 17.

Department of Radiology, University of Tokyo Hospital, Tokyo 113-8655, Japan.

A standard treatment for patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgery, and subsequently develop local failure or intrathoracic oligo-recurrence, has not yet been established. The present study aimed to assess the feasibility of stereotactic body radiotherapy (SBRT) for this subgroup of patients. Consequently, a retrospective analysis was conducted of patients with NSCLC recurrence who were treated with SBRT, and previously underwent curative surgical resection between October 2011 and October 2016. Post-SBRT survival [overall survival (OS); progression-free survival (PFS); and local control (LC)] and toxicity were analyzed. Prognostic factors for OS were identified using univariate and multivariate analysis. A total of 52 patients and 59 tumors were analyzed. The median follow-up time was 25 months (35 months for surviving patients), and median OS following salvage SBRT was 32 months. The 1- and 3-year OS rates were 84.4 and 67.8%, respectively. 1- and 3-year PFS rates were 80.8 and 58.7%, respectively. Only 4 patients (7.7%) developed local failure. Median LC was 71 months and 1- and 3-year LC rate were 97.9 and 94.9%, respectively. A total of 4 patients experienced grade 3 or higher adverse events (AEs) and two experienced grade 5 AEs (pneumonitis and hemoptysis). Central tumor location and the possibility of re-operation were independent prognostic factors for OS. The present study indicated that post-operative salvage SBRT is a promising therapeutic option for patients with NSCLC with locoregional or intrathoracic oligo-recurrence. We regard toxicity was also acceptable. However, further research is required on the appropriate selection of subjects, and stratification of the analysis by certain risk factors would increase the accuracy of the conclusions.
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http://dx.doi.org/10.3892/ol.2020.11407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068670PMC
April 2020

Clinical Application of Next-generation Sequencing for the Diagnosis of Lung Squamous Cell Carcinoma: Is It Primary or Secondary?

Intern Med 2020 May 12;59(10):1299-1302. Epub 2020 Feb 12.

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Japan.

An 80-year-old man with a history of cutaneous squamous cell carcinoma (SCC) was referred to our department for a solitary lung nodule. The nodule was surgically resected and diagnosed as SCC. Because the lung lesion and a previous skin lesion showed similar histological findings, the origin of the lung tumor was uncertain. Next-generation sequencing using a targeted driver oncogene panel was applied for the further examination. The lung lesion was diagnosed as primary lung SCC, as the two tumors possessed distinct somatic mutations in TP53. Recent advances in clinical sequencing have enabled us to obtain an accurate diagnosis in pathologically challenging cases.
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http://dx.doi.org/10.2169/internalmedicine.3682-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303454PMC
May 2020

[Reexpansion Pulmonary Edema and Atrial Fibrillation after Resection of a Giant Solitary Fibrous Tumor of the Pleura].

Kyobu Geka 2019 Nov;72(12):997-1000

Department of Thoracic Surgery, The University of Tokyo, Tokyo, Japan.

We report a case of giant solitary fibrous tumor( SFT) of the pleura postoperatively complicated with probable reexpansion pulmonary edema and atrial fibrillation. An 85-year-old woman was diagnosed to have a 13 cm sized intrathoracic neoplasm. Upon thoracotomy, the tumor was found to pedunculate from the right lung with no direct invasion to the surrounding structures. Complete resection of the tumor and expansion of the right lung was obtained. Histopathology revealed the tumor was a benign SFT arising from the visceral pleura. An infiltrative shadow in the right lower lung field soon after the surgery suggested a reexpansion pulmonary edema, which eventually recovered within a week. The patient suffered from a refractory atrial fibrillation that led to a congestive heart failure requiring an intensive medical treatment. It is emphasized that thoracic surgeons should be aware of these postoperative complications in treating such a case like this.
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November 2019

Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti-Programmed Cell Death-1 Therapy in NSCLC.

J Thorac Oncol 2019 12 23;14(12):2071-2083. Epub 2019 Aug 23.

Department of Immuno-Oncology, Kawasaki Medical School, Okayama, Japan. Electronic address:

Introduction: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits.

Methods: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing.

Results: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8 T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004).

Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.
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http://dx.doi.org/10.1016/j.jtho.2019.08.008DOI Listing
December 2019

Impact of Previous Malignancy on Outcome in Surgically Resected Non-Small Cell Lung Cancer.

Ann Thorac Surg 2019 12 14;108(6):1671-1677. Epub 2019 Aug 14.

The University of Tokyo, Tokyo, Japan.

Background: Patients with lung cancer with a history of treatment often undergo curative surgical resection. However, the impact of previous cancer treatment on the outcome of lung cancer remains unclear.

Methods: We conducted a retrospective study of patients who underwent curative resection for non-small cell lung cancer between 1998 and 2011. We collected clinicopathologic data and patients were divided into groups by previous history of cancer treatment. Comparisons between groups, estimation of survival rates, and multivariate analyses were performed. Propensity score matching was used to create cohorts with reduced bias.

Results: Of 878 patients, 196 (22.3%) had previous extrathoracic malignancies, and stage I lung cancer was more frequent in this group (P < .001). In multivariate analysis of the whole cohort, older patients, men, non-adenocarcinoma histologic type, more advanced pathologic stage of lung cancer, interstitial pneumonia, and previous extrathoracic malignancies were associated with appreciably worse prognosis. When propensity score matched cohorts were compared, prognosis was significantly worse in patients with previous extrathoracic malignancies than patients without (5-year survival rates, 75.3% vs 82.7%; P = .009), although recurrence was not frequently seen (5-year recurrence-free rates, 78.7% vs 83.0%; P = .491).

Conclusions: Because treatment history of extrathoracic malignancy was not associated with postsurgical lung cancer recurrence, proposing curative resection could be justifiable if the previous cancer is deemed cured or controlled. However, the results showing that patients with previous cancer history have a worse survival rate than patients without should be taken into account when curative surgery is considered.
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http://dx.doi.org/10.1016/j.athoracsur.2019.06.074DOI Listing
December 2019

Differences Between Patients With Idiopathic Pleuroparenchymal Fibroelastosis and Those With Other Types of Idiopathic Interstitial Pneumonia in Candidates for Lung Transplants.

Transplant Proc 2019 Jul - Aug;51(6):2014-2021. Epub 2019 Jul 11.

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Introduction: The prognostic implications of having patients with idiopathic pleuroparenchymal fibroelastosis (IPPFE) on lung transplantation waiting lists have been unclear. In Japan, where a severe shortage of brain-dead donors remains a major limitation for organ transplantation, it is particularly important to predict the prognoses of patients when they are listed for transplantation. The purpose of this study was to investigate the characteristics of lung transplantation candidates with IPPFE and the influence of those characteristics on prognosis.

Methods: This was a retrospective review of 29 consecutive adult lung transplant candidates with idiopathic interstitial pneumonia between January 2014 and April 2018.

Results: Eight patients with IPPFE and 21 with other types of idiopathic interstitial pneumonia were included. Body mass index (median 17.1 kg/m vs 23.5 kg/m, P < .01) and ratio of anteroposterior to transverse diameter of the thoracic cage were significantly lower (0.530 vs 0.583, P = .02) in the IPPFE group. Patients with a body mass index <20.0 kg/m (P = .02), 6-minute walk distance <250.0 m (P < .01), ratio of PaO to fraction of inspiratory oxygen <300.0 mm Hg (P < .01), and an inability to perform the diffusing capacity of carbon monoxide test (P < .01) had significantly shorter survival times in the other idiopathic interstitial pneumonia, but not in the IPPFE, group. Some patients with IPPFE survived for long enough to undergo transplantation.

Conclusions: Patients with IPPFE waiting for transplantation have some distinctive characteristics and should be retained on waiting lists to receive transplants.
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http://dx.doi.org/10.1016/j.transproceed.2019.04.035DOI Listing
November 2019

Use of electromagnetic navigation bronchoscopy in virtual-assisted lung mapping: the effect of on-site adjustment.

Gen Thorac Cardiovasc Surg 2019 Dec 16;67(12):1062-1069. Epub 2019 May 16.

Department of Thoracic Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Objective: Conventional virtual-assisted lung mapping (VAL-MAP), also termed multi-spot preoperative bronchoscopic lung marking, necessitates post-mapping computed tomography (CT) to confirm the locations of dye markings. We hypothesized that electromagnetic navigation bronchoscopy (ENB) simplifies VAL-MAP by omitting post-mapping CT.

Methods: Under general anesthesia, real-time navigation bronchoscopy was conducted using ENB to reach a site as close to the planned location as possible, and indigo carmine was injected. Initially, surgery was then performed (no-adjustment group; 5 lesions of 3 patients). Later, on-site adjustment was added before surgery (adjustment group; 4 lesions of 4 patients), in which the locational information of ENB was transferred to a radiology workstation to construct an adjusted three-dimensional image. The accuracy of each predicted marking location was graded based on intraoperative observation. After the analysis, 19 patients with 21 lesions underwent ENB VAL-MAP with on-site adjustment (practice set) to evaluate the surgical outcomes.

Results: The accuracy of the predicted marking location was significantly higher in the adjustment than no-adjustment group (4.7 ± 0.7 vs. 3.4 ± 1.2, respectively; P = 0.01), especially among the markings for which the bronchoscope did not reach the planned location (4.5 ± 0.8 vs. 2.6 ± 0.5, respectively; P = 0.004). In the practice set, the lung map quality was satisfactory and the resection outcome was successful with a sufficient macroscopic resection margin in 19/21 lesions (90.5%).

Conclusion: The ENB VAL-MAP quality was improved by adding on-site adjustment, achieving clinical outcomes similar to conventional VAL-MAP. The logistic challenge of post-mapping CT in conventional VAL-MAP can be partially overcome by ENB VAL-MAP with on-site adjustment.
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http://dx.doi.org/10.1007/s11748-019-01137-zDOI Listing
December 2019

Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma.

Cancer Immunol Res 2019 07 14;7(7):1148-1161. Epub 2019 May 14.

Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II-IV glioma patients (glioblastoma, IDH-wild-type, = 8; grade II-III astrocytoma, IDH-mutant, = 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the "neoantigen expression ratio," decreased significantly at recurrence ( = 0.003). This phenomenon was particularly pronounced for "high-affinity," "clonal," and "passenger gene-derived" neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0599DOI Listing
July 2019

Competing Risk Analysis in Lung Cancer Patients Over 80 Years Old Undergoing Surgery.

World J Surg 2019 07;43(7):1857-1866

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: This study aimed to analyze cause-specific mortality in lung cancer patients over 80 years old undergoing surgery.

Methods: This retrospective, multi-institutional analysis included patients aged ≥ 80 years who underwent radical surgery for primary lung cancer from January 1998 to December 2015. Preoperative clinical data, surgical results, survival, and cause of death were evaluated. Competing risk analysis for cause-specific mortality was performed.

Results: Of the 337 patients (median age 82 years) enrolled and analyzed, 68.1% were male. There were 52 and 44 cancer-specific and non-cancer-specific deaths, respectively. On competing risk regression analysis, non-cancer-specific deaths were significantly associated with male sex (hazard ratio [HR]: 3.06, 95% confidence interval [CI]: 1.02-9.12, p = 0.046), coronary artery disease (HR: 2.49, 95% CI: 2.49 [1.14-5.47], p = 0.02), interstitial pneumonia (HR: 3.58, 95% CI: 1.73-7.40, p < 0.001), and pathological stage III (HR: 3.83, 95% CI: 1.44-10.13, p = 0.007). In contrast, cancer-specific deaths were significantly associated with limited resection (HR: 1.99, 95% CI: 1.02-3.89, p = 0.04) and pathological stage III (HR: 3.13, 95% CI: 1.44-6.80, p = 0.004). The 5-year cumulative incidences of lung cancer-specific and non-cancer-specific deaths were 18.0% and 15.9%, respectively.

Conclusions: Prognostic factors for non-cancer-specific death were different from those of cancer-specific death, except for pathological stage. Each prognostic factor should be considered when deciding surgical indication and procedure and monitoring for pulmonary events during outpatient follow-up.
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http://dx.doi.org/10.1007/s00268-019-04982-4DOI Listing
July 2019

Low truncal muscle area on chest computed tomography: a poor prognostic factor for the cure of early-stage non-small-cell lung cancer†.

Eur J Cardiothorac Surg 2019 Mar;55(3):414-420

Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Objectives: Depletion in skeletal muscle is closely associated with limited physical ability and high mortality. In this study, we evaluated the prognostic significance of skeletal muscle depletion in patients with early-stage non-small-cell lung cancer.

Methods: A retrospective analysis of patients with pathological stages I-II lung cancer, who underwent curative resection between 2009 and 2013, was conducted. The truncal muscle index (TMI) (area/height2) at the first lumbar vertebral level was measured by preoperative axial computed tomography. Overall survival and recurrence-free survival were compared between the lowest gender-specific quartile of the TMI and the other quartiles.

Results: A total of 314 subjects were included in the study. The cumulative 5-year recurrence-free and overall survival rates were significantly shorter in patients with lower TMIs (69% vs 83.5%, P = 0.028; 64.8% vs 80.1%, P = 0.003, respectively). In multivariable models, the TMI was identified as an independent prognostic factor for overall survival (P =  0.017, hazard ratio 1.84, 95% confidence interval 1.12-3.05), after adjusting for age, gender, preoperative serum albumin, carcinoembryonic antigen, neutrophil to lymphocyte ratio and pathological stage.

Conclusions: A low preoperative TMI was associated with a poor postoperative outcome in patients with early-stage non-small-cell lung cancer. This factor may be included in the preoperative assessment of patients, for whom surgical intervention is considered.
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http://dx.doi.org/10.1093/ejcts/ezy324DOI Listing
March 2019

High CCR4 expression in the tumor microenvironment is a poor prognostic indicator in lung adenocarcinoma.

J Thorac Dis 2018 Aug;10(8):4741-4750

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Clinical trials of anti-CCR4 antibody for solid cancers with or without other immune-modulating agents including immune checkpoint blockade therapy are currently underway. However, little is known about the roles of CCR4 lymphocytes and their prognostic impact in lung cancer. We hypothesized that high CCR4 expression in the tumor microenvironment would be associated with a poor prognosis and would act as a biomarker in lung adenocarcinoma.

Methods: First, the prognostic impact of gene expression was explored using pooled data from public transcriptomic databases with online survival analysis software. Second, tissue microarrays (TMAs) were constructed from resected lung adenocarcinoma specimens from tumors up to 3 cm in size. The density of CCR4 lymphocytes infiltrating the tumor was then assessed by immunohistochemistry and related to survival. Confounding factors were controlled for by multivariate analysis using the Cox proportional hazards model.

Results: Higher than median expression of the gene was identified as an independent poor prognostic factor for overall survival (OS) by multivariate analysis of 720 lung adenocarcinoma patients in the public databases [HR =1.55 (95% CI: 1.03-2.35), P=0.037]. Consistent with this, high CCR4 tumor-infiltrating lymphocyte (TIL) density was found to be an independent poor prognostic factor for both OS [HR =2.24 (1.01-5.34), P=0.049] and recurrence-free survival (RFS) [HR =2.20 (1.16-4.39), P=0.017] in the patients from whom TMA were obtained (n=180). Age, male gender, predominantly non-lepidic histological subtype, nodal involvement, and low CD8 TIL density were also independent poor prognostic factors. However, gene expression and Foxp3 lymphocyte infiltration did not possess any prognostic value in either study.

Conclusions: High CCR4 expression in the tumor microenvironment may be a poor prognostic factor in lung adenocarcinoma. Patients with high CCR4 lymphocyte infiltration may have a poor prognosis and thus be suitable candidates for clinical trials of anti-CCR4 antibody treatment.
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http://dx.doi.org/10.21037/jtd.2018.07.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129889PMC
August 2018

Risk factors for postoperative complications and long-term survival in lung cancer patients older than 80 years.

Eur J Cardiothorac Surg 2018 05;53(5):980-986

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Objectives: The number of octogenarian lung cancer patients undergoing radical surgery has been increasing recently. However, knowledge regarding the risk factors for postoperative complications and reliable predictive factors for long-term survival is limited. This study aimed to investigate the risk factors of postoperative complications, and reliable prognostic factors, in lung cancer patients older than 80 years.

Methods: Lung cancer patients aged 80 years or older who underwent radical surgery were retrospectively studied; a multi-institutional analysis was conducted from January 1998 to December 2015. Preoperative and postoperative clinical data, including age, gender, smoking history, body mass index, respiratory function, Charlson Comorbidity Index, Glasgow Prognostic Score, surgical procedure, cancer histology, clinical and pathological stage, surgical result and survival time, were collected.

Results: A total of 337 patients, comprising 216 (64.1%) men and 121 (35.9%) women were enrolled. The median age was 82 (range 80-92) years. Of the 337 patients, 205 (60.8%) had preoperative comorbidities. Postoperative complications were observed in 119 (35.3%) patients; postoperative mortalities occurred in 6 (1.8%) patients. Univariate and multivariate analyses showed that male gender (P = 0.01) and operation time (P = 0.047) were associated with postoperative complications; in contrast, pathological Stage III (P < 0.001), male gender (P = 0.01), Charlson Comorbidity Index ≥2 (P = 0.03) and Glasgow Prognostic Score = 1/2 (P = 0.04) were independent prognostic factors for overall survival.

Conclusions: The risk factors for postoperative complications (male gender and operation time) and the predictive factors affecting long-term survival (male gender, Charlson Comorbidity Index, Glasgow Prognostic Score and P-stage) should be taken into account for the effective management of patients older than 80 years with lung cancer, undergoing surgery.
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http://dx.doi.org/10.1093/ejcts/ezx437DOI Listing
May 2018

NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer.

Biochem Biophys Res Commun 2018 01 15;495(2):2058-2065. Epub 2017 Dec 15.

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan.

To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.
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http://dx.doi.org/10.1016/j.bbrc.2017.12.083DOI Listing
January 2018

The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma.

Oncoimmunology 2017;6(8):e1338996. Epub 2017 Jun 16.

Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.

Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation ("neoAg frequency") did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC ( = 0.032), especially at stage I-II ( = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression ( = 0.036, = 0.026, and = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression ( = 0.0064, = 0.017, = 0.033 and = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments.
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http://dx.doi.org/10.1080/2162402X.2017.1338996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593715PMC
June 2017

An Immunogram for the Cancer-Immunity Cycle: Towards Personalized Immunotherapy of Lung Cancer.

J Thorac Oncol 2017 05 11;12(5):791-803. Epub 2017 Jan 11.

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of antitumor immunity as a dynamic spatiotemporal process is required for each individual patient. To this end, we developed an immunogram for the cancer-immunity cycle by using next-generation sequencing.

Methods: Whole exome sequencing and RNA sequencing were performed in 20 patients with NSCLC (12 with adenocarcinoma, seven with squamous cell carcinoma, and one with large cell neuroendocrine carcinoma). Mutated neoantigens and cancer germline antigens expressed in the tumor were assessed for predicted binding to patients' human leukocyte antigen molecules. The expression of genes related to cancer immunity was assessed and normalized to construct a radar chart composed of eight axes reflecting seven steps in the cancer-immunity cycle.

Results: Three immunogram patterns were observed in patients with lung cancer: T-cell-rich, T-cell-poor, and intermediate. The T-cell-rich pattern was characterized by gene signatures of abundant T cells, regulatory T cells, myeloid-derived suppressor cells, checkpoint molecules, and immune-inhibitory molecules in the tumor, suggesting the presence of antitumor immunity dampened by an immunosuppressive microenvironment. The T-cell-poor phenotype reflected lack of antitumor immunity, inadequate dendritic cell activation, and insufficient antigen presentation in the tumor. Immunograms for both the patients with adenocarcinoma and the patients with nonadenocarcinoma tumors included both T-cell-rich and T-cell-poor phenotypes, suggesting that histologic type does not necessarily reflect the cancer immunity status of the tumor.

Conclusions: The patient-specific landscape of the tumor microenvironment can be appreciated by using immunograms as integrated biomarkers, which may thus become a valuable resource for optimal personalized immunotherapy.
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http://dx.doi.org/10.1016/j.jtho.2017.01.005DOI Listing
May 2017

Prediction and prioritization of neoantigens: integration of RNA sequencing data with whole-exome sequencing.

Cancer Sci 2017 Feb 9;108(2):170-177. Epub 2017 Feb 9.

Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.

The importance of neoantigens for cancer immunity is now well-acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus reported neoantigen loads vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole-exome sequencing and RNA sequencing (RNA-Seq) of four non-small-cell lung cancer patients was carried out. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped ≥1), resulting in 124 candidate neoantigens (strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was undertaken; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (strategy III). Sequence information was extracted from RNA-Seq to confirm the presence of mutated mRNA. Variant allele frequencies ≥0.04 in RNA-Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (strategy IV). Without additional amplicon sequencing of cDNA, strategy IV was comparable to strategy III. We therefore propose strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. It is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied.
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http://dx.doi.org/10.1111/cas.13131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329159PMC
February 2017

[Neoantigens and Whole-Exome Sequencing].

Gan To Kagaku Ryoho 2016 Jul;43(7):791-7

Dept. of Thoracic Surgery, The University of Tokyo Hospital.

During cancer progression, many somatic mutations accumulate in cancer cells. Antigens derived from tumor-specific mutated genes are primary sources ofneoantigens in cancer immunology. As compared with non-mutated self-antigens, neoantigens are thought to have higher antigenicity, and are expected to be ideal targets for tumor rejection. Recent studies demonstrate that T cells recognize neoantigens and elicit immune responses against tumor cells. The importance ofneoantigens in cancer immunity has been well acknowledged, and development ofneoantigen -targeted cancer immunotherapy is in progress worldwide. High-throughput detection ofsomatic mutations by whole-exome sequencing is combined with computational algorithm for MHC-peptide binding affinity to predict potential neoantigens. After the antigenicity is confirmed by immunological assays, personalized vaccines targeting the identified neoantigens will be generated with peptides, dendritic cells, or RNAs. Such neoantigen-targeted cancer vaccines are being developed for practical use. In fact, several clinical trials have already been initiated in Europe and the US.
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July 2016

Advances in personalized cancer immunotherapy.

Breast Cancer 2017 Jan 21;24(1):16-24. Epub 2016 Mar 21.

Department of Surgery, Kansai Medical University, Hirakata, Japan.

There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the "Cancer-Immunity Cycle") is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the "Cancer-Immunity Cycle". Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.
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http://dx.doi.org/10.1007/s12282-016-0688-1DOI Listing
January 2017

Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma.

Cancer Immunol Res 2016 05 15;4(5):463-71. Epub 2016 Mar 15.

Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.

Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or β2-microglobulin(β2M) revealed that an A-neo(hi)/HLA-A(hi) or ABC-neo(hi)/β2M(hi) phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. Cancer Immunol Res; 4(5); 463-71. ©2016 AACR.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0225DOI Listing
May 2016

Identification of Individual Cancer-Specific Somatic Mutations for Neoantigen-Based Immunotherapy of Lung Cancer.

J Thorac Oncol 2016 Mar 29;11(3):324-33. Epub 2015 Dec 29.

Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: Two strategies for selecting neoantigens as targets for non-small cell lung cancer vaccines were compared: (1) an "off-the-shelf" approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole-exome sequencing data on each patient's tumor.

Methods: The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole-exome sequencing of the patient's own samples.

Results: The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off-the-shelf pNeoAgs for each adenocarcinoma (range 5-13) and 9 (range 5-12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole-exome sequencing (range 33-899) in adenocarcinoma and 164.5 (range 26-232) in SCC. This resulted in a median of 46 pNeoAgs (range 13-659) for adenocarcinoma and 95.5 (range 10-145) for SCC in the personalized set. We found that only one or two off-the-shelf pNeoAgs were included in the set of personalized pNeoAgs-and then in only three patients, with no overlap seen in the remaining 12 patients.

Conclusions: Use of an off-the-shelf pipeline is feasible but may not be satisfactory for most patients with non-small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen-targeted cancer immunotherapies.
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http://dx.doi.org/10.1016/j.jtho.2015.11.006DOI Listing
March 2016

Life-Threatening Postpneumonectomy Syndrome Complicated with Right Aortic Arch after Left Pneumonectomy.

Case Rep Surg 2015 28;2015:768067. Epub 2015 May 28.

Department of Thoracic Surgery, JR Tokyo General Hospital, 2-1-3 Yoyogi, Shibuya-ku, Tokyo 151-8528, Japan.

A 54-year-old man with right aortic arch underwent left lower lobectomy and lingular segmentectomy, followed by complete pneumonectomy, for refractory nontuberculous mycobacterial infection. Three months after the pneumonectomy, he developed acute respiratory distress. Computed tomography showed an excessive mediastinal shift with an extremely narrowed bronchus intermedius and right lower bronchus compressed between the right pulmonary artery and the right descending aorta. Soon after the nearly obstructed bronchus intermedius was observed by bronchoscopy, he began to exhibit frequent hypoxic attacks, perhaps due to mucosal edema. Emergent surgical repositioning of the mediastinum and decompression of the bronchus was indicated. After complete adhesiolysis of the left thoracic cavity was performed, to maintain the proper mediastinal position, considering the emergent setting, an open wound thoracostomy was created and piles of gauze were inserted, mildly compressing the heart and the mediastinum to the right side. Thoracoplasty was performed three months later, and he was eventually discharged without any dressings needed. Mediastinal repositioning under thoracostomy should be avoided in elective cases because of its extremely high invasiveness. However, in the case of life-threatening postpneumonectomy syndrome in an emergent setting, mediastinal repositioning under thoracostomy may be an option to save life, which every thoracic surgeon could attempt.
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http://dx.doi.org/10.1155/2015/768067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464006PMC
June 2015

Opsoclonus-myoclonus syndrome associated with non-small cell lung cancer.

Asian Cardiovasc Thorac Ann 2015 Nov 1;23(9):1113-5. Epub 2015 Jun 1.

Department of Thoracic Surgery, JR Tokyo General Hospital, Tokyo, Japan.

A 68-year-old man developed progressive vertigo, saccadic eye movements, and tremors. Computed tomography showed multiple lung nodules. Surgery was performed and the pathological diagnosis was large cell neuroendocrine carcinoma in the left upper lobe with ipsilobar metastases, and adenocarcinoma in the left lower lobe. The neurological symptoms resolved dramatically after complete resection of the tumors. Opsoclonus-myoclonus syndrome associated with non-small-cell lung carcinoma is extremely rare. Surgery should not be delayed if a complete resection is expected.
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http://dx.doi.org/10.1177/0218492315587994DOI Listing
November 2015

Imaging of thoracic duct in a patient with right-sided descending aorta.

Ann Thorac Surg 2015 Feb;99(2):713

Department of Thoracic Surgery, JR Tokyo General Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.athoracsur.2014.10.019DOI Listing
February 2015
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