After working as a medical doctor specializing in respiratory medicine for 13 years and performing mainly clinical studies and some translational research during graduate courses, I wanted to perform basic science research during postdoctoral training in the USA. I worked as a postdoctoral fellow in Dr. David Paul Carbone’s laboratory from May 2015 to January 2019. Dr. Carbone is one of the leading physician scientists who was an erstwhile president of the International Association for the Study of Lung Cancer (IASLC). In his lab, basic and translational studies are conducted to improve the outcome of the patients with advanced thoracic malignancies. Professor Takahashi, who is the head of the Department of Respiratory Medicine at Juntendo University, supported me in my postgraduate training in Dr. Carbone’s lab.
In this article, I have summarized the studies that I did with Dr. Carbone. I have written and published one review article titled “Predictive Markers for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Lung Cancer,” one case report titled “Lung Cancer Patients with Germline Mutations Detected by Next-Generation Sequencing and/or Liquid Biopsy, ”and two research articles titled “Surrogate endpoints for overall survival in advanced non-small cell lung cancer patients treated with anti-PD-1/PD-L1 therapy” and “The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non-Small Cell Lung Cancer.”
Extranodal natural killer (NK)/ T-cell lymphoma, nasal type (ENKL), is an aggressive lymphoma that rapidly disseminates to various sites, resulting in a very poor prognosis. Antigen-specific cytotoxic T lymphocyte (CTL) therapy to target and kill tumor cells induces durable remissions in selected malignancies such as melanomas. As ENKL is invariably infected by Epstein-Barr virus (EBV), this lymphoma is a good target of CTL therapy. However, for most tumors, clinical utility is limited because CTL are continuously exposed to viral or tumor antigens and become exhausted. Exploiting fully rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific CTL would be a powerful approach. After we reported the robust antitumor effect and survival advantage of rejuvenated CTL against EBV-infected tumor, we started a preclinical study utilizing this novel immunotherapy to EBV-associated lymphoma. We believe that iPSC-derived rejuvenated CTL therapy targeting EBV will provide a promising salvage therapy for ENKL.
Objective: Renal cell carcinoma (RCC) accounts for 3-5% of all cancers, and approximately 15% of these are metastatic at diagnosis. Treatment of metastatic RCC often relies on molecular targeted drug therapy, which has become the mainstream approach. Recently, the mTOR inhibitors are one typical molecular targeting drug for metastatic RCC. The mTOR is a type of serine/threonine kinase from the phosphatidylinositol kinase-related kinase family. Activation of its pathway has been found to enhance cancer cell growth, apoptosis inhibition and angiogenesis. The aim of this study was to determine the relevance of mTOR expression and activation and to analyze their putative role as a biomarker for systemic treatment in RCC.
Materials: We conducted a clinicopathological verification by performing an immunostaining of mTOR and p-mTOR from RCC specimens from 210 patients who underwent nephrectomy or partial nephrectomy at the Jikei University Hospital following RCC diagnosis.
Results: The mTOR and p-mTOR were expressed mainly in the cytoplasm and cell membrane in 21.1% and 35.4% of all RCC specimens, respectively. Our findings showed no statistically significant difference in terms of individual clinical features, such as gender, histological type, tumor diameter, or prognosis. The p-mTOR expression tended to suggest a poor prognosis but did not show a statistically significant difference. As for RCC subtype, 21% of clear cell RCC showed mTOR expression, and papillary RCC had high mTOR expression frequency (71%), whereas chromophobe RCC had relatively low frequency (8%).
Conclusions: As p-mTOR expression tended to suggest a poor prognosis, further analyses of the expression of the mTOR signaling pathway might contribute to a precision medicine for advanced RCC.
Objective: Gender differences in therapeutic and side effects of anticancer drugs have been reported. In our previous study with a small sample size, we reported that female patients are significantly more allergic than male allergic (Alg) patients to oxaliplatin (L-OHP), a platinum-based anticancer drug (platinum compound). On the other hand, there are no studies showing significant gender differences in drug allergy to non-anticancer drugs. And the presence of gender differences in drug allergy to anticancer drugs has not been established. In addition, there are studies showing an increase in peripheral white blood cell (WBC) count after Alg diseases and some drug allergy. However, there have been no studies on fluctuation of WBC count and blood cell fractionation in drug allergy to anticancer drugs. Therefore, in this study, with a larger sample size, we examined gender differences in drug allergy to anticancer drugs and fluctuation of WBC count and blood cell fractionation during Alg reactions.
Materials: Between April 2016 and March 2019, 1,090 patients who were treated with four platinum compounds were retrospectively analyzed.Methods: Data obtained from the peripheral blood samples collected from each patient was used to determine WBC count.
Results: A total of 35 patients were found to be allergic. The overall results for all platinum compounds showed a higher incidence of drug allergy in female patients than in male patients (p=0.049). The reactions were more pronounced in female patients receiving carboplatin (CBDCA)(p=0.034). In the Alg group, WBC count after Alg reactions was significantly higher (no statistically) and the percentage of neutrophils significantly increased (p=0.024), whereas the percentage of monocytes was significantly decreased (p=0.024). There were no gender differences in the incidence of leukocytosis before Alg reactions. However, the incidence of leukocytosis after Alg reactions was significantly higher in female patients than in male patients (p=0.031). Additionally, fluctuation in the percentage of blood cells, such as an increase in neutrophils (p=0.006) and a decrease in monocytes (p=0.023), were more prominent in female patients than in male patients. However, there was no statistically significant gender difference in the percentage of lymphocytes.
Conclusions: This study revealed the possibility of gender differences in drug allergy to anticancer drugs including platinum compounds. Furthermore, this study showed new findings on fluctuation of WBC count and blood cell fractionation after Alg reactions.
Objective: To establish a Japanese version of the Athlete Burnout Questionnaire (ABQ) - an internationally renowned standard assessment tool for athlete burnout (Study 1) - and to determine the association of athlete burnout with depressive states using this questionnaire (Study 2).
Methods: Participants in Study 1 were 516 Japanese university athletes (M=19.9, SD=1.29) who played 13 different sports. We verified the test-retest reliability, internal consistency, and construct validity of the Athlete Burnout Questionnaire-Japanese version (ABQ-J). We also assessed its concurrent validity in comparison with the Athlete Burnout Inventory (ABI), which is based on a psychopathological model of depression within Japanese culture. Participants in Study 2 were 373 different Japanese university athletes (M=20.01, SD=1.27) from 21 sports. Severity of participants’ depressive states was measured using the Zung Self-Rating Depression Scale.
Results: In Study 1, no items exhibited a floor or ceiling effect. The ABQ-J showed high internal consistency and a three-factor structure, similar to the original questionnaire. A confirmatory factor analysis indicated that the ABQ-J had a good model fit and the test-retest reliability coefficients were satisfactory. In Study 2, a positive correlation was found between athlete burnout and depressive states. Individuals with severe athlete burnout faced 3-4 times the risk of moderate-to-severe depressive states than individuals without severe athlete burnout.
Conclusions: The ABQ-J effectively measures burnout among Japanese university athletes. Cross-sectional evidence suggests a positive association between athlete burnout and severity of depressive states or depressive disorder.
As a Bordetella pertussis gene test, the loop-mediated isothermal amplification (LAMP) method has become widely used for the diagnosis in clinical practice. The diagnostic usefulness of the LAMP method was investigated in 11 infant patients and their 12 families retrospectively, who were judged as having intrafamilial pertussis infection.
Eleven pediatric patients (Index cases) and their 26 family members (10 families) who developed cough and characteristic symptoms of pertussis, that persisted for 2 weeks or longer and were clinically diagnosed as having pertussis between May 2010 and February 2013, 37 patients in total, were investigated.
Thirty-three of 37 patients were definitively diagnosed with pertussis and 31 of them (83.4%) were LAMP-positive. Culture and LAMP tests were simultaneously performed in 10 families (26 patients). Among these families, all infants (11 patients) were LAMP-positive, 8 of their siblings, and 10 parents were LAMP-positive, and the positive rate was higher than the culture positive rate. Since LAMP positivity persists for a relatively prolonged period after disease onset, adult patients with atypical symptoms can be diagnosed and the source of pertussis infection in the family can be clarified. The disease through silent transmission may become aggravated when infants have received DTP vaccine. The positive rate on the LAMP test for Bordetella pertussis was higher than that on the culture test, after 4 weeks or more after the onset.
It should be examined for the asymptomatic family members in the case of the pertussis onset. Because pertussis infection cannot become clear only for a symptom. Additional vaccination of pertussis for adult is necessary even though vaccination has been completed in infancy.
The morbidity rate of pancreatic cancer has increased globally over the last 50 years and it is the most difficult cancer to cure. However, treatments for pancreatic cancer are rapidly advancing. Combination chemotherapy using gemcitabine and nab-paclitaxel (GnP) or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard first-line therapy. However, small molecule agents may cause side-effects, such as myelosuppression. Immunotherapy for cancer has attracted attention and was recognized as the most important scientific advance in 2013 by the journal Science. Immunotherapies include effector cell therapy, treatment via immune checkpoint inhibitors, and cancer vaccines. Currently, only immune checkpoint inhibitors are used for treating pancreatic cancer. Pembrolizumab is an immune checkpoint inhibitor that can be used to treat pancreatic cancer and is indicated for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) solid tumors. MSI-H generates neoantigens, the expression of which increases the number of tumor-infiltrating lymphocytes. Through this mechanism, pembrolizumab can significantly improve the clinical condition of patients. However, MSI-H is present in only 2% of pancreatic cancers, such that 98 out of 100 patients receive no benefit from pembrolizumab. IL-13Rα2 is a cancer-testis antigen targeted by the immunotoxin, IL-13 (Pseudomonas exotoxin). A total of 70% of pancreatic cancers strongly express IL-13Rα2, and IL-13PE shows anti-cancer effects in orthotopic mouse models. Clinical trials of IL-13PE, for the treatment of glioblastoma multiforme and adrenocortical carcinoma, are currently being performed. Immunotherapy will likely emerge as the fourth pillar of cancer treatment, along with surgery, chemotherapy, and radiation therapy.