Miyagi Cancer Center Research Articles

External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed From a Hospital-Based Administrative Database.

Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.

Morphometric analysis of nuclear shape irregularity as a novel predictor of programmed death-ligand 1 expression in lung squamous cell carcinoma.

Immune checkpoint inhibitor (ICI) therapy has been established as one of the key treatment strategies for lung squamous cell carcinoma (LUSQ). The status of programmed death-ligand 1 (PD-L1) in tumor cells and/or immune cells using immunohistochemistry has been primarily used as a surrogate marker for determining ICI treatment; however, when the tissues to be examined are small, false-negative results could be unavoidable due to the heterogeneity of PD-L1 immunoreactivity. To overcome this practical limitation, we attempted to explore the status of nuclear atypia evaluated using morphometry as a potential predictor of PD-L1 status in LUSQ. We correlated the parameters related to nuclear atypia with PD-L1 status using two different cohorts of LUSQ patients (95 cases from The Cancer Genome Atlas database and 30 cases from the Miyagi Cancer Center). Furthermore, we studied the gene mutation status to elucidate the genetic profile of PD-L1 predictable cases. The results revealed that nuclear atypia, especially morphometric parameters related to nuclear shape irregularity, including aspect ratio, circularity, roundness, and solidity, were all significantly associated with PD-L1 status. Additionally, LUSQ cases with high PD-L1 expression and pronounced nuclear atypia were significantly associated with C10orf71 and COL14A1 mutations compared with those with low PD-L1 expression and mild nuclear atypia. We demonstrated for the first time that nuclear shape irregularity could represent a novel predictor of PD-L1 expression in LUSQ. Including the morphometric parameters related to nuclear atypia in conjunction with PD-L1 status could help determine an effective ICI therapeutic strategy; however, further investigation is required.

Enhanced recovery after surgery program involving preoperative dexamethasone administration for head and neck surgery with free tissue transfer reconstruction: Single-center prospective observational study

BackgroundThere are few reports on Enhanced Recovery After Surgery (ERAS)-based perioperative management following head and neck surgery with free tissue transfer reconstruction (HNS-FTTR). Here, we prospectively evaluated our ERAS program involving preoperative glucocorticoid administration in HNS-FTTR. MethodsThis prospective study included 60 patients who underwent HNS-FTTR at the Miyagi Cancer Center from June 2017 to December 2018. Their treatment plan included receiving perioperative management in accordance with our head and neck ERAS program. Major outcomes of hospitalization periods, early mobilization, early enteral nutrition, and patient satisfaction were assessed, and blood date and vital signs were compared with control patients who underwent HNS-FTTR from January 2014 to September 2016 at our institution before ERAS was implemented. ResultsThe duration of hospital stay and the duration until completion of the discharge criteria was a median of 25 days and 17 days, respectively. Early mobilization was achieved in 86.0% of the patients at postoperative-day (POD)1 and 96.5% at POD2. Enteral nutrition was started in 80.1% at POD1 and 100% at POD2. Postoperative pain was controlled at mean VAS scores of 1.51–3.13. Clavien–Dindo grade II or higher postoperative complications were evident in 27.6% of the patients. The mean QOR40 score was 179.6 preoperatively, 146.1 at POD3, and 167.8 at POD7. Compared with the control group, there were significantly lower C-reactive protein levels, higher albumin levels, a lower body temperature, a lower neutrophil-to-lymphocyte ratio, less body weight fluctuation, and fewer incidences of decreased blood pressure in the ERAS group. ConclusionPatients who underwent HNS-FTTR with ERAS-based perioperative management achieved early mobilization, early enteral nutrition, favorable pain control, remarkable recovery of patient satisfaction at POD7, and there was evidence of better hemodynamic stability and less inflammatory response compared with control patients.

BEX2 Suppresses Mitochondrial Activity and Is Required for Dormant Cancer Stem Cell Maintenance in Intrahepatic Cholangiocarcinoma

Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma. Funding Statement: This research was supported in part by the Biomedical Research Core of Tohoku University Graduate School of Medicine. This research was supported in part by JSPS KAKENHI grant numbers JP: 19K08430, 17K10716, and 16K07132, and Practical Research for Innovative Cancer Control from AMED by grant number JP17ck0106197, The Cooperative Research Project Program of Joint Usage/Research Center at The Institute of Development, Aging and Cancer, Tohoku University, and Takeda Medical Foundation. Declaration of Interests: There are no financial conflicts of interest. Ethics Approval Statement: This study was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Ethics Committees at Miyagi Cancer Center (Natori, Japan) and Tohoku University Graduate School of Medicine (Sendai, Japan). The protocol of animal experiments was approved by the Miyagi Cancer Center Animal Care and Use Committee (permit number: MCC-AE-2019-8).

Regional current status of head and neck cancer treatment from Miyagi Cancer Center

Regional current status of head and neck cancer treatment from Miyagi Cancer Center

Impact of chemotherapy on overall survival and hospitalization in elderly patients with gastric cancer

Abstract Background Research on chemotherapy (CT) for elderly patients with cancer is currently being performed. We studied how CT affects overall survival (OS) and hospitalization length/incidence in elderly patients with incurable gastric cancer. Methods We retrospectively evaluated patients with incurable gastric cancer at Miyagi Cancer Center from May 2014 to February 2018. Patient characteristics, clinical courses, and prognoses were analyzed using logistic regression, multivariate Cox regression, and scatter plot analyses and the Kaplan¯Meier Method. Results We included 67 men and 29 women; 21 and 75 patients were aged ≥75 and Conclusion Patients aged ≥75 years had better outcomes, like in those aged

Thinking about how to work - How should our division do its job with a limited number of people?

Abstract The Division of Head and Neck Cancer, Miyagi Cancer Center was established in 2016 and is currently in its fourth year. Although the chief of the division is alone in charge of medical treatment, I am supported by people from various divisions and job types, and treatment is carried out continuously without interruption. Many workplaces are required to carry our their duties with limited staff resources. On the contrary, some workplaces seem poorly managed even when workers are available. Here, I focus on what I have felt and experienced in working with a small number of people, and on issues that I am particularly concerned about.

Clinicopathological features of intraoperative pleural lavage cytology for non-small cell lung cancer

The significance of clinicopathological features of pre- and post-resection pleural lavage cytology (PLC) for non-small cell lung carcinoma (NSCLC) currently remains unknown. Between January 2010 and December 2012, pre- and post-resection PLC were performed for NSCLC in 565 patients at Tohoku University, Miyagi Cancer Center, or Sendai Medical Center. The relationship between the clinicopathological features and patient outcomes was analyzed. Twenty-two patients (3.9%) had positive findings from pre- or post-resection PLC. Both PLC were correlated with pT and pl factors, while only post-resection PLC was correlated with pN factor (p < 0.005). The 5-year disease-free survival (DFS) rate of the positive pre-resection PLC was significantly poorer than that of negative (26.7% vs. 76.9%, p < 0.0001). In addition, the 5-year DFS of the positive post-resection PLC was also poorer than that of negative (14.3% vs. 76.0%, p < 0.0001). Multivariate analyses revealed that both PLC were not independent prognostic factors in our study. A significant association of post-resection PLC with N factor is considered to be characteristics of post-resection PLC different from pre-resection PLC. A prognostic impact of post-resection PLC and its detailed difference from pre-resection PLC should be clarified by further investigations.

Professional Oral Health Care at General Dental Clinic Reduces Postoperative Complications of Head and Neck Free-Flap Reconstruction Surgery.

Background: Extensive resection and free-flap reconstruction surgery has become the standard treatment for locally advanced head and neck cancer. Surgical site infection (SSI) is one of the serious complications of this treatment. This study aimed to investigate the risk factor for onset of SSI, particularly focusing on whether preoperative professional oral health care in cooperation with general dental clinics is effective in reducing the occurrence of SSI.Methods: From March 2003 to August 2011, 183 patients who underwent head and neck free-flap reconstructive surgery by the same plastic surgeon at Miyagi Cancer Center for Head and Neck Surgery were investigated retrospectively.Results: Of the 183 patients, 135 and 48 were men and women, respectively, with a mean age of 62 (range, 29-82) years. The tumor was located in the oral cavity (n = 76), hypopharynx (n = 55), oropharynx (n = 28), and others (n = 24). Clinical stages were stage I/II in 18, stage III/IV in 164 patients, and benign tumor in one patient, based on UICC classification. SSI occurred in 66 patients (36.1%). Based on multivariate analysis, professional oral health care [P = 0.0076, odds ratio (OR) = 0.39] and radiation therapy history (P = 0.0214, OR = 2.820) were shown as factors that are significantly related to SSI.Conclusion: This study identified history of radiation therapy as a significant risk factor for SSI from univariate and multivariate analysis and revealed that patients receiving preoperative professional oral health care at general dental clinics reduce the risk of SSI. Preoperative professional oral health care in cooperation with general dental clinics has been shown to reduce SSI of head and neck free-flap reconstructive surgery.

O3-3-3 - The effectiveness of cancer chemotherapy among elderly patients: a retrospective study in Miyagi Cancer Center

O3-3-3 - The effectiveness of cancer chemotherapy among elderly patients: a retrospective study in Miyagi Cancer Center

Effect of Educational Interventions on Adverse Drug Reaction Reporting in a Cancer Institute in Japan: A Questionnaire Study.

Background: Limited data regarding knowledge and factors related to understanding the adverse drug reaction (ADR) reporting system of health care professionals are available in Japan. Objective: The objective of this study was to identify factors related to understanding the ADR reporting system in Miyagi Cancer Center and to find ways to increase the number and quality of ADR reports. Methods: Self-administered questionnaire surveys were administered before and after the educational meeting among health care professionals who were working in our hospital during the study period. Subanalyses restricted to nurses were also performed. Main Outcome Measure: Understanding ADR reporting system among healthcare professionals. Results: The percentage of respondents who understood the ADR reporting system in the questionnaire after the educational meeting was significantly higher than that in the questionnaire before the educational meeting. In the questionnaire after the educational meeting, multivariate logistic regression analysis found that having over 30 years of practical experience (odds ratio [OR], 3.852; 95% confidence interval [CI], 1.228-12.081 for 20-29 years, 7.695; 1.650-35.881 for over 30 years), being a physician (8.071; 1.923-33.878), being a pharmacist (18.357; 3.847-87.585), and participating in the educational meeting (5.111; 1.700-15.365) were factors associated with understanding the ADR reporting system. Multivariate logistic regression analysis of the questionnaire results before the educational meeting among nurses showed that working at outpatient departments (8.330; 3.008-23.069) was significantly and independently associated with understanding the ADR reporting system. Conclusions: The present study demonstrated that many years of practical experience, profession (physicians, pharmacists), and educational interventions were associated with good understanding of the ADR reporting system among health care professionals.

Prognostic survey at the Miyagi Cancer Center

Prognostic survey at the Miyagi Cancer Center

Understanding the concept of a ‘good death’ in Japan: Differences in the views of doctors, palliative and non-palliative ward nurses

Achieving a 'good death' is the ultimate goal for medical staff caring for terminally ill cancer patients, but the exact definition of a 'good death' is subject to interpretation. This exploratory study investigates the differences in how Japanese cancer care staff perceive a 'good death' by using factor analysis. Participants included doctors, palliative and non-palliative ward nurses working in Miyagi Cancer Center, Natori, Japan. The various components of a 'good death' for cancer patients have been identified in a previous Japanese study. In the present study, respondents were asked to state the percentages of patients for which the component had been achieved, the extent to which the respondent contributed to achieving the component, and the concrete means they would use to ensure that patients were free from psychological distress and prepared for dying. Medical staff had largely similar views on the percentage of patients for which a component of 'good death' was achieved. All the achievement ratings determined in the present study were considerably lower than the necessity ratings given by non-medical staff in a previous study. There were differences among medical staff with respect to their contribution to achieving a component of 'good death' and the concrete means they would use to achieve a 'good death'.

Management of the Patients with Hypopharyngeal Cancer: Eight-Year Experience of Miyagi Cancer Center in Japan

The aim of this study is to evaluate the results of treatment for hypopharyngeal cancer and indicate the future prospect of the treatment. Seventy-four patients with squamous cell carcinoma of the hypopharynx admitted to Miyagi Cancer Center from 1993 through 2000 are reviewed. Sixty-four patients received radical treatment, and 10 patients received palliative treatment or no treatment. The cancer was advanced (stages III and IV) in 82% of all the patients. The overall 5-year survival rate of all the patients was 38%. The overall 5-year survival rate of 64 patients received radical treatment was 43%. The ten patients who received palliative treatment or no treatment died of cancer within 16 months. Fifty-two out of the 74 patients underwent neck dissection for the neck lymph node involvement; forty of the 52 patients underwent ipsilateral neck dissection and 12 underwent bilateral neck dissection. Four out of the 40 patients, who underwent ipsilateral neck dissection alone, developed late contralateral regional recurrence but were successfully treated by contralateral neck dissection at the time of recurrence. Twenty-three out of 74 patients had multiple primary cancers synchronously or metachronously (31%). Cause of the death of six patients out of 74 patients was confirmed to be primary cancers other than hypopharyngeal cancer, as judged by physicians in other department or other hospitals. Most of the patients died due to distant metastasis from hypopharyngeal cancer or other primary cancers. We therefore conclude that contralateral elective neck dissection which is frequently chosen for the treatment of hypopharyngeal cancer surgery is unnecessary. Even if locoregional control is accomplished, distant metastasis or multiple primary cancers emerge and make prognosis poor. To improve the prognosis, we should develop some strategy against hypopharyngeal cancer for each patient. New strategies including chemoprevention and surgery against distant metasistasis are necessary.

Life‐Prolonging Effect of Immunocell BAK (BRM‐Activated Killer) Therapy for Advanced Solid Cancer Patients: Prognostic Significance of Serum Immunosuppressive Acidic Protein Levels

AbstractFor Abstract see ChemInform Abstract in Full Text.

Protein expression of p53 and Bcl-2 has a strong correlation with radiation resistance of laryngeal squamous cell carcinoma but does not predict the radiation failure before treatment

To examine what factors can precisely predict the radio-sensitivity or radio-resistance of early stage laryngeal squamous cell carcinomas (LSCC), protein expression of p53, Bcl-2 and Bax and loss of heterozygosity (LOH) at 3p and 9p loci were investigated. From June 1994 through June 1999, specimens of primary tumors were obtained by biopsy from 21 patients diagnosed as early stage LSCC at Miyagi Cancer Center Hospital under approved protocol. Labeling indexes of p53 and Bcl-2 were markedly increased in the recurrent tumors (n=8) and the differences were significant by statistical analysis (p=0.043 and p=0.015). However, when labeling indexes of the samples before treatment from non-recurrent cases were compared with those of the samples before treatment from recurrent tumors (n=13), no significant difference was observed. When LOH was examined, 16 out of these 21 cases were acceptable for evaluation, 4 of which (25%) had a relapse. Allelic loss at the 9p21 and 3p21 loci was found in 6 of 13 cases (46%) and 10 of 16 cases (63%), respectively. The frequency of LOH at the 3p21 locus in the recurrent cases was 100% (4 out of 4) and that in non-recurrent cases was 50% (6 out of 12). The frequency of LOH in recurrent tumors was apparently higher than that in non-recurrent tumors. Preservation rates of the larynx of the patients with 3p21 LOH negative tumors was very high (100%) and that of the patients with 3p21 LOH positive tumors was low. These results indicate that although expression of p53 and Bcl-2 had a strong correlation with recurrent LSCC treated by irradiation, immunohistochemical analysis of p53 and Bcl-2 in the sample before treatment was not able to predict the radiation failure. Moreover, our results also indicated that molecular research on genetic instability such as allelic loss may be more sensitive for the detection of radio-resistant tumor cells.

Life-prolonging effect of immunocell BAK (BRM-activated killer) therapy for advanced solid cancer patients: prognostic significance of serum immunosuppressive acidic protein levels.

We devised an innovative type of immunocell therapy called BRM (biological response modifier)-activated killer (BAK) therapy, which utilizes most of non-MHC (major histocompatibility complex) restricted lymphocytes, CD56+ cells including gammadelta T cells and NK cells. Peripheral blood lymphocytes were selected by immobilizing them with anti-CD3 monoclonal antibody, cultured for 2 weeks with serum-free medium containing IL-2, and then were reactivated by 1,000 U/ml of IFN-alpha for 15 min. The patients were infused with about 6x10(9) BAK cells by intravenous drip infusion at 1-month intervals. All advanced solid cancer patients who had received chemotherapy but for whom it was not effective or have refused chemotherapy were included in the present study. A good marker of impairment of host immune response by chemotherapy is an immunosuppressive acidic protein (IAP) level in serum above 580 microg/ml; survival rates were compared with the high (> 580 microg/ml) and the low (< or = 580 microg/ml) serum IAP groups. We enrolled in this study 23 immunosuppressed patients whose IAP levels in serum were over 580 microg/ml, and 42 immunoreactive solid cancer outpatients whose IAP level in serum were under 580 degreesg/ml and whose performance statuses were over 80% on the Karnofsky scale. After giving informed consent, patients were treated with BAK therapy on an outpatient basis at our hospital. The ethical review board of the Miyagi Cancer Center approved this pilot study. Treated with BAK therapy, the mean survival of immunosuppressed patients was 4.6 months. On the other hand, survival for one of immunoreactive advanced postoperative patients (stage IV) and inoperable lung cancer patients (stage IIIb) was 24.7 months. The difference in survival between the 2 groups was significant (P < 0.01). This shows that BAK therapy is not indicated for an advanced cancer patient whose serum IAP is over 580 microg/ml, perhaps due to extensive chemotherapy. Overall response to BAK therapy was complete response (CR) in 5 cases, partial response (PR) in 1 case, and prolonged no change (NC) in 26 cases, with an effectiveness rate at 76.2% in 42 advanced stage IIIb and IV cancer patients. BAK therapy has a life-prolonging effect without any adverse effects and maintains satisfactory quality of life (QOL) for advanced cancer patients.

Radiation therapy for limited-stage small-cell esophageal cancer.

Between 1985 and 1999, 20 patients with limited-stage small-cell carcinoma of the esophagus (SCEC) received radiation therapy at Tohoku University Hospital and Miyagi Cancer Center Hospital. Twelve patients received definitive radiation therapy and eight patients received postoperative prophylactic irradiation after surgery. The 1-, 2-, and 5-year survival rates of all cases were 44%, 37%, and 19%, respectively. Distant metastasis was the most frequent pattern of recurrence. Survival rates differed significantly between the 6 patients who were not treated with chemotherapy (median survival time, 5 months) and the 14 patients who were (24 months) (p = 0.0061). Good local control rates can be obtained by definite or postoperative radiation therapy for SCEC. However, SCEC should be regarded as a systemic disease, and chemotherapy should be given. Multiinstitutional studies are needed to obtain sufficiently large populations for investigation and optimization of local therapy for this disease.