[Case of a Patient with Cancer of Unknown Primary in the Poor Prognosis Group Who Had a Experienced a Beneficial Treatment Course].

A 47-year-old woman with general malaise and abdominal pain presented with multiple liver tumors and lymph node metastasis. She was diagnosed with small cell carcinoma on the basis of a lymph node biopsy; however, the primary lesion was not identified. Finally, we diagnosed her with cancer of unknown primary lesion and placed her in the poor prognosis group. Although her general condition was poor, she experienced a relatively good response to treatment for small cell carcinoma.

[Dendritic Cell Therapy with Neoantigens and Oncoantigens].

We treated 3,164 patients with advanced cancer with dendritic cell therapy between July 2005 and March 2020. The effective rate in patients treated with dendritic cell therapy more than 3 times was 19.0%. Among them, we treated 133 cancer patients with a combination of immune checkpoint inhibitors and dendritic cell therapy between June 2015 and March 2020. The effective rate in these patients was 54.1%. We treated 98 cancer patients with dendritic cell therapy with neoantigens between March 2018 and March 2020. The effective rate in these patients treated with neoantigens was 38.7%. The effective rate in patients treated without neoantigens was 18.3%. Dendritic cell therapy with neoantigens enhanced the effective rate. The effective rate of dendritic cell therapy with both immune checkpoint inhibitors and neoantigens was 60.7%.

[Combination of Immunotherapy and Hyperthermia].

We treated 123cancer patients with a combination of immune checkpoint inhibitor and dendritic cell therapy between June 2015 and April 2019. The effective rate of cases administered for B3times was 51.5%. Hyperthermia was found to enhance the effects of radiotherapy, chemotherapy, and immunotherapy. In addition, hyperthermia enhanced the effects of combined immunotherapy. In clinical cases and animal models, immunohistochemical staining showed that the expression of PD-L1 and MHC classⅠ and invasion of CD8 cells were increased after hyperthermia.

[Effects of Immune Checkpoint Inhibitor Combined with Dendritic Cell Therapy and Hyperthermia].

In this study, 97cancer patients were treated with combined immune checkpoint inhibitor therapy and dendritic cell thera- py between June 2015 and April 2018. We administered nivolumab with 2-3mg/kg bw every 2-3weeks. The rate of progress in cases where nivolumab was administered more than 3 times was 55.2%. Dendritic cell therapy enhanced the immune checkpoint inhibitor therapy. In cases where the effect of combined immune checkpoint inhibitor therapy and dendritic cell therapy was restricted, hyperthermia and radiation therapy are useful for the recovery of combined therapy.

[Enhancing Antitumor Effects Using Hyperthermia(Including Immune Checkpoint Inhibitor)].

Hyperthermia enhances the efficacies of radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy. In this study, we investigated whether hyperthermia enhanced the efficacy of immune check point inhibitor therapy. The LLC tumor inoculated in mouse was heated and immunostained, which showed increase in PD-L1 staining post-heating. PD-L1 and HLA class I staining increased after heating samples derived from a case of analinvasion of rectalcancer associated with Lynch syndrome.

[The Present State of Inter-Laboratory Differences in Setting and Practicing Critical Values -Results of a Questionnaire Survey Performed to the Laboratories of Keio University-Associated Hospitals].

Presently we, Keio Endocrine and Metabolite Survey (KEMS) study group conducted a questionnaire sur- vey with respect to panic values in the laboratories belonging to Keio University-associated hospitals. As to the initial setting, most of the laboratories answered to play a leading role in preparing the necessary matters to implementation of panic values and revise them corresponding to physician's request on each occasion. In almost all laboratories, they did not verify whether the notification procedure does work to exert appropriate clinical action. The numbers of critical values answered by the 18 laboratories distributed widely in the test items (8-39) and their critical limits (10-68). As to the critical limits, the lower limits of serum K and blood glucose converged among the laboratories, however, the limits of other test items diverged. The results of the present survey regarding to critical values, although being in small scale, may submit the im- portant issue to be solved in near future. [Short Communication].

[Administration of Immune Checkpoint Inhibitor for Cancer except for Melanoma and Lung Cancer].

We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent cancer - analyses by cancer type and recurrence form].

We treated 1,939 patients with advanced or recurrent cancer using hyperthermia and or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. There were 309(15.9%)patients who experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 52 CR cases. The effective rate of immunotherapy increased from 9.9%to 19.1%using hyperthermia. The effective rate for patients with hyperthermia-alone was 3.6%, and skin and regional lymph node metastases disappeared. Immunotherapy alone was effective for liver or lung metastases. Combined hyperthermia and immunotherapy had a beneficial effect on multiple metastases observed in important plural solid organs. Ovarian cancer had the highest effective rate (25.0%), followed by prostate cancer.

[The effect of immunotherapy and hyperthermia for advanced or recurrent head and neck cancer - 74 clinical cases].

We treated 74 patients with advanced or recurrent head and neck cancer using hyperthermia and/or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. Fifteen(21.4%) patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 4 CR cases. Hyperthermia alone was effective for one patient only. A combination of dendritic cell therapy and hyperthermia was beneficial for the remaining 14 patients. One patient was effectively treated with cetuximab, and γδ lymphocytes and dendritic cell therapy.

[The effect of immunotherapy and hyperthermia on advanced or recurrent ovarian and uterine cancer - 229 clinical cases].

We treated 116 advanced or recurrent ovarian cancer and 102 uterine cancer patients with hyperthermia and/or immunotherapy(2005/7-2013/11). Of these, 63, 31, and 8 patients had cervical cancer, endometrial cancer, and uterine sarcoma, respectively. Standard therapy showed no effect or was refused by these patients. Twenty-nine(25.0%)ovarian cancer patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months). The effective rate of a combination of therapies including activated lymphocyte therapy, dendritic cell therapy, and hyperthermia was 47.5%. Thirteen(12.7%)uterine cancer patients experienced a clinical benefit. The effective rates for cervical cancer, endometrial cancer, and uterine sarcoma were 7.9%, 22.5%, and 12.5%, respectively. Both hyperthermia and immunotherapy were administered to successfully treat these patients.

[Investigation of the procalcitonin and microbiology test and antibiotics situation from our hospital].

Procalcitonin (PCT) was first described as a sepsis-associated protein in 1993. PCT is increased in the blood at the time of infection by bacteria. Therefore, it is used as an auxiliary indicator of sepsis diagnosis. In addition, PCT is reduced quickly by antibiotics. And use as a stop or change marker is also expected. We have investigated the antimicrobial use and microbial testing of measurement patient and PCT running performance. Number of requests was 3,387 cases (inpatient 2,649 and outpatient 742 cases) for one year. It was subject to the 820 cases that had inspection request to July to October 2012. In 820 cases, 57 cases had exhibited a PCT >0.5 ng/ml and diagnosed with infectious diseases. In 57 cases, 44 cases (77%) were performed microbiology and blood culture. And only blood culture performed in 8 (14%), blood culture and microbiology is not performed for 5 cases (9%), In 21 (40%) cases of 52 cases performed the blood culture shown positive. Detecting bacteria accounted for more than half in 17 cases of Gram-negative bacilli. Also, it had exhibited a systemic inflammatory response syndrome (SIRS) in 18 cases. Antibiotics have been used in all cases regardless of implementation of the microbiology test. If sepsis is suspected, it is necessary for diagnosis is done correctly and quickly. Therefore, PCT has been suggested high usefulness by examining in the hospital. It is required that the reference identification and drug susceptibility results of the pathogenic bacterium combination of microbiology test and the PCT. We considered useful to PCT monitoring that as an indicator of antimicrobial agents change or shorten of antibiotic use period. Future, proactive use of clinical practice is expected.

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent breast cancer].

We treated 172 patients with advanced or recurrent breast cancer using hyperthermia or immunotherapy between July 2005 and September 2012. In these patients, standard therapy showed no results, or it was refused. Clinical benefit( complete response [CR], partial response[PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients( 17.4%), including CR in 5 patients. The effective rate of immunotherapy increased from 7.7% to 26.0% using hyperthermia. The effective rate of hyperthermia was only 5.1%. The standard therapy had not been altered in 23 of the 30 patients in whom clinical benefit was observed. Thus, immunotherapy or hyperthermia had benefited these 23 patients. Of the 23 effectively treated patients, skin or regional lymph node metastases disappeared in 3 patients treated with hyperthermia alone, and lung metastases disappeared and carcinomatous pleuritis improved in 1 patient treated with immunotherapy alone. In the remaining 19 effectively treated patients, multiple metastases were observed in important solid organs such as the liver, lung, bone, and brain. Combined hyperthermia and immunotherapy was used to treat these 19 patients to good effect.

[Immunotherapy and hyperthermia for the treatment of patients with advanced or recurrent colorectal cancer].

We treated 226 patients with advanced or recurrent colorectal cancer using hyperthermia or immunotherapy between July 2005 and September 2012. Clinical benefit (complete response [CR], partial response [PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients (13.3%), including CR in 5 patients. The effective rate of immunotherapy increased from 14.3% to 16.1% using hyperthermia. The effective rate of hyperthermia was 3.9%. Of the 30 effectively treated patients, liver metastases disappeared in 2 patients treated with hyperthermia alone, and lung metastases disappeared in 2 patients treated with immunotherapy alone. In the remaining 26 effectively treated patients, multiple metastases were observed in solid organs. Both hyperthermia and immunotherapy were administered and were found to be effective in the treatment of patients with advanced or recurrent colorectal cancer.

Accuracy of the Contour® Next Link 2.4 blood glucose monitoring system in Japanese individuals: a single-center study.

Aims: Self-monitoring of blood glucose is a useful method for monitoring blood glucose. It is often a key role of a management plan to reduce glycemic variability and diabetic complications. Wireless monitoring systems to connect blood glucose and insulin pumps can facilitate glycemic control. In this study, we evaluated the accuracy of Contour® Next Link 2.4, a blood glucose monitoring system that cooperates wirelessly with most insulin pumps, in Japanese individuals. Methods: In this study, finger-stick samples from 59 individuals were collected at the Tokyo Saiseikai Central Hospital. Blood glucose concentrations were measured with the monitoring systems against an available reference. We evaluated the accuracy of the system based on the ISO 15197:2013 Section 6.3 accuracy criteria. Results: In the present study, 100% of the results fulfilled the ISO 15197:2013 Section 6.3 accuracy criteria (95% within ± 15 mg/dL or ± 15% of reference for glucose < 100 and ≥ 100 mg/dL, respectively). The Parkes-Consensus Error Grid analysis showed that 100% of the results fulfilled within Zone A. Conclusions: The Contour® Next Link 2.4 blood glucose monitoring system fulfilled the ISO 15197:2013 accuracy criteria limit and the consensus error grid criterion. Therefore, this monitoring system for observing blood glucose levels is accurate for Japanese individuals.

[Immunotherapy with hyperthermia for advanced or recurrent breast cancer patients in whom standard therapy showed no effect or was refused].

We treated 168 advanced or recurrent breast cancer patients with hyperthermia or immunotherapy (2005/7-2011/12). In these cases, standard therapy showed no effect or was refused. Clinical benefit( complete response: CR, partial response, and long stable disease) was observed in 26 cases; CR occurred in 4 cases. The effective rate of immunotherapy increased from 9.1% to 23.9% using hyperthermia. Both hyperthermia and immunotherapy needed to be used together to be effective in 20 cases with distant metastases to solid organs.

Transanal total mesorectal excision after incomplete endoscopic submucosal dissection for early-stage low rectal cancer: A small case series.

Endoscopic submucosal dissection (ESD) for colorectal cancer is challenging but is gradually being performed worldwide. It is less invasive than surgical resection and can be performed on lesions in which malignancy cannot be diagnosed. In low rectal cancers, changes such as scarring after ESD may make it challenging to preserve the anus when additional surgical resection is required. Transanal total mesorectal excision (TaTME) is a novel surgical technique involving transanal endoscopic manipulation. It is useful for lesions in the deep pelvis near the anus. Herein, we report six cases of TaTME after ESD for early-stage low rectal cancer that resulted in incomplete resection. As a representative case, a 77-year-old female was referred to our hospital, and colonoscopy revealed low rectal cancer. ESD was performed, and the pathological diagnosis was an invasion of the submucosal layer and microscopic lymphovascular invasion. We performed an additional laparoscopic low anterior resection with TaTME. Lymph node metastasis was observed, and the final diagnosis was pT1b, pN1a, pStage IIIa, and R0. In other cases, the anus can also be preserved, and the distal margin can be secured. TaTME enabled anal preservation without being affected by the ESD scars. It is considered useful for additional resection after ESD of low rectal cancer.

[Hyperthermic immunotherapy was effective in 3 CR cases as the standard treatments had no effects or could not be enforced].

We treated 1, 225 advanced or recurrent cancer patients with hyperthermia or immunotherapy (2005/7-2010/12). We had 174 (14.7%)clinical benefit cases (CR, PR and long SD) including 32 complete response (CR) cases. CASE 1: A 63-year-old male, rectal cancer, post operative recurrence with MRSA abscess located in abdomen. He was treated with dendritic cell therapy and hyperthermia. He showed a CR. CASE 2: A 62-year-old female, ovarian cancer, post operative recurrence. She was treated with standard chemotherapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR. CASE 3: A 46-year-old female, lung cancer, postoperative recurrence. She was treated with standard chemotherapy and molecular target therapy, but she showed a PD. Then she was treated with dendritic cell therapy and hyperthermia. She showed a CR.

[Hyperthemia enhances activated lymphocytes and molecular target therapy].

We already informed that a combination therapy of hyperthermia and activated lymphocytes therapy reduced the tumor growth and lung metastasis synergistically in mice model. In this study we treated mice inoculated LLC tumors with hyperthermia or molecular target drugs (erlotinib 25 mg/kg/day and sorafenib 10 mg/kg/day). Both of hyperthermia and molecular target therapy reduced not only tumor growth but also lung metastasis. And a combination therapy of hyperthermia and molecular target therapy reduced more of the tumor growth and lung metastasis synergistically. The expression of HER2 and VEGFR was reduced by hyperthermia and molecular target drugs. Apoptosis was enhanced by hyperthermia and molecular target drugs synergistically.

Effectiveness of suicide prevention gatekeeper training for university teachers in Japan.

Suicide is a leading cause of death among Japanese college and university students. Our previous study showed that the gatekeeper training (GKT) program significantly improved competence and confidence in the management of suicidal students in university administrative staff. However, we could not determine which component of the program was effective, nor if this program was effective for university teachers as well. In the current study, 81 university teachers were recruited; 63 of them received a general mental health lecture (MHL) and 18 of them received a 2.5 -h GKT program based on the Mental Health First Aid program. Competence and confidence in managing suicide intervention and behavioral intention as a gatekeeper were assessed by a self-report questionnaire before and immediately after the intervention. As a result, we found a significant improvement in competence in the management of suicidal students in the GKT group compared to the MHL group. We also found significant improvements in confidence in the management of suicidal students and behavioral intention as gatekeepers in the GKT group, although the questionnaires for these outcomes were not validated. The program satisfaction score was significantly higher in the GKT group than in the MHL group. To our knowledge, this is the first study to evaluate a GKT program for university teachers in Japan. By comparing the two groups, we explicitly confirmed that active involvement of the participants is crucial for effective suicide prevention training.