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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Background Thromboembolism (TE) is a well-known complication during chemotherapy in cancer patients. However, the risk of TE associated with immune checkpoint inhibitors (ICIs) is unknown. This study was performed to investigate the incidence of TE and associated risk factors in patients treated with ICIs.Methods We conducted a retrospective chart survey of patients receiving at least one ICI at Shinshu University Hospital between September 2014 and October 2021. Age, sex, cancer type, body mass index, medical history, laboratory data at commencement of treatment, and medication data were obtained from electronic medical records. TE events (venous thromboembolism [VTE], arterial thromboembolism [ATE]) were identified after ICI initiation.Results The study population consisted of 550 patients with a median age of 70.0 (19–89) years, 71.3% men, and a median follow-up of 15.1 months (range; 0.16–72.0 months). Nivolumab was the most commonly used ICI (45.8%), followed by pembrolizumab (24.0%), pembrolizumab plus anticancer drugs (7.8%), and nivolumab plus ipilimumab (5.1%). Forty cases of TE (7.3%) occurred (22 VTE, 16 ATE). Risk factors significantly associated with TE in multivariate logistic analysis were urothelial cancers (OR 2.86; 95%CI, 1.13–7.21; p = 0.026), dyslipidemia (OR 2.33; 95%CI, 1.13–4.81; p = 0.023), Khorana score ≥ 2 (HR 2.22; 95%CI, 1.07–4.61; p = 0.032). Overall survival was not significantly different from patients without TE (p = 0.886).Conclusion These results suggested that the frequency of TE is higher than expected and should be considered and monitored in patients treated with ICIs.

A 71-year-old man presented with cough and bloody sputum. Computed tomography showed a mass in the lower lobe of the left lung. Histological findings in biopsy tissue revealed a malignant peripheral nerve sheath tumor (MPNST). The patient was diagnosed with primary lung MPNST based on a systemic examination. Although initial chemotherapy treatment with doxorubicin failed to control the disease, radiotherapy considerably shrank the tumor. Primary lung MPNSTs are rare, and there is no established treatment for inoperable cases. This case suggests that radiotherapy is a treatment option for primary lung MPNST.

The prognostic implications of palliative chemotherapy for advanced or recurrent thymic carcinomas require full elucidation. The lung immune prognostic index (LIPI) is a novel prognostic index whose effectiveness has recently been reported in lung cancer patients. This study aimed to evaluate the clinical value of the LIPI in advanced or recurrent thymic carcinoma patients.We retrospectively analyzed 41 advanced or recurrent thymic carcinoma patients undergoing palliative chemotherapy between January 2001 and December 2020. Survival-time analysis was conducted using the Kaplan-Meier method and log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to investigate the predictive and/or prognostic value of the LIPI.Median progression-free survival (PFS) for first-line chemotherapy and overall survival (OS) were significantly longer in the good-LIPI group (LIPI: 0) than in the intermediate/poor-LIPI group (LIPI: 1 or 2) (PFS: 13.4 vs. 6.8 months, p = 0.025; OS: 48.2 vs. 28.9 months, p = 0.00506). Multivariate analysis revealed that intermediate/poor LIPI was the adverse prognostic factor for PFS. With regard to OS, serum albumin3.5 g/dl and an intermediate/poor LIPI were identified as independent adverse prognostic factors.Our study indicates that the LIPI is a potential prognostic marker in patients with advanced or recurrent thymic carcinoma undergoing palliative chemotherapy.

Background: Nivolumab, a programmed death-1 antibody, is an immune checkpoint inhibitor approved in Japan in March 2017 for the treatment of recurrent or metastatic head and neck cancers (RM-HNCs) after platinum drug administration. This study aimed to evaluate the effectiveness and safety of nivolumab and to determine the prognostic factors affecting the treatment outcome, in a real-world setting in Japanese RM-HNCs. Methods: Forty-six patients with RM-HNCs treated with nivolumab between April 2017 and April 2021 at Shinshu University Hospital were retrospectively assessed in this cohort study. Results: The overall response rate was 17.4%, and the disease control rate was 41.3%. The median first and second progression-free survival (PFS1 and PFS2) were 2.6 and 10.3 months, respectively. The median overall survival (OS) was 14.8 months. Multivariate analysis showed that performance status (PS) (p = 0.003) and a decrease in neutrophil-lymphocyte ratio (NLR) (p = 0.02) were significantly associated with a better OS, and a decrease in NLR (p = 0.035) was associated with a better PFS2. Conclusions: This study is the first report of PFS2 in RM-HNCs treated with nivolumab; the long PFS2 may contribute to prolonged OS. We propose that the PS and a decrease in NLR could be useful clinical prognostic markers of nivolumab therapy, which can easily be evaluated in the clinical setting.

Background Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1–3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method In this study we report the clinical courses of three cases with HDGC from a single Japanese family. Results The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. Conclusion It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

Treatment of synchronous multiple primary cancers is clinically difficult. We report four cases of synchronous primary cancers, including advanced and metastatic non-small cell lung cancer (NSCLCs) highly positive for programmed death-ligand 1 (PD-L1) expression and initially treated with pembrolizumab. Pembrolizumab was efficacious in two patients with NSCLC lesions, followed by chemoradiotherapy for esophageal cancer (case 1) and chemotherapy for gastric cancer (case 2). Both cancers in case 1 showed a complete response for 3 years, while progression of the accompanying gastric cancer resulted in mortality at 20 months in case 2. Both NSCLC and gastric cancer in case 3 failed to respond to pembrolizumab, but the accompanying laryngeal cancer in case 4 showed a complete response, and cytotoxic chemotherapy for NSCLC was continued for 18.0 months. Our clinical experience suggests that pembrolizumab is a useful therapeutic approach for patients with synchronous cancers, including NSCLC that highly expresses PD-L1.

Background; Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method; Here, we describe four cases of HDGC in a single Japanese family. Results; The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in three relatives, which revealed abnormal small pale mucosal patches, small ulcerative lesion, and no abnormal findings, respectively. Random and targeted biopsies were compatible with the pathological diagnosis of HDGC. They underwent total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection. Conclusion; In the management of HDGC, multidisciplinary and family-oriented approaches are critical, including genetic analysis of CDH1 variants in the proband, presymptomatic diagnosis of at-risk relatives through careful genetic counseling, and random biopsy-based surgery or prophylactic total gastrectomy.

Introduction: Extrapulmonary neuroendocrine carcinoma (EPNEC) is a clinicopathological entity distinct from neuroendocrine carcinoma (NEC) of the lung. Here, we reviewed the clinical features, treatment modalities, and prognosis of EPNEC patients in a single-institution series. Methods: We retrospectively reviewed the medical records of EPNEC patients, and examined the clinical profiles and treatment outcomes at our hospital between 2013 and 2021. Results: Thirty-one EPNEC patients (21 men, 10 women) with a median age of 65 years were included. The primary sites were as follows: stomach (n = 7); rectum and bladder (n=3 each); prostate, esophagus, cervix and pancreas (n=2 each); maxillary sinus, parotid gland, gallbladder, anal canal, larynx, uterine body, ovary, appendix, anterior mediastinum, and unknown primary lesion (n = 1 each). Thirteen patients had locally advanced stage and 18 cases had distant metastases. Chemotherapy using platinum-combined CPT-11 or VP-16 was mainly performed. Various therapeutic modalities were used, especially in locally advanced cases. Ten patients underwent surgery, including initial surgery in 5 and conversion in 5 after chemotherapy. The response rate to initial chemotherapy was 56.5% and the median overall survival in all patients was 12.8 (95%CI: 9.6–34.5) months. Survival was significantly longer in patients with locally advanced (80.3 months) and receiving surgery (not reached) than in those with metastatic disease (9.9 months) and without surgery (9.6 months). Disscussion/Conclusion: EPNEC occurs in various organs and has poor prognosis. Long-term survival may be possible with surgical resection in cases with early-stage disease or tumor shrinkage due to chemotherapy.

Thymic epithelial tumor is a rare, potentially progressive disease that commonly infiltrates mediastinal structures. In rare cases, it may cause superior vena cava syndrome. Pretreatment histopathological diagnosis is essential to determine the most effective treatment strategy. Percutaneous endovascular biopsy is a rarely reported non-surgical diagnostic option for large vessel tumoral involvement. We report two cases of thymic epithelial tumor with superior vena cava syndrome diagnosed by percutaneous endovascular biopsy. No procedural complications occurred, and subsequent systemic treatment was promptly administered. This procedure may have potential as a useful diagnostic method for patients with mediastinal tumors involving large vessels.

Fanconi anemia (FA) is characterized clinically by bone marrow failure, congenital malformations, sensitivity to DNA cross-linking agents, and increased risk of malignancy. Hematological cancer is the best-described malignancy in patients with FA, but the susceptibility to the development of solid tumors is also well documented, especially after hematopoietic stem cell transplantation (HSCT). With regard to the development of solid tumors in patients with FA, head and neck, esophageal, and anal squamous cell carcinoma are well known, but reports of lung cancer are extremely rare. Here, we describe an FA patient with a history of HSCT that developed 3 serial cancers – oral, esophageal, and nonsmall cell lung cancer – over a period of 6 years. The third lesion was nonsmall cell lung cancer and its location corresponded closely to the field of irradiation treatment for prior esophageal cancer. The occurrence of lung cancer in patients with FA is uncommon, but FA patients should be screened regularly and serially. Our case also indicated the importance of the irradiated field as a location for subsequent cancer development.

Objective This study was performed to validate the epidemiology, initial treatment, and clinical practice in lung cancer patients in the Hokushin region, Japan. Methods We surveyed retrospective data of newly diagnosed and registered lung cancer patients in 22 principal hospitals in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017. Results A total of 5503 lung cancer cases were newly diagnosed in Hokushin region during the study period. These patients consisted of 3677 (66.8%) men and 1826 (33.2%) women, with a median age of 72.2 years (range, 27 – 103 years). Diagnoses were small cell lung cancer in 512 (9.4%) cases, squamous cell carcinoma in 1083 (19.7%), and non-squamous non-small cell lung cancer in 3906 (70.9%). The population with stage I disease in Toyama prefecture (41.1%) was lower than in the other three prefectures associated with reduced selection of initial surgery therapy and increased frequencies of stage IV disease (33.2%) and best supportive care (18.6%). Initial chemotherapy for stage IV non-squamous NSCLC consisted of tyrosine kinase inhibitors in 39.3% of cases for EGFR and 4% of cases for ALK-positive non-squamous NSCLC, followed by platinum compounds (25.9%) non-platinum compounds (12.9%), and immune checkpoint inhibitors (10.2%). Carboplatin was the commonly prescribed first-line cytotoxic chemotherapeutic agent in 65.4% of patients under 75 years old and in 96.7% of patients over 75 years old. Conclusion This study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan.

Background: Malignant pleural mesothelioma (MPM) is a major occupational and environmental neoplasm. The purpose of this study was to validate the clinical and epidemiological factors, diagnosis, and initial treatment among MPM patients.Methods: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals.Results: A total of 166 MPM cases were newly diagnosed. These patients consisted of 136 men and 30 women, with a median age of 69 years old. We estimated the incidence rate for MPM to be 0.55 cases per 100,000 person-years in this study. The ratio per 100,000 population-years was 0.39 in Fukui, 0.60 in Ishikawa, 1.02 in Toyama and 0.35 in Nagano. Forty-five patients were discovered at follow-up of other diseases. Forty-six cases were diagnosed as localized disease, while 13 had accompanying regional lymph node metastasis. Furthermore, 44 cases showed infiltration into adjacent organs. A histo-cytological diagnosis was made in 164 cases (98.8%). A surgical approach, chemotherapy, and radiotherapy were performed for 33, 88, and 6 patients, respectively, while 44 patients (26.5%) received best supportive care. Multimodality therapy was conducted in just 3.0% of the MPM patients.Conclusion: MPM has a tragically rapid progression if discovered during follow-up of other diseases. Workers in health-related fields should be on high alert for aggressive MPM. New therapeutic options for MPM are urgently required.

We describe a case of an anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third‐generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance., A patient with ALK‐rearranged advanced non‐small cell lung cancer presented acquired resistance to alectinib and uterine metastasis. Gene analysis using the tissue from the uterine metastasis revealed the presence of 1151Tins. Lorlatinib showed antitumor activity on this disease for one year.

Potential disparities between cancer patients with and without disabilities remained to be validate in Japan. We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate. We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles. These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.

The PACIFIC trial established durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the predictive factors of durvalumab efficacy in this population. This study aimed to validate the predictive use of inflammation-related parameters in patients with LA-NSCLC treated with CCRT plus durvalumab.We recruited 76 LA-NSCLC patients who received CCRT followed by durvalumab from 10 Japanese institutions. The neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), and prognostic nutrition index (PNI) were measured before (pre-treatment) and 2 months after (post-treatment) durvalumab induction. Cox proportional hazards analysis was used to examine prognostic factors associated with progression-free survival (PFS) after durvalumab therapy.The median follow-up time was 17 (range, 3.3-35.8) months. The median PFS and overall survival (OS) times were 26.1 and 33.7 months, respectively. Durvalumab was discontinued in 47 (61.8%) patients, with non-infectious pneumonitis being the most common reason. Post-treatment CAR (cutoff, 0.2) was a significant stratifying factor in survival comparison (0.2 vs. ≥ 0.2, median PFS, not-reached vs. 9.6 months. Log-rank, p = 0.002). Multivariate analysis with a Cox proportional hazards model showed that post-treatment CAR was an independent prognostic factor for PFS (hazard ratio, 3.16, p = 0.003).This study suggests that post-treatment CAR has predictive value for LA-NSCLC patients treated with CCRT plus durvalumab consolidation therapy.

Background This study was performed to clarify the treatment outcome of patients with primary mediastinal germ cell tumors (PMGCTs), focusing on the clinical manifestations and management during definitive therapy and long‐term follow‐up. Methods In this study, we retrospectively reviewed the medical records of patients with PMGCTs treated at Shinshu University School of Medicine, and examined the clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal GCTs treated at our hospital between 1983 and 2019. Results Five patients were diagnosed with pure seminoma and 17 had nonseminomatous GCT. A total of 21 patients were treated with cisplatin‐based chemotherapy and 15 patients (68.2%) underwent thoracic surgery after chemotherapy. Although all cases of nonseminomatous GCT were negative for tumor markers after cisplatin‐based chemotherapy, two cases showed variable GCT cells and two had somatic components (angiosarcoma and rhabdomyosarcoma) in resected specimens. Three relapsed soon after surgery. Growing teratoma syndrome developed during chemotherapy in four cases. Urgent thoracic surgery was performed in three patients, but one case was inoperable. The calculated 10‐year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. During follow‐up, second non‐GCT malignancies developed in three patients (colon cancer, 190 months; thyroid cancer, 260 months; non‐small cell lung cancer, 250 months after the initial chemotherapy) and one patient with primary mediastinal seminoma was associated with multiple type I endocrine tumors. Conclusions Our experiences demonstrated that long‐term survival and/or cure can be achieved with adequate chemotherapy followed by local surgical treatment even in patients with mediastinal GCTs. However, the clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied. In addition, the development of secondary malignancies should be taken into consideration for long‐term follow‐up. Clinicians should be aware of the various clinical features and secondary malignancies in primary mediastinal GCTs., The clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal germ cell tumors (GCT) treated at our hospital between 1983 and 2019 were examined in this retrospective study. The calculated 10‐year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. The clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied.

Introduction: Patients with unresectable or recurrent gastric cancer who have an objective response (OR) to nivolumab monotherapy are expected to have a good long-term prognosis. However, the OR rate for nivolumab treatment is low at 11%, and there is a need for biomarkers to predict the treatment response. This study aimed to analyze the significance of systemic inflammation-related variables and clinicopathologic characteristics as predictive markers of response to nivolumab monotherapy in patients with advanced gastric cancer. Methods: In this retrospective cohort study, we enrolled 71 consecutive patients who received nivolumab monotherapy for unresectable or recurrent gastric cancer. Receiver operating characteristic curve analysis was performed to determine the cutoff values of systemic inflammation-related variables, predictors of treatment response, and other prognostic factors related to nivolumab therapy. We focused on systemic inflammation-related variables measured before nivolumab induction and 2 weeks after its first administration and performed multivariate analysis to assess whether they could be used as prognostic factors. Results: Multivariate analysis revealed that a lymphocyte-to-monocyte ratio (LMR) of ≤3.28 after 2 weeks of initial nivolumab treatment (2wLMR) is a statistically significant predictor of treatment response (p = 0.012). The progression-free survival (PFS) rate of patients with liver metastasis was significantly worse than that of the other patients (1-year PFS: 0.0 vs. 24.4%, respectively; p = 0.005). The overall survival (OS) of patients with a low 2wLMR was significantly longer than that in patients with a high 2wLMR (1-year OS: 37.4 vs. 18.9%, respectively; p = 0.022). Conclusions: Thus, the 2wLMR could be a useful biomarker to predict response to nivolumab treatment and the prognosis of unresectable and recurrent gastric cancer.

Papillary cystadenocarcinoma is an uncommon disease with low-grade histological and clinical features. Although the tumor has the potential to produce regional lymph node metastasis, there have been no reports of cases with distant metastasis. We describe a case of papillary cystadenocarcinoma arising from the maxilla that developed pulmonary metastasis 3 years after radical surgery of the primary tumor and regional lymph node. The histological findings were confirmed on resected specimens of the pulmonary nodule and a pathological diagnosis of a metastatic lesion derived from papillary cystadenocarcinoma was made. To our knowledge, this is the first report of the development of pulmonary metastasis in a patient with papillary cystadenocarcinoma. The present case suggests that papillary cystadenocarcinoma has the potential to produce lung metastasis in the clinical course. Based on our experience, we emphasize that long-term follow-up and/or careful examination are necessary in patients with cystadenocarcinoma, especially in patients with lymph node metastasis during the initial surgical therapy.

Purpose Neuroendocrine neoplasms are rare disease and could originate from throughout the body, however, there have been little epidemiological studies in Japan, especially the organ distribution. This study was to examine the epidemiological information of neuroendocrine neoplasms in the Japanese population using data from a hospital-based cancer registry. Methods Using data from the national database of hospital-based cancer registries, we examined the organ distribution, the stage and initial treatment of neuroendocrine neoplasms newly diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. In the present study, neuroendocrine neoplasms consisted of neuroendocrine tumors and carcinoma. Results A total of 33,215 (17,485 neuroendocrine carcinomas and 15,730 neuroendocrine tumors) cases were diagnosed. The majority in neuroendocrine carcinoma occur in lung (31.1%) followed in decreasing frequency by stomach (12.9%), pancreas (7.5%), rectum (6.7%) and esophagus (5.8%). On the other hand, the half of neuroendocrine tumor originated rectum (50.9%) and followed by pancreas (13.9%), duodenum (9.0%), lung/bronchus (8.9%), and stomach (8.7%). Neuroendocrine carcinoma presented at more advanced stage and higher age than neuroendocrine tumors. Most cases of neuroendocrine tumors were treated surgically, while half of neuroendocrine carcinomas were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy. Conclusions Our results demonstrated that neuroendocrine neoplasms could originate from various organs and the site distribution was different between neuroendocrine carcinoma and tumor. The national database of hospital-based cancer registries in Japan is a valuable source for evaluating the organ distribution of the rare systemic disease.

Objective: Appropriate monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with prophylactic antiemetics is important for cancer patients. This study was performed to validate the clinical practice of antiemetic use with carboplatin-based chemotherapy in lung cancer patients in the Hokushin region (Toyama, Ishikawa, Fukui, and Nagano prefectures), Japan.Methods: We surveyed retrospective data of newly diagnosed and registered lung cancer patients initially treated with carboplatin-based chemotherapy in 21 principal hospitals in the Hokushin region linked with health insurance claims data between 2016 and 2017.Results: A total of 1082 lung cancer patients (861 [79.6%] men, 221 [20.4%] women; median age 69.4 years [range, 33 – 89 years]). All patients received antiemetic therapy, with 613 (56.7%) and 469 patients (43.3%) receiving 5-hydroxytryptamine-3 receptor antagonist/dexamethasone double regimen and 5-hydroxytryptamine-3 receptor antagonist/dexamethasone/neurokinin-1 receptor antagonist triple regimen, respectively. However, the rates of double regimen and use of palonosetron were higher in Toyama and Fukui prefectures. Thirty-nine patients (3.6%) changed from double to triple regimen, while 41 patients (3.8%) changed from triple to double regimen after the second cycle, but six of these returned to triple antiemetics in subsequent cycles.Conclusion: Adherence to antiemetic guidelines in clinical practice was high in Hokushin region. However, rates of double and triple antiemetic regimens differed between the four prefectures. Simultaneous analysis of nationwide registry and insurance data was valuable for evaluating the status of cancer treatment and management.

A 67-year-old man with a history of esophageal cancer resection was referred to our hospital because of nausea and appetite loss. Laboratory findings showed severe hyponatremia and were compatible with syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Chest computed tomography (CT) revealed a nodule measuring 13 mm in the lower lobe of the right lung. Right thoracotomy was performed, and the histopathological diagnosis was small-cell lung cancer (T1bN0M0; Stage 1b). Although SIADH is frequently associated with small-cell lung cancer, it is extremely rare as the initial clinical feature in stage I small-cell lung cancer.

Objective To quantitate plasma interleukin-6 (IL-6) levels in healthy individuals and to clarify how these levels are affected by blood sample handling procedures during short-term storage. Methods Ethylenediaminetetraacetic acid (EDTA)-treated plasma samples were simultaneously collected from 14 healthy individuals and stored on ice prior to analysis of the IL-6 levels. White blood cells (WBCs), red blood cells, and platelets were counted immediately after blood collection. IL-6 levels were analyzed every 30 minutes using a commercial electrochemiluminescence immunoassay. Results Correlation coefficients between plasma IL-6 levels and WBC counts ranged between 0.605 and 0.554, higher than those for other cell types. The lowest IL-6 value in healthy individuals was estimated at 0.04 pg/mL and the mean values remained under 2 pg/mL over time. Conclusion Analysis of IL-6 levels in EDTA-treated plasma samples centrifuged within 1 hour and stored on ice can be performed within 90 minutes of short-term storage if the analytical method has a sensitivity in the range of 10 fg/mL.

Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan.Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment.We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%).This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.

Adolescents and young adults with cancer encounter age-related challenges. Cancer treatment and support are not always tailored to the needs of each patient due to difficulty in the collection of accurate data. The present study aimed to investigate cancer among children and adolescents and young adults in the four adjacent prefectures of Japan (Toyama, Ishikawa, Fukui and Nagano) by analyzing data from a unique regional cancer database. We retrieved and analyzed the data of pediatric and adolescent and young adult patients aged between 0 and 39 years at cancer diagnosis (including carcinoma in situ), which was registered in the Hokushin Ganpro database between 2010 and 2015. A total of 5718 cases (1571 males and 4147 females) were identified during this period. The overall male-to-female ratio was 1:2.6. There was no distinct difference in the number of cancer cases per 100 000 population between males and females until 19 years of age. The difference became more pronounced after 20 years of age. The number of cancer cases (per 100 000 population) in the 0–14-, 15–19-, 20–29- and 30–39-year age groups was estimated to be 13.4, 14.5, 44.0 and 101.5, respectively. Carcinomas were the most common type of cancer in the adolescents and young adults (15–39 years) population (74%), whereas they were not the predominant cancer type in the pediatric (0–14 years) population. Although further research is needed to understand the needs of adolescents and young adults with cancer, we believe that our findings will help guide efforts to improve the management strategy for adolescents and young adults with cancer.

A 60‐year‐old woman was urgently admitted to our hospital because of vertigo and left hemiplegia. Laboratory examination showed thrombocytopenia, high levels of D‐dimer and carcinoembryonic antigen. Brain magnetic resonance imaging (MRI) revealed multiple bilateral cerebral infarctions. Chest computed tomography (CT) showed an irregularly shaped tumor in the upper lobe of the left lung and mediastinal node swelling. The histopathological findings revealed adenocarcinoma negative for anaplastic lymphoma kinase fusion gene, sensitive epidermal growth factor receptor mutations. A diagnosis of lung adenocarcinoma initially presenting as arterial thromboembolism was made, and she was treated with direct oral anticoagulant (DOAC). Subsequently, pembrolizumab therapy was initiated because tumor cells were positive for programmed cell death protein 1 (PD‐L1;60%), and resulted in reduction of the tumor with normalization of the platelet count and d‐dimer. The treatment has been continued for over one year without any recurrence of the disease or thromboembolism., The prognosis in patients with NSCLC initially presenting as Trousseau's syndrome is extremely poor. This is the first report in which a patient was successfully treated with DOAC and immune‐check point inhibitor in lung adenocarcinoma initially presenting as Trousseau's syndrome.

Ganglioneuroblastoma is an uncommon malignant tumor of the sympathetic nervous system, which is considered a disease of children with the majority of cases in patients less than four years old and it rarely occurs in adults. We encountered a very unusual case of a posterior mediastinal ganglioneuroblastoma that developed in a 17‐year‐old male adolescent who underwent successful excision of the mediastinal mass and remained stable postoperatively. However, he developed lumbago one year after the surgery. Radiographic findings revealed osteolytic lesions in the lumbar vertebra and histological analysis confirmed bone metastasis of ganglioneuroblastoma. Here, we report the clinical course and present a review of the literature regarding adolescent and adult onset mediastinal ganglioneuroblastoma.

Background: The prognostic implications of palliative chemotherapy for advanced or recurrent thymic carcinomas require full elucidation. The lung immune prognostic index (LIPI) is a novel prognostic index whose effectiveness has recently been reported in lung cancer patients. This study aimed to evaluate the LIPI’s clinical value in advanced or recurrent thymic carcinoma patients. Methods: We retrospectively analyzed 41 advanced or recurrent thymic carcinoma patients undergoing palliative chemotherapy between January 2001 and December 2020. Survival-time analysis was conducted using the Kaplan–Meier method and log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to investigate the LIPI’s predictive and/or prognostic value.Results: Median progression-free survival (PFS) for first line chemotherapy and overall survival (OS) were significantly longer in the good-LIPI group (LIPI: 0) than in the intermediate/poor-LIPI group (LIPI: 1 or 2) (PFS: 13.4 vs. 6.8 months, p=0.0425; OS: 48.2 vs. 28.9 months, p=0.00506.). Multivariate analysis revealed that serum albumin Conclusions: Our study indicates that the LIPI is a potential prognostic marker in patients with advanced or recurrent thymic carcinoma undergoing palliative chemotherapy.

Background: The purpose of this study was to validate the clinical and epidemiological factors, diagnosis and initial treatment among thymic carcinoma patients.Methods: We surveyed retrospective data from 152,921 cancer patients in 22 principal hospitals.Results: A total of 88 thymic carcinoma cases were newly diagnosed. These patients consisted of 49 men and 38 women, with a median age of 66 years old. Eight patients were discovered in cancer screening, 9 in a voluntary setting, 14 at health checkups, 25 at follow-up of other diseases, and 32 cases by introduction from another hospital. Only 14 cases had been diagnosed with localized disease, but 5 cases were accompanied by regional lymph node metastasis. Furthermore, 12 cases showed infiltration into adjacent organs, and 24 cases had distant metastasis. Eighty-three cases were diagnosed by a pathological diagnosis. A surgical approach, chemotherapy, and radiotherapy were performed for 29, 35 patients, and 31 patients, respectively, while 17 patients received best supportive care.Conclusion: The diagnosis of thymic carcinoma is still difficult, and this disease has a tragically rapid progression if when discovered during follow-up of other diseases. An innovative modality for the early detection of thymic carcinoma is needed in modern medical society.

A 22-year-old male was diagnosed with a metastatic nonseminomatous germ cell tumor in the mediastinum with an elevated serum alpha-fetoprotein(AFP)concentration. Histopathological findings following percutaneous biopsy revealed the presence of a mature teratoma. Bleomycin, etoposide, and cisplatin(BEP)chemotherapy resulted decreased his serum AFP. However, the tumor became enlarged and was deemed inoperable due to size. Radiographic examination indicated diffuse calcification of the tumor mass. Growing teratoma syndrome in a patient with a primary mediastinal nonseminomatous germ cell tumor is extremely rare.

Purpose: The development of immune-related adverse events (irAEs) in patients undergoing immunotherapy has been reported to be a favorable prognostic factor in several studies. We aimed to examine the correlation between irAEs and prognosis in patients with non-small cell lung cancer (NSCLC) and further reveal the patient characteristics associated with response to immunotherapy among treatment responders who developed irAEs. Methods: We retrospectively enrolled 80 patients with NSCLC who received immunotherapy at Shinshu University Hospital between February 2016 and February 2020. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and those without irAEs. We examined the prognostic factors associated with PFS and OS using univariate and multivariate Cox proportional-hazards models. We further analyzed the patients who developed irAEs by classifying them into responders and non-responders. Results: Twenty-five patients developed irAEs. The median PFS and OS of the patients with irAEs were significantly longer than those of the patients without irAEs (6.8 vs. 1.9 months, p < 0.001, and 37.8 vs. 8.1 months, p < 0.001, respectively). Multivariate analysis associated with PFS and OS indicated that the development of irAEs was an independent favorable prognostic factor. Among the patients developing irAEs, the responder group had a significantly higher incidence of multiple irAEs than the non-responder group (41.7 vs. 0.0%, p = 0.009). Conclusion: Our findings revealed that the development of irAEs was associated with clinical benefits in NSCLC patients who received immunotherapy. In particular, patients with multiple irAEs might have good prognoses.

A relationship has been proposed between increases in oral Candida concentrations and host immunity. Therefore, the present study was conducted to investigate the relationship between oral Candida mannan concentrations and symptoms/signs of ill health and the immune status and also to examine whether health/the immune status may be evaluated based on oral Candida mannan concentrations. The health conditions of 25 healthy individuals and 10 cancer patients receiving cytotoxic chemotherapy were assessed using a questionnaire and oral rinse solutions collected on consecutive days. Candida mannan concentrations in oral rinse solutions were measured using a commercial sandwich ELISA kit. The use of dentures was identified as a significant independent factor increasing Candida mannan concentrations. In a stratified analysis based on the use of dentures, significantly increased Candida mannan concentrations were detected in healthy volunteers with chills and in cancer patients with slight/moderate fever (37.5–38.4 °C) (multivariate analysis, p

Introduction: Small-cell lung cancer (SCLC) is a very chemosensitive solid tumor but is characterized by rapid progression. The modified Glasgow prognostic score (mGPS) has been shown to be an independent prognostic factor in various tumors. However, there have been few reports regarding the prognostic value of mGPS in extensive disease (ED)-SCLC. Objective: This study was designed to clarify the clinical significance of mGPS focusing on its usefulness as a prognostic indicator for the survival and serial administrations of chemotherapies in patients with ED-SCLC. Methods: We retrospectively analyzed the clinical records of ED-SCLC patients diagnosed and treated at Shinshu University School of Medicine between January 2005 and December 2018. Overall survival (OS) was compared according to mGPS and we examined whether mGPS could be a prognostic factor in ED-SCLC using the Kaplan-Meier method and univariate and multivariate Cox hazard analyses. Results: Eighty-three patients were enrolled in this study. The median OS of mGPS 0, mGPS 1, and mGPS 2 groups were 13.6, 9.2, and 5.7 months, respectively. The OS of the mGPS 0 group was significantly longer than those of mGPS 1 and mGPS 2 groups (log-rank, p = 0.025 and 0.008, respectively). The rates of second-line chemotherapy administration in mGPS 0, mGPS 1, and mGPS 2 groups were 79.4, 61.9, and 33.3%, respectively. The rate in the mGPS 0 group was significantly higher than that in the mGPS 2 group (p = 0.003). Multivariate analyses indicated that mGPS 2 was an independent unfavorable prognostic factor in addition to old age (≥75 years), poor performance status (2–3), and elevated serum lactate dehydrogenase level (≥223 IU/L). Conclusion: In ED-SCLC patients, mGPS was useful as a prognostic indicator for OS.

Herein, we report a case of an angiosarcoma in a mediastinal non-seminomatous germ cell tumor that exhibited growing teratoma syndrome during chemotherapy. A 26-year-old man presented with a giant anterior mediastinal mass, which was diagnosed as a non-seminomatous germ cell tumor. The patient was administered three cycles of chemotherapy (bleomycin, etoposide, and cisplatin), but the mass grew despite normalization of tumor markers. Massive bleeding during thoracic surgery resulted in incomplete resection, and the mass was clinically and pathologically diagnosed as growing teratoma syndrome (only mature teratoma). The residual mass continued to grow, and complete resection was subsequently achieved after a detailed analysis of its vascular anatomy using angiography. The final pathological findings revealed angiosarcoma, which indicated a rare somatic type of mediastinal non-seminomatous germ cell tumor.

Dysregulation of T-cell–mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA–paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation–positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder–associated, and T-LGLL–associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation–positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation–negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.

Background Liposarcoma has been subclassified histologically into well‐differentiated, myxoid, pleomorphic, and dedifferentiated types. The dedifferentiated type generally shows poorer prognosis than the well‐differentiated type. Because of its rarity, the clinicopathological features and clinical outcomes of primary mediastinal dedifferentiated liposarcoma remain unclear.

Along with the expansion of therapeutic options for metastatic melanoma, the development of useful biomarkers is urgently required to predict and monitor treatment response. Serum 5-S-cysteinyldopa (5-S-CD) has been identified as a diagnostic marker of malignant melanoma, but its utility as a biomarker for emerging therapeutic agents remains unknown. We assessed serum 5-S-CD in 12 metastatic melanoma patients (median age, 76 years; six men and six women) who had been treated with nivolumab (Nivo) at Shinshu University Hospital between 2014 and 2016. Serum 5-S-CD and lactate dehydrogenase levels before and at 3-6 weeks of Nivo treatment were obtained and their changes were compared with clinical responses as defined by the Response Evaluation Criteria in Solid Tumors criteria (version 1.1). A decrease of 10 nmol/L or more of serum 5-S-CD was observed only in partial response patients (2/3 cases, 67%), while an increase of 10 nmol/L or more of serum 5-S-CD was witnessed only in progressive disease patients (4/8 cases, 50%). Serum 5-S-CD changes were within ±10 nmol/L in the remaining six patients (partial response, one; stable disease, one; progressive disease, four). The results of the four moderately affected progressive disease patients were suspected to have been influenced by small-sized metastatic lesions, a mixed response that included diminished and enlarged metastatic lesions, prior therapy to Nivo with BRAF inhibitors or radiation, or the development of brain metastasis. Serum 5-S-CD in the early phase of Nivo treatment may be helpful to predict therapeutic response in metastatic melanoma.

This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type. Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged