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Abstract 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 548 patients with a median age of 70.0 (19–89) years, 71.4% 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 (23.9%), pembrolizumab plus anticancer drugs (7.8%), and nivolumab plus ipilimumab (5.1%). Thirty-eight cases of TE (6.9%) occurred (22 VTE, 16 ATE). Risk factors significantly associated with TE in multivariate logistic analysis were dyslipidemia (OR 2.44; 95% CI 1.17–5.09; p = 0.017), Khorana score ≥ 2 (HR 2.40; 95% CI 1.14–5.04; p = 0.021). Overall survival was not significantly different from patients without TE (p = 0.963). Conclusion These results suggested that the frequency of TE is higher than expected and should be considered and monitored in patients treated with ICIs.

Introduction: Lung adenocarcinoma with parathyroid hormone (PTH)-related hypercalcemia is uncommon. Case Presentation: A 69-year-old man was admitted to our hospital due to anorexia and fatigue. Serum calcium (15.0 mg/dL) and carcinoembryonic antigen (361.7 ng/mL) were extremely high, and PTH-related protein (PTH-rP) also elevated (16.7 pmol/L). Systemic computed tomography revealed multiple enlarged lymph nodes and disseminated peritoneal nodules, with irregularly shaped nodules in the upper lobe in the left lung. Ultrasound-guided biopsy from the axillary lymph node revealed adenocarcinoma. Immunohistological staining showed the tumor cells to be positive for cytokeratin 7 and PTH-rP and negative for cytokeratin 20 and thyroid transcription factor-1. Although the primary origin remains undetermined despite detailed examinations, possible primary tumor was considered to be lung adenocarcinoma in the present case. The serum calcium level was reduced by denosumab, but the patient died 20 days after admission. Conclusion: The present case demonstrated the importance of considering oncological emergency, such as hypercalcemia and/or PTH-rP-producing hypercalcemia, in patients with adenocarcinoma.

Abstract Objective This study was performed to validate the epidemiology, initial treatment, and clinical practice of lung cancer patients in the Hokushin region, Japan. Methods We retrospectively surveyed data of 5503 newly diagnosed and registered lung cancer patients in 22 principal hospital-based cancer registries in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017. Results The patients consisted of 3677 (66.8%) men and 1826 (33.2%) women with a mean (range) age of 72.2 (27–103) years). Diagnoses were small cell lung cancer (n = 512, 9.4%), squamous cell carcinoma (n = 1083, 19.7%), and non-squamous non-small cell lung cancer (NSCLC; n = 3906, 70.9%). The population with stage I disease in Toyama prefecture (41.1%) was smaller than in the other three prefectures associated with reduced selection of initial surgical 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 (65.4% of patients under 75 years and in 96.7% of patients over 75 years). Conclusion This study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan. Simultaneous analysis of nationwide registry and insurance data could provide valuable insights for the development of lung cancer screening and medical treatment strategies. In addition, the comparative data analysis with other lesions or countries will be useful for evaluating the differences in clinical practice of cancer managements.

Abstract 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 and comparing the differences in the status of antiemesis and management.

Abstract Thymic carcinoma is a highly malignant tumor and treatment options are limited. Lenvatinib, a novel multitargeted kinase inhibitor, has recently been approved for the treatment of unresectable thymic carcinoma. There are no reports of complete surgical resection after the administration of first‐line lenvatinib in advanced thymic carcinoma. A 50‐year‐old man visited our hospital because a computed tomography (CT) scan of the chest showed a large thymic squamous cell carcinoma. We suspected malignant pericardial effusion, invasion of the left upper lobe of the lung, and left mediastinal lymph node metastases. The patient was diagnosed with WHO classification stage IVb disease. Lenvatinib therapy was started at 24 mg/day as first‐line therapy. Gradual dose reduction to 16 mg/day was required because of hypertension, diarrhea, and palmar‐plantar erythrodysesthesia syndrome as side effects. Chest CT findings after 6 months of lenvatinib therapy showed reduction of the main tumor, disappearance of the mediastinal lymph node metastases, and pericardial effusion. Complete salvage resection was successfully performed a month after discontinuation of lenvatinib. The patient has been disease‐free for 1 year without adjuvant therapy. Lenvatinib therapy is one of the promising therapeutic options for thymic carcinoma and may make salvage surgery increasingly useful for advanced thymic carcinoma.

Abstract Here, we report a case of mediastinal mesenchymal tumor with a pericytic neoplasm feature that responded to radiation therapy. A 43‐year‐old man visited our hospital with a complaint of esophageal obstruction and chest pain. Chest computed tomography revealed a middle mediastinal tumor and a mesenchymal tumor was diagnosed with a pericytic neoplasm feature by video‐assisted thoracoscopic biopsy. The definitive treatment for soft tissue tumor is surgical resection; however, the mediastinal tumor was unresectable because of esophageal and tracheal invasion. Radiation therapy was administered and there was a partial tumor response and 2 years disease‐free status. With a review of the literature, we discuss the clinical and pathological characteristics of this rare tumor and its treatment.

Abstract 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.

Abstract Backgrounds 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. Methods 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. Results 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 (

Introduction Germ cell tumor with malignant transformation is extremely rare. We present a case of testicular primitive neuroectodermal tumor with multiple metastases that was effectively managed by surgery, irradiation, and second‐line chemotherapy. Case presentation A 22‐year‐old man was diagnosed as having teratoma including primitive neuroectodermal tumor with lymph node and multiple bone metastases. Five months afterwards the first‐line therapy, his skull metastasis recurred. Vincristine, doxorubicin, and cyclophosphamide therapy followed by vincristine, actinomycin D, and cyclophosphamide therapy was given as second‐line chemotherapy. Computed tomography revealed no disease progression 3 months after the treatments. Conclusion Metastatic primitive neuroectodermal tumor may be successfully managed by multidisciplinary cancer treatment.

Abstract 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.

Abstract 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 clinical value of the LIPI 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 predictive and/or prognostic value of the LIPI. 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 = 0.025; 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 albumin

Carotid body paraganglioma is a rare neuroendocrine tumor presenting with low-grade histological and clinical features. However, the tumor has the potential to produce distant metastasis, and due to its rarity, little information is available regarding chemotherapy for such metastatic lesions. Here, we report a case of carotid body paraganglioma with development of pulmonary and bone metastases 10 years after radical surgery for the primary lesion in the neck. The lesions showed a good response to cyclophosphamide, vincristine, and dacarbazine chemotherapy. A beneficial therapeutic outcome by chemotherapy is extremely rare in patients with metastatic carotid body paraganglioma.

Abstract Here, we report a case of carbohydrate antigen (CA) 19‐9‐producing mediastinal neuroendocrine tumor (NET) (atypical carcinoid). A 54‐year‐old woman with no specific relevant medical history was referred to our hospital because of increased CA19‐9 (95.3 U/ml) detected on health screening. Chest computed tomography (CT) revealed an anterior mediastinal mass without localized lymphadenopathy. Thoracic surgery was performed and the histopathological diagnosis was thymic CA19‐9‐positive NET. The patient developed mediastinal lymph node metastasis at 1 year (CA19‐9: 413 U/ml) and multiple bone metastases 4 years (CA19‐9: 2303 U/ml) after surgery. Increased CA19‐9 levels paralleled the clinical courses of relapse. To our knowledge, this is the first report of CA19‐9‐producing thymic NET.

Abstract 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.

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.

Abstract Background Nivolumab is a second‐line chemotherapy for non‐small cell lung cancer (NSCLC). This study explored the impact of clinical biomarkers such as neutrophil:lymphocyte ratio (NLR), C‐reactive protein:albumin ratio (CAR), and modified Glasgow prognostic score on the efficacy and outcome of nivolumab monotherapy in previously treated NSCLC patients. Methods We retrospectively analyzed advanced or postoperative recurrence of NSCLC in 113 patients in two Japanese facilities from January 2015 to December 2019. Optimal cutoff values of NLR and CAR were assessed by the area under the receiver operating characteristic curves predicting death events to conduct regression analysis. Baseline values and values collected eight weeks after nivolumab treatment were measured to investigate time‐series changes of these markers. Results The patients showed median overall survival (OS) and progression‐free survival (PFS) of 14.0 months and 2.3 months, respectively, with both being significantly longer in patients with partial response (PR) than in patients with progressive disease (PD). Optimal cutoff levels for NLR and CAR were 5.8 and 0.83, with significant decrease in CAR (P = 0.002) from baseline levels in PR patients and significant increase in PD patients. Baseline CAR ≥0.83 was significantly associated with one‐year mortality events and overall survival (OS), and multivariate analysis showed significant association of age ≤70 years, an Eastern Cooperative Oncology Group performance status score of 2 or 3, and a baseline CAR ≥0.83 with inferior OS. Conclusions For second‐line nivolumab therapy, evaluation of baseline CAR and subsequent changes in CAR may be predictive of therapeutic response to nivolumab and long‐term survival in NSCLC patients. Key points Significant findings of the study The baseline value of C‐reactive protein:albumin ratio was significantly associated with one‐year mortality and overall survival in non‐small cell lung cancer patients treated with nivolumab. What this study adds Time‐series change of C‐reactive protein:albumin ratio may be useful for predicting the treatment efficacy in patients treated with nivolumab.

Abstract 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.

Abstract Background Due to its rarity, little is known about the clinical presentations and responses to systemic chemotherapies in advanced and/or metastatic cases of paratesticular liposarcoma. Case presentation Here, we report the case of a 75-year-old Japanese man with giant paratesticular liposarcoma. Imaging studies revealed a 26 cm tumor in his right scrotum and lung metastases at presentation. He underwent radical orchiectomy followed by systemic chemotherapies. Pathological findings of the resected primary tumor confirmed a dedifferentiated liposarcoma. He then started chemotherapy treatment with gemcitabine plus docetaxel. His disease status was stable for 1 year. Eribulin was used for second-line chemotherapy. He had a relapse at 5 months after eliburin and died at 22 months after diagnosis. Conclusion Early diagnosis and curative radical surgery are important for treatment of paratesticular liposarcoma. However, a giant paratesticular liposarcoma could cause metastases, and systemic chemotherapy may be helpful for prolonging survival in patients with metastatic paratesticular liposarcoma.

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.

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.

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.

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.

Background The efficacy of amrubicin for relapsed small‐cell lung cancer (SCLC) has been reported in previous studies. Few reports, however, describe the efficacy and survival benefit of third‐line amrubicin chemotherapy in patients with extensive disease (ED)‐SCLC. Methods We retrospectively analyzed the clinical records of ED‐SCLC patients treated with amrubicin salvage chemotherapy as a third‐line chemotherapy between January 2005 and July 2016 (salvage amrubicin group). The efficacy and toxicities of amrubicin were evaluated. Overall survival (OS) in the amrubicin salvage group was compared with OS among ED‐SCLC patients treated with at least second‐line chemotherapy between May 2000 and July 2016 and without subsequent amrubicin salvage chemotherapy. Results A total of 18 patients with a median age of 70 years were analyzed in the amrubicin salvage group. The median number of treatment cycles of amrubicin was four. The response rate was 27.8% (95% confidence interval (CI), 7.1%–48.5%), and the disease control rate (DCR) was 66.7% (95% CI, 44.9%–88.4%). Median progression‐free survival was 2.9 months (95% CI, 1.0–4.9 months), and median OS after an initial chemotherapy was 18.1 months (95% CI, 10.2–26.0 months). OS in the amrubicin salvage group was significantly longer than in the no‐amrubicin group (n = 19; 12.6 months, 95% CI, 11.5–13.8 months, P = 0.005). The frequency of neutropenia greater than grade 3 was 72.2%, with febrile neutropenia developing in 38.9% of patients in the amrubicin salvage group. Conclusions Despite a high frequency of febrile neutropenia, amrubicin salvage chemotherapy may improve OS in patients with relapsed ED‐SCLC.

A 32‐year‐old woman was referred to our hospital because of severe psychosis and was found to have an ectopic ACTH‐producing thymic neuroendocrine tumor. Laboratory data revealed an elevated serum cortisol and plasma ACTH level, hypokalemia, and metabolic alkalosis. Chest computed tomography (CT) revealed an anterior mediastinal mass and multiple pulmonary nodules. As the patient was unable to communicate because of her consciousness disturbance, she was managed with artificial ventilation and deep sedation. Metyrapone and potassium supplementation were administered, and steroid psychosis gradually improved. Thoracic surgery was performed and the histopathological diagnosis was thymic neuroendocrine tumor with positive anti‐ACTH immunohistochemical staining. Here we present details of the case and review the literature.

Patients with stage I testicular germ cell tumors have a long life expectancy, but the tumors have a potential to relapse after treatment. Although relapse is observed within a few years in most cases, late relapse over 10 years after initial treatment has also been reported in patients with stage I testicular germ cell tumors. We encountered a case of testicular seminoma that developed mediastinal lymph node metastasis 13 years after radical surgery for the primary tumor. The relapsed disease progressed rapidly and the patient died within 1 month due to respiratory failure without any chance for therapy. On postmortem examination, the thoracic lesions were pathologically confirmed to be metastases from the testicular seminoma with yolk sac tumor. Here, we report the clinical course and a review of the relevant literature. Based on our experience, we emphasize long-term follow-up and/or careful examination in patients with stage I testicular germ cell tumors.

Background Fluorine‐18‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) uptake in primary lesions has been well studied, but little information is available about metastatic bone lesions in patients with lung cancer. The present study was performed to evaluate the relationships between metastatic bone FDG uptake and clinical parameters in patients with lung cancer. Methods FDG uptake was evaluated as the maximum standardized uptake (SUVmax) value of each targeted bone lesion, and the bone to primary lesion ratio of SUVmax (B/P ratio) was calculated. Forty‐nine patients (27 men and 22 women) with a diagnosis of lung cancer (small cell lung cancer [SCLC], n = 7; non‐small cell lung cancer [NSCLC], n = 42) with bone metastasis, and a total of 185 bone metastatic lesions were evaluated. Results The SUVmax in bone and the B/P ratio were significantly higher in patients with pain and subsequent development of skeletal‐related events than in those without pain or skeletal‐related events, respectively. In addition, the SUVmax in metastatic bone lesions and the B/P ratio in SCLC were significantly lower than those in NSCLC, despite similar FDG uptake in the primary tumor. Conclusion Our findings suggest that FDG‐PET evaluation in metastatic bone lesions could be useful to predict initial pain and subsequent clinical outcomes of local bone status in initially diagnosed lung cancer patients with bone metastasis. In addition, our results suggest that there could be histological differences in the biological activity of bone metastatic lesions in lung cancer, especially between SCLC and NSCLC.

Abstract Background Recently, several reports investigating tumor doubling times (TDTs) in lung cancer have demonstrated that lung cancer patients with shorter TDTs have poor prognoses. Although data have shown that the solid component of a tumor is clinically more important, relationships between solid component TDTs and lung cancer prognoses remain unclear. Methods To evaluate relationships between TDT and survival, we retrospectively evaluated 231 patients who underwent surgical resection for non-small cell lung cancer. The TDTs of whole and solid components were calculated using preoperative thin-slice chest computed tomography scans with a cut-off of 400 d between scans. Results Patients with short TDTs (

Pulmonary artery intimal sarcoma is a rare malignant tumor. Due to its low prevalence, little is known about efficacious systemic chemotherapies in cases where the tumors are unresectable or metastatic. In addition, the location of the disease can contribute to poor survival regardless of the response to therapy, as the tumor’s position can cause pulmonary artery hypertension either rapidly or chronically. We encountered a case of unresectable pulmonary artery intimal sarcoma with lung metastases. Treatment with several cytotoxic agents resulted in prolonged survival of 14.2 months. Here, we report the clinical course of this case and present a review of the relevant literature.

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.

A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.

Pulmonary neuroendocrine tumors are rare, and there have been very few reports regarding optimal chemotherapeutic regimens. Two molecular targeted agents, everolimus and sunitinib, have recently been shown to provide an additional treatment benefit for pulmonary neuroendocrine tumors. However, little information is available regarding the usefulness of streptozocin chemotherapy. Here, we encountered a case of relapsed and refractory mediastinal atypical carcinoid tumor associated with multiple endocrine neoplasia type 1 for various cytotoxic and molecular targeted agents. The patient showed a good response to streptozocin monotherapy. We describe the case and review streptozocin chemotherapy in patients with pulmonary neuroendocrine tumors.

Abstract Background Single soft tissue metastasis of medullary thyroid carcinoma is extremely rare. In addition, several occult medullary thyroid carcinomas with distant metastasis were reported, but undetectable primary lesion at diagnosis was also extremely rare. Case presentation A 74-year-old man was admitted to our hospital because of a painful nodule in his left buttock for over 1 year. Needle biopsy was performed, and the histological findings revealed adenocarcinoma positive for thyroid transcription factor-1. No evidence of a primary tumor, including the lung and thyroid gland, could be found elsewhere despite detailed examinations, including thyroid echography, chest computed tomography, and fluorodeoxyglucose-positron emission tomography. The soft tissue tumor was resected with a wide margin. Immunohistochemical analysis showed the tumor cells to be positive for cytokeratin-AE1/3, cytokeratin 7, synaptophysin, chromogranin A, calcitonin, and carcinoembryonic antigen, but negative for cytokeratin 20, Napsin A, Pax8, and p40, resulting in a diagnosis of metastasis of medullary thyroid carcinoma. Conclusion Initial presentation with a single metastasis to soft tissue and undetectable primary tumor in the thyroid gland is an extremely rare clinical manifestation in patients with medullary thyroid carcinoma.

We report a case of pleomorphic carcinoma with exon 18 mutation (G719X) of the epidermal growth factor receptor (EGFR), which showed good response to afatinib and resulted in successful resection. To our knowledge, this is the first report on the use of afatinib for pleomorphic carcinoma followed by the surgical resection. The patient was a 59-year-old woman, who visited our hospital because chest computed tomography showed a 28 × 28-mm nodule in the left upper lobe. Bronchoscopy was performed and the histological findings of transbronchial biopsy revealed adenosquamous carcinoma positive for G719X mutation in exon 18 of the EGFR. Since fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography revealed a positive accumulation in the bilateral hilar and mediastinal lymph nodes, the disease was diagnosed as cT1bN3M0, stage IIIB. After 3 months of afatinib therapy, FDG accumulation in primary tumor was almost gone. However, FDG accumulation in lymph nodes remained unchanged. Video-assisted thoracic surgery was planned for further diagnostic information and left upper lobectomy with mediastinal lymph node dissection was performed. The resected tumor included adenocarcinoma, squamous cell carcinoma, and spindle cell components, without lymph node metastasis. Thus, the disease was diagnosed as pleomorphic carcinoma (pT2aN0M0, stage IB). All components in the resected specimen had the same G719X mutation in exon 18 of the EGFR. The patient has shown no signs of recurrence at 1 year after the operation. The present case indicates the possibility of minor EGFR mutations in pleomorphic carcinoma and successful outcome by the use of afatinib and surgical resection.

Key message This is the first report of a thymoma developing with unusual invasion into the oesophageal lumen.

BACKGROUND/AIMS:Cancer-related activation of cytokine networks are central aspects of tumor development. The goal of the study was to examine the possibility of plasma cytokines for the screening of colorectal cancer (CRC). METHODS:We carried out a multicenter, hospital-based case-control study in 66 adult Japanese patients with CRC and 87 healthy adult Japanese. A multiplex bead array immunoassay was used to examine 27 different plasma cytokines. Their association with the presence of CRC was evaluated by logistic regression analysis after adjusting for potential confounding factors. RESULTS:Thirteen plasma cytokines were notably associated with the presence of CRC (p< 0.05). Receiver operating characteristic analysis revealed that the combinatorial assessment of some of these plasma cytokines showed "good" capability for discriminating between CRC patients and control subjects (area under the curve (AUC): 0.819 for the combination of IL-9, Eotaxin, G-CSF, and TNF-α; 0.832 for the combination of IL-4, IL-8, Eotaxin, IP-10, and TNF-α). Individual cytokine assessments presented lower AUCs (0.657-0.755) than the combinatorial cytokine assessments. CONCLUSIONS:The levels of several plasma cytokines varied significantly between CRC patients and control subjects, suggesting the possibility of differentially expressed plasma cytokines as potential biomarkers for detecting the presence of CRC. Our results should be validated in other populations.

Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents.

Objective To develop a combinatorial panel of salivary cytokines that manifests the presence of non-small cell lung cancer (NSCLC) that will eventually improve prognosis by facilitating the early diagnosis and management of this common cancer. Methods We performed a case-control study comparing salivary cytokine profiles of 35 adult subjects with NSCLC with those of 35 matched, healthy nonsmokers. Multiplex bead array assays were used to quantify 27 cytokines in saliva, serum, and oral mucosal transudate samples. Logistic regression analysis was used to develop an informative cytokine panel. Receiver operating characteristic (ROC) curves were generated to evaluate the discriminant ability of the panel. Results A combinatorial 12-cytokine panel (interleukin receptor antagonist [IL1RN], IL1B, IL6, IL7, IL8, IL10, C-C motif chemokine ligand 11 [CCL11], tumor necrosis factor, C-X-C motif chemokine ligand 10 [CXCL10], C-C motif chemokine ligand 3, C-C motif chemokine ligand 4, and platelet-derived growth factor-BB) distinguished patients with NSCLC from healthy controls. Further, ROC analysis revealed that a cytokine panel comprising IL10 (odds ratio, 1.156) and CXCL10 (odds ratio, 1.000) discriminated NSCLC with a sensitivity of 60.6% and specificity of 80.8% (area under the ROC curve, 0.701). Conclusion A combinatorial panel of select salivary cytokines indicates the presence of NSCLC.

Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.

Little information is available about the usefulness of concurrent chemoradiotherapy for locally advanced thymic carcinoma due to a rare anterior mediastinal tumor. We experienced a case of locally advanced thymic carcinoma that responded well to concurrent thoracic radiotherapy combined with cisplatin plus vinorelbine chemotherapy. The patient showed remarkable tumor regression and has remained disease free for over 4 years following combined therapy. Concurrent chemoradiotherapy seems to be effective for locally advanced thymic carcinoma, and cisplatin plus vinorelbine could be an alternative chemotherapy regimen in combination with thoracic radiotherapy in patients with thymic carcinoma.

Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16−18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.

We present here a case of diffuse tracheobronchial wall spread of metastatic breast cancer who was successfully treated with trastuzumab plus vinorelbine chemotherapy. The patient had a left radical mastectomy for breast cancer in March 2000 and developed persistent cough and dyspnea in November 2006. Pulmonary function test demonstrated an obstructive pattern. Chest computed tomography showed a wall thickening of trachea and right side bronchus, but radiographic findings including 18F-fluorodeoxyglucose positron emission tomography failed to detect the locations of disease in the lung. The findings on bronchofiberscopy showed edematous tracheobronchial mucosa, but also failed to visually detect direct masses. Transbronchial biopsy specimens revealed involvement of metastatic breast cancer. The patient was treated with trastuzumab plus vinorelbine chemotherapy and the wall thickening of bronchial tree and clinical symptoms were improved. Although endobronchial metastasis in metastatic breast cancer is not uncommon, diffuse spread without forming intraluminal mass is extremely rare. The pattern of endobronchial metastasis should be considered in patients with malignancies even when radiographic abnormalities are undetectable.

The optimal chemotherapeutic regimen for cancer of unknown primary (CUP) remains uncertain. We encountered 3 cases with CUP who presented with thoracic lymph node metastasis. Detailed physical examination and diagnostic tests, including laboratory investigations, bronchoscopy, upper and lower gastrointestinal studies, computed tomography of the head, neck, abdomen and pelvis and 18F-fluorodeoxyglucose positron emission tomography, failed to identify the primary site in these cases. The patients were treated with the cisplatin plus docetaxel chemotherapy regimen. Concomitant thoracic radiotherapy was conducted in one patient and surgical resection in another. All patients showed good response to the chemotherapy and achieved long-term disease-free survival.

Koichi Ono1, Tomonobu Koizumi2, Rikimaru Nakagawa1, Sumiko Yoshikawa2, Tetsutarou Otagiri11Department of Anesthesiology and Resuscitation; 2First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, JapanPurpose: The present study was designed to examine effects of different mean airway pressure (MAP) settings during high-frequency oscillation (HFO) on oxygenation and inflammatory responses to acute lung injury (ALI) in rabbits.Methods: Anesthetized rabbits were mechanically ventilated with a conventional mechanical ventilation (CMV) mode (tidal volume 6 ml/kg, inspired oxygen fraction [FIo2] of 1.0, respiratory rate [RR] of 30/min, positive end-expiratory pressure [PEEP] of 5 cmH2O). ALI was induced by intravenous administration of oleic acid (0.08 ml/kg) and the animals were randomly allocated to the following three experimental groups; animals (n = 6) ventilated using the same mode of CMV, or animals ventilated with standard MAP (MAP 10 cmH2O, n = 7), and high MAP (15 cmH2O, n = 6) settings of HFO (Hz 15). The MAP settings were calculated by the inflation limb of the pressure-volume curve during CMV.Results: HFO with a high MAP setting significantly improved the deteriorated oxygenation during oleic acid-induced ALI and reduced wet/dry ratios, neutrophil counts and interleukin-8 concentration in bronchoalveolar lavage fluid, compared to those parameters in CMV and standard MAP-HFO.Conclusions: These findings suggest that only high MAP setting during HFO could contribute to decreased lung inflammation as well as improved oxygenation during the development of ALI.Keywords: lung protective ventilation, open lung ventilation, IL-8, neutrophil

OBJECTIVES: Pulmonary ground-glass nodules (GGNs) are occasionally diagnosed as invasive adenocarcinomas. This study aimed to evaluate the clinicopathological features of patients with pulmonary GGNs to identify factors predictive of pathological invasion. METHODS: We retrospectively evaluated 101 pulmonary GGNs resected between July 2006 and November 2013 and pathologically classified them as adenocarcinoma in situ (AIS; n = 47), minimally invasive adenocarcinoma (MIA; n = 30), or invasive adenocarcinoma (I-ADC; n = 24). The age, sex, smoking history, tumor size, and computed tomography (CT) attenuation of the 3 groups were compared. Receiver operating characteristic (ROC) curve analyses were performed to identify factors that could predict the presence of pathologically invasive adenocarcinomas. RESULTS: Tumor size was significantly larger in the MIA and I-ADC groups than in the AIS group. CT attenuation was significantly greater in the I-ADC group than in the AIS and MIA groups. In ROC curve analyses, the sensitivity and specificity of tumor size (cutoff, 11 mm) were 95.8% and 46.8%, respectively, and those for CT attenuation (cutoff, -680 HU) were 95.8% and 35.1%, respectively; the areas under the curve (AUC) were 0.75 and 0.77, respectively. A combination of tumor size and CT attenuation (cutoffs of 11 mm and -680 HU for tumor size and CT attenuation, respectively) yielded in a sensitivity and specificity of 91.7% and 71.4%, respectively, with an AUC of 0.82. CONCLUSIONS: Tumor size and CT attenuation were predictive factors of pathological invasiveness for pulmonary GGNs. Use of a combination of tumor size and CT attenuation facilitated more accurate prediction of invasive adenocarcinoma than the use of these factors independently.

We have developed a new internal cooled electrode for radiofrequency ablation (RFA) (Japan Application no. 2006-88228) suitable for forceps channel bronchoscopy. Here, we present our clinical experience with bronchoscopy-guided RFA under computed tomography (CT) monitoring for patients with peripheral-type non-small-cell lung cancer (NSCLC). Bronchoscopy-guided RFA was performed in two patients (80 and 70 years old) with NSCLC, who had no lymph node involvement and distant metastases (T1N0M0), but not indicated for surgery because of other complications, such as advanced age, poor pulmonary function, and refusal of thoracic surgery. The locations of the tumors were right S2 and left S3, respectively. Although the tumors showed ground-glass opacity (GGO) with solid components in both cases, radiographic findings changed to reduced mass-like shadow and remained stable for 4 and 3.5 years after bronchoscopy-guided RFA. As the former case developed progressive disease on chest CT, bronchoscopy-guided RFA was repeated in the same lesion, resulting in no change for the subsequent 1 year. There were no adverse reactions during the procedures. Thus, bronchoscopy-guided RFA is a safe and feasible procedure that represents a potentially useful therapeutic tool in local control in medically inoperable patients with stage I NSCLC.