Febrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab.

BACKGROUND Nivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. CASE REPORT A 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again. CONCLUSIONS Care needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.

The scab-like sign: A CT finding indicative of haemoptysis in patients with chronic pulmonary aspergillosis?

OBJECTIVES: The aim of this study was to assess the CT findings that characterise haemoptysis in patients with chronic pulmonary aspergillosis (CPA). METHODS: We retrospectively identified 120 consecutive patients with CPA (84 men and 36 women, 17-89 years of age, mean age 68.4 years) who had undergone a total of 829 CT examinations between January 2007 and February 2017. In the 11 patients who underwent surgical resection, CT images were compared with the pathological results. RESULTS: The scab-like sign was seen on 142 of the 829 CT scans, specifically, in 87 of the 90 CT scans for haemoptysis and in 55 of the 739 CT scans obtained during therapy evaluation. In 48 of those 55 patients, haemoptysis occurred within 55 days (mean 12.0 days) after the CT scan. In the 687 CT scans with no scab-like sign, there were only three instances of subsequent haemoptysis in the respective patients over the following 6 months. Patients with and without scab-like sign differed significantly in the frequency of haemoptysis occurring after a CT scan (p<0.0001). Pathologically, the scab-like sign corresponded to a fibrinopurulent mass or blood crust. CONCLUSIONS: The scab-like sign should be considered as a CT finding indicative of haemoptysis. KEY POINTS: • Haemoptysis is commonly found in patients with CPA. • A CT finding indicative of haemoptysis in CPA patients is described. • Scab-like sign may identify CPA patients at higher risk of haemoptysis.

CD83(+) dendritic cells and Foxp3(+) regulatory T cells in primary lesions and regional lymph nodes are inversely correlated with prognosis of gastric cancer.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells that are central to the regulation, maturation, and maintenance of the cellular immune response against cancer. In contrast, CD4(+)CD25(+) regulatory T cells (Tregs) play a central role in self-tolerance and suppress antitumor immunity. In this study, we investigated the clinical significance of mature CD83(+) DCs and Foxp3(+) Tregs in the primary tumor and regional lymph nodes from the viewpoint of the two opposing players in the immune responses. METHODS: We investigated, immunohistochemically, the density of CD83(+) DCs and Foxp3(+) Tregs in primary lesions of gastric cancer (n = 123), as well as in regional lymph nodes with (n = 40) or without metastasis (n = 40). RESULTS: Decreased density of CD83(+) DCs and increased density of Foxp3(+) Tregs were observed in the primary tumor and metastatic lymph nodes. Density was significantly correlated with certain clinicopathological features. Poor prognosis was observed in patients with a low density of CD83(+) DCs and a high density of Foxp3(+) Tregs in primary lesions. For patients with metastatic lymph nodes, the density of CD83(+) DCs in negative lymph nodes was found to be an independent prognostic factor by multivariate analysis. CONCLUSION: The density of CD83(+) DCs and Foxp3(+) Tregs was inversely correlated with tumor progression and reflected the prognosis of gastric cancer.

Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival.

BACKGROUND: Claudin, occludin, and zonula occludens (ZO)-1 are known as tight-junction-associated proteins. The aim of this study was to examine the expression of these proteins in gastric carcinoma. METHODS: Gastric cancer tissues (n = 124) were obtained from 124 patients who underwent gastrectomy at our hospital between January 2000 and December 2004. The expression of the above tight-junction-associated proteins in carcinoma, normal mucosa, and metaplastic epithelium was examined using immunohistochemistry. In addition, the expression of claudin-4 mRNA was examined in fresh frozen tissue obtained from 34 patients. RESULTS: Significant correlations were seen between the expression of claudin-4, occludin, and ZO-1. In regard to claudin-4, significant correlations were seen between the expression of claudin-4 evaluated by immunohistochemistry and the expression of claudin-4 mRNA. Claudin-4 expression was significantly decreased in tumors with undifferentiated-type adenocarcinoma, advanced T stage, lymph node metastasis, and peritoneal metastasis. Occludin and ZO-1 expression was significantly decreased in tumors with undifferentiated-type adenocarcinoma. Overall survival was significantly shorter in patients with low claudin-4 expression. Cox multivariate analysis revealed that low claudin-4 expression was independently associated with significantly decreased overall survival. CONCLUSION: Tight-junction-associated proteins, particularly claudin-4, may play important roles in determining invasiveness, metastatic potential, and survival in gastric cancer.

Detection of cancer cells disseminated in bone marrow using real-time quantitative RT-PCR of CEA, CK19, and CK20 mRNA in patients with gastric cancer.

BACKGROUND: To determine the significance of bone marrow disseminated tumor cells in gastric cancer, we investigated the mRNA expression levels of carcinoembryonic antigen (CEA), cytokeratin 19 (CK19), and cytokeratin 20 (CK20) using the real-time quantitative reverse-transcription polymerase chain reaction (RQ-PCR). METHODS: Bone marrow samples were aspirated from the sternum at the time of surgery in 65 patients with resectable gastric cancer. Total RNA was extracted from bone marrow; and the expression levels of CEA, CK19, and CK20 mRNA were determined by RQ-PCR using an ABI PRISM 7000 and quantified against the GAPDH mRNA level. RESULTS: The detection limits of these genes were determined in the gastric cancer cell line MKN-45 and the colon cancer cell line C-1, which had been serially diluted in peripheral blood mononuclear cells (PBMCs). A rate of 1 cancer cell/million PBMCs was obtained by detecting CEA and CK19 mRNA in MKN-45 and by detecting CK20 mRNA in C-1. In the clinical samples, only 1 of the 65 gastric cancer patients (1.5%) who had stage IV disease was positive for CEA, CK19, and CK20 mRNA; none of CEA, CK19, or CK20 mRNA was positive in the remaining 64 patients. No significant correlation was observed between disseminated cancer cells in bone marrow and clinicopathological features, including simultaneous or metachronous hepatic metastasis and patient survival. CONCLUSION: The incidence of disseminated cancer cells in bone marrow in our study appears low, unlike that in previous reports. The significance of disseminated cancer cells in bone marrow may also be quite low in gastric cancer.

Understanding the response of dendritic cells to activation by streptococcal preparation OK-432.

BACKGROUND: The streptococcal preparation OK-432 induces maturation of T cells and dendritic cells (DCs). However, the mechanisms by which OK-432 induces DC maturation are not well understood. MATERIALS AND METHODS: The effects of OK-432 and TNF-alpha on peripheral blood mononuclear cells (PBMCs) were compared. Antibody-based approaches were used to detect proteins characteristic of antigen-presenting cells and cytokines. Cytotoxicity was evaluated by measuring the release of LDH after incubation of effector and target cells. The TLR-4 levels were measured by real-time quantitative PCR. RESULTS: Changes in cell surface marker levels were detected in both treatment groups but OK-432 had a greater effect on induction of Th-1-type cytokines. Furthermore, TLR-4 mRNA was up-regulated in cells from two out of five patients in response to OK-432, but not in response to TNF-alpha. CONCLUSION: OK-432 has a more profound effect on human DCs than TNF-alpha and may act through multiple signaling pathways.

[A case of complete response after neoadjuvant chemotherapy for advanced esophageal cancer with low-dose FP therapy].

The patient was a 58-year-old man complaining of vomit and body-weight loss of 10 kg with advanced lower thoraco-abdominal esophageal cancer, which was 9 cm in length and with a maximum diameter of 5.5 cm on thoracic CT examination. Moderately differentiated squamous cell carcinoma diagnosed by pre-operative endoscopic biopsy. Low-dose FP therapy (continuous 5-FU div of 500 mg/day with intermittent CDDP div of 5 mg/day) was performed during 4 weeks as neoadjuvant chemotherapy. The side effect was little, and the tumor size was remarkably reduced. A histological complete response was diagnosed with no carcinoma cells evident in the resected specimen. The patient is alive and healthy with no relapse of the carcinoma 30 months after operation. We are first planning neoadjuvant chemotherapy, and then considering the additional radiotherapy after estimating the effect of chemotherapy. Low-dose FP therapy with low-dose cisplatin as a modulator does not show much side effect and is useful for esophageal cancer. We consider that the chemotherapy is more effective preoperatively than postoperatively because it preserves the feeding vessels for transporting the medicine to the focus of the disease.

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer.

BACKGROUND: This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU). METHODS: A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1M tegafur--0.4 M 5-chloro-2,4-dihydroxypyridine--1 M potassium oxonate (S-1 [TS-1]) were also compared, using three human gastric cancer xenografts in nude mice. RESULTS: There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity. CONCLUSION: DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.