Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti‐human podoplanin mAb, NZ‐1, and a rat–human chimeric anti‐human podoplanin antibody, NZ‐8, derived from NZ‐1, which induced antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity against podoplanin‐positive MPM cell lines. In this study, we showed the antitumor effect of NZ‐1, NZ‐8, and NZ‐12, a novel rat–human chimeric anti‐human podoplanin antibody derived from NZ‐1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ‐1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI‐H290/PDPN or NCI‐H226 orthotopic xenograft mouse models. NZ‐8 and human natural killer (NK) (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ‐12 induced potent ADCC mediated by human MNC, compared with either NZ‐1 or NZ‐8. Antitumor effects were observed following treatment with NZ‐12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ‐12 mediated by human NK (CD56+) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin‐targeting immunotherapy using both NZ‐12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8 + T cells by fibrocytes was examined in MLRs with a 3 Hthymidine incorporation assay. Fibrocytes expressed CD80 low and CD86 high as a costimulatory molecule, and expressed PD-L1 high , but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8 + T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8 + T cells induced by fibrocytes. Anti-PD-L1 Ab further enhanced the proliferation of CD8 + T cells, even in the OVA-specific MLR with OT-1Rag 2/2 mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8 + T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8 + T cells when the activity is further enhanced by PD-L1/PD-1 blockade.

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Small-cell lung cancer (SCLC) accounts for 15 -20% of lung cancer (1) and presents aggressive clinical behavior characterized by rapid growth, metastatic spread to the distant organs (2). Despite the high response rate to initial chemotherapy, most patients subsequently experience a relapse of the primary tumor or distant metastasis, and the prognosis is still poor. SCLC is clinically categorized as two stages, limited disease (LD) and extensive disease (ED). LD-SCLC is defined as to be confined to the ipsilateral hemithorax and regional nodes, and able to be included in a single tolerable radiotherapy port. LD-SCLC is primarily treated with a combination of chemotherapy and radiotherapy, and its prognosis is improved by the development novel effective radiation therapy, such as accelerated hyperfractionated thoracic radiotherapy (AHF-TRT) (3). On the other hands, for ED-SCLC which is beyond the boundaries of LD including distant metastases, malignant pericardial, or pleural effusion and contralateral supraclavicular and contralateral hilar involvement, platinum-based combination chemotherapy alone is used as the initial therapy (4 -6). Despite the several novel anticancer agents against non-small cell lung cancer were developed and shown to have favorable outcome, the chemotherapy regimens against SCLC were not making any progress in recent decade, which leads to the poor prognosis of ED-SCLC.In the past, several studies were performed to reveal the prognostic factors in SCLC (7 -19). In these studies, male, poor performance status (PS) and weight loss as the host factors, and the extent of disease, number of metastatic sites, brain metastasis, bone metastasis, liver metastasis, elevated white blood cell (WBC) counts, neutrophil counts, serum lactate dehydrogenase (LDH), alkaline phosphatase (ALP), decreased platelet (PLT) counts, albumin (ALB), sodium, and C -reactive protein (CRP) as the tumor -related factors were reported to be unfavorable prognostic factors in multivariate analysis. Among these factors, existence of distant organ metastasis become easily a major problem of treatment in clinics, and metastatic involvement of the central nervous system, the bone marrow, or the liver is usually unfavorable compared with other sites.For the brain metastasis of SCLC, whole brain radiotherapy (WBRT) was mainly performed currently in the combination with chemotherapy. Moreover, novel stereotactic irradiation (STI) techniques were developed recently, such as stereotactic radiosurgery (SRS) or volumetric-modulated arc therapy (VMAT), resulted in improving the management of adverse events and prognosis (20 -23). For the bone metastasis, not only palliative radiotherapy (24), but also novel bone modifying agents (BMAs), such as zoledronic acid or denosumab can be used in recent days (25)(26). On the other hands, we still have few treatment strategies against liver metastasis, and frequently faced lethal clinical courses of aggressive and uncontrollable liver metastasis.Given that most of data regarding the prognostic...

BackgroundPneumonitis is a rare complication of bacillus Calmette-Guerin (BCG) immunotherapy seen in patients with urothelial cancer following the repeated administration of BCG. However, no case of BCG-induced pleurisy has been reported.Case presentationWe here report the first case of pneumonitis with lymphocytic pleurisy following bacillus Calmette-Guerin (BCG) immunotherapy. Although marked T helper cell alveolitis was found by bronchoalveolar lavage and transbronchial biopsies, no acid-fast bacillus could be identified in recovered BALF or pleural effusion. The lymphocyte stimulation test of BCG was strongly positive. However, levels of serum and bronchoalveolar lavage fluid KL-6, a useful marker for hypersensitivity pneumonitis (HP), were within normal ranges.ConclusionWe speculate that the pathogenesis of our case may be a hypersensitive reaction to the proteic component of BCG entering the lung and pleural space, which is different from the etiology of the common type of HP.

An 83-year-old woman was admitted to our hospital with abdominal pain. Examination revealed mediastinal lymphoadenopathy, hepatosplenomegaly, and infiltration of abnormal cells into the bone marrow with hemophagocytosis, and CD5-positive diffuse large B cell lymphoma was diagnosed. Chemotherapy was administered and progressive weakness of the limbs, resembling a Guillain-Barré-like syndrome, subsequently appeared. Cerebrospinal fluid examination indicated lymphoma cell infiltration. Although immune globulin and steroid therapies were not effective, intrathecal injection of methotrexate, predonisolone, and cytarabine improved these symptoms. Subsequent to chemotherapy, cell surface antigen changes were observed in the cerebrospinal fluid relative to those in bone marrow.

The feasibility and required sensitivity of circulating free DNA (cfDNA)-based detection methods in second-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment are not well elucidated. We examined T790M and other activating mutations of EGFR by cfDNA to assess the clinical usability. In 45 non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations, cfDNAs were prepared from the plasma samples. EGFR mutations in cfDNA were detected using highly sensitive methods and originally developed assays and these results were compared to tissue-based definitive diagnoses. The specificity of each cfDNA-based method ranged 96–100% whereas the sensitivity ranged 56–67%, indicating its low pseudo-positive rate. In EGFR-TKI failure cohort, 41–46% samples were positive for T790M by each cfDNA-based method, which was comparable to re-biopsy tissue-based T790M positive rates in literature. The concordance of the results for each EGFR mutation ranged from 83–95%. In eight patients, the results of the cfDNA-based assays and re-biopsy-derived tissue-based test were compared. The observed overall agreement ranged in 50–63% in T790M, and in 63–100% in activating EGFR mutations. In this study, we have newly developed three types of assay which have enough sensitivity to detect cfDNA. We also detected T790M in 44% of patients who failed prior EGFR-TKI treatment, indicating that cfDNA-based assay has clinical relevance for detecting acquired mutations of EGFR .

Patient: Male, 44-year-old Final Diagnosis: Central pontine myelinolysis Symptoms: Bulbar paralysis • locked-in syndrome • tetraplegia Medication: — Clinical Procedure: Brain MRI Specialty: Neurology • Rehabilitation Objective: Unusual clinical course Background: Central pontine myelinolysis (CPM) includes symmetric demyelination of the central pons. CPM is a rare neurological disorder that generally develops after rapid correction of hyponatremia in individuals having underlying conditions, such as malnutrition, alcoholism, and severe burns. It can cause severe long-term disabilities. However, there is currently no pharmacotherapy capable of promoting remyelination, a process crucial for recovery from CPM. We present the case of a patient with alcoholism and malnutrition-related CPM, which developed following rapid correction of hyponatremia but then improved remarkably with supportive physical therapy. Case Report: A 44-year-old alcoholic and malnourished man was admitted to an emergency hospital for disorientation due to overdrinking, but later developed bulbar palsy after hyponatremia was unexpectedly, but rapidly, corrected. Axial scans of the diffusion-weighted brain MRI revealed a characteristic lesion known as a piglet sign in the central pons. Based on his underlying conditions, present episode of sodium correction, and MRI finding, the patient was diagnosed as having CPM, which progressively worsened, resulting in locked-in syndrome after 12 days. The patient was then transferred to a long-term care unit and received simple motion exercise daily, but no specific medication. His symptoms gradually improved, achieving discontinuation of tube feeding on day 21, independent walking on day 110, and discharge after 6 months. Conclusions: This report highlights the importance of physical therapy, the potential of which is often underestimated despite its broad benefits for human health, as a readily applicable intervention for patients with CPM. Further understanding of mechanisms underlying exercise-induced myelination should contribute to establishing novel therapies for a wide spectrum of brain disorders.