TIM-3 expression induces resistance to PD-1 inhibitor in G-CSF-producing lung spindle cell carcinoma: A case report.

Lung spindle cell carcinoma is an aggressive subtype of pleomorphic lung cancer resistant to cytotoxic chemotherapy. Programmed cell death-1 (PD-1) inhibitors have been reported to have clinical effects in patients with spindle cell carcinoma; however, the resistance mechanism to PD-1 inhibitors is yet to be fully elucidated. Herein, we report the case of an 88-year-old man with G-CSF-producing spindle cell carcinoma who acquired resistance to PD-1/PD-ligand 1 (L1) inhibitor in an early setting after a remarkable response. A histopathological review of the resistant specimen revealed a low count of CD8+ T cells and a predominant presence of M2 and TIM-3+ macrophages, indicating the presence of an immunosuppressive microenvironment. Our findings suggest a novel resistance mechanism to PD-1/PD-L1 inhibitors in G-CSF-producing spindle cell carcinoma.

A refractory pleural effusion caused by a pleural capillary hemangioma.

A 69-year-old man presented with a left pleural effusion. Even after repeated drainage, the pleural effusion had been increasing for more than two years. Thoracoscopy unexpectedly showed a pleural mass on the parietal pleura, and it was completely removed. The diagnosis was pleural capillary hemangioma, and the effusion has not recurred after the resection. Pleural hemangioma is one of the crucial differential diagnoses of refractory pleural effusion.

A novel method for rapid detection of Streptococcus pneumoniae antigens in blood.

In this study, we used "RAPIRUN(®)Streptococcus pneumoniae HS (otitis media/sinusitis) (RAPIRUN-HS)," a rapid S. pneumoniae antigen detection kit, to investigate methods for detecting S. pneumoniae antigens in blood of 32 bacterial pneumonia patients. We simultaneously performed PCR to detect S. pneumoniae in blood samples. The results of these tests were compared based on pneumonia severity, determined using the Pneumonia Severity Index (PSI) score classification. Four S. pneumoniae PCR-positive patients of the six severe pneumococcal pneumonia patients (PSI risk class IV/V) also tested positive using RAPIRUN-HS. Twenty-four mild to moderate pneumonia patients (PSI risk class I-III) were S. pneumoniae PCR-negative; of these, 21 tested negative using RAPIRUN-HS. The pneumococcal pneumonia patients testing positive using RAPIRUN-HS had low leukocyte counts and elevated C-reactive protein and procalcitonin levels, indicating that RAPIRUN-HS results were correlated with pneumonia severity. The time course evaluations of the laboratory tests for severe pneumococcal pneumonia patients showed that RAPIRUN-HS and S. pneumoniae PCR yielded positive results earlier than the changes in procalcitonin and IL-6. Thus, concomitant pneumococcal bacteremia was strongly suspected in patients testing positive using RAPIRUN-HS. In conclusion, RAPIRUN-HS may be useful for determining whether to admit patients into hospitals and selecting the appropriate antimicrobial agents.

[A TUBERCULOUS PSEUDO-ANEURYSM OF THE ABDOMINAL AORTA COMPLICATED BY MILIARY TUBERCULOSIS].

A 66-year-old man was transferred to our hospital on November 2010 owing to a diagnosis of miliary tuberculosis. Treatment was initially started with INH, RFP, PZA, and EB. However, PZA and EB were discontinued because of their adverse effects. Subsequently, chest radiographic and laboratory findings gradually improved. However, the patient experienced lumbago, which exacerbated towards the end of March 2011. An abdominal CT scan showed an abdominal mass at the L3-L5 level between the abdominal aorta and lumbar vertebra. On the basis of the findings of abdominal ultrasonography, MRI, and PET-CT, infectious abdominal aortic aneurysm was highly suspected. Therefore, vascular graft replacement surgery was performed at the beginning of May 2011. The result of histopathological analysis showed the presence of acid-fast bacteria in the aneurysm and the lymph nodes around it, revealing that the aneurysm was due to systemic miliary tuberculosis. After the surgery, the patient was administered LVFX in addition to INH and RFP for 18 months and showed no recurrence.

High efficiency CD91- and LOX-1-mediated re-presentation of gp96-chaperoned peptides by MHC II molecules.

Exogenous antigens enter antigen-presenting cells through non-specific mechanisms and are presented by the MHC II molecules. We show here that antigens chaperoned by the heat shock protein gp96 enter dendritic cells and B cells through a specific, CD91- and LOX-1-mediated mechanism, and are presented by MHC II molecules, in addition to MHC I molecules as previously demonstrated. Receptor utilization results in high efficiency uptake such that antigen concentrations as low as 10(-9) M, if chaperoned by gp96, lead to productive antigen presentation. Chaperoning by gp96 increases the efficiency of uptake over un-chaperoned peptides by up to two orders of magnitude. Consistent with these studies in vitro, immunization of mice with gp96-peptide complexes (containing 5 ng peptide) results in generation of a peptide-specific CD4+ T cell response. The high efficiency suggests a mechanism in which dendritic cells, exposed in vivo to heat shock protein-chaperoned peptides liberated by virus-infected host cells or by the lysis of infecting bacteria, may prime and expand specific CD4+ responses.

Heat shock protein-antigen presenting cell interactions.

The heat shock protein-antigen presenting cell interaction lies at the center of the unique properties of heat shock proteins as immunogens. This interaction is a key event in adaptive immune response elicited by heat shock protein-chaperoned peptides, naturally derived or artificially reconstituted. The heat shock protein-antigen presenting cell interaction results in a primitive and fundamental chain of events, i.e., translocation of the NF-kappaB complex into the nuclei of antigen presenting cells, leading to a chain of transcriptional events including secretion of cytokines and expression of various antigen presenting and co-stimulatory molecules. The heat shock protein-antigen presenting cell interaction thus results in enrollment of not only the adaptive but also the innate component of the immune response. Here, we discuss the different methods involved in the in vitro study, of heat shock protein-antigen presenting cell interactions.