Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma

We recently identified three HLA-A2402-restricted epitope peptides derived from cancer-testis antigens (CTA), TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3) for the development of immunotherapies against esophageal squamous cell carcinoma (ESCC). In order to evaluate their immunotherapeutic potential in ESCC patients, we estimated by ELISPOT assay the TTK-, LY6K-, or IMP-3-specific T-cell immune responses in tumor-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL), and peripheral blood lymphocytes (PBL) expanded from 20HLA-A2402 (+) ESCC patients, and correlated their immune activity with the expression levels of TTK, LY6K, and IMP-3, and MHC class I in the tumors. Induction of TTK-antigen specific T-cell response in TIL to the peptide-pulsed target cells was detected in 14 out of 20 (70%) cases, while LY6K or IMP-3 specific T-cell activity was observed in 11 of 20 (55%) or in eight of 20 (40%) cases, respectively. Furthermore, T-cell activity in RLNL and PBL was detectable in the similar proportion of the 20 ESCC patients. Interestingly, CTA-specific T-cell immune response was found in 13 of 14 (93%) TIL obtained from ESCC tumors with strong MHC class I expression, while it could be observed only in two of six (33%) TIL from ESCC tumors with weak MHC class I expression. These results strongly suggest the pre-existence of specific T-cell responses to HLA-A24-restricted epitope peptides from TTK, LY6K, and IMP-3 in ESCC patients. Monitoring antigen-specific T-cell responses, as well as the expression levels of MHC class I and epitope CTA in tumors, should be a selection index for application of cancer vaccine therapies to the patients who are likely to show good immune response. ( Cancer Sci 2008; 99: 1448–1454)     

Small cell carcinoma of the prostate treated with amrubicin

We describe the use of amrubicin hydrochloride to treat small cell carcinoma of the prostate in a 23-year-old man. Initial radiological examinations of the patient revealed a pelvic tumor associated with bilateral hydronephrosis, pelvic lymph node swelling, and lumbar vertebral bone metastases. The pathological diagnosis was small cell carcinoma originating in the prostate, based on positive immunohistochemical staining for neuron-specific enolase, synaptophysin, and myoglobulin; and negative staining for CD3e, CD20, leukocyte common antigen, and CD99. The clinical stage was T4N1M1. A bilateral nephrostomy was performed to improve renal function, and an ileostomy was established to prevent ileus. The first induction chemotherapy consisted of amrubicin 35 mg/m² (days 1, 2, 3, monthly). The amrubicin regimen caused a dramatic reduction in tumor size, but could not be continued, because of the occurrence of grade 4 diarrhea. A different regimen was then administered, consisting of one cycle of a 50% dose and a second cycle of a 75% dose of etoposide (100 mg/m² days 1, 2, 3), coadministered with carboplatin (AUC 5, plasma concentration curve). Five months after the induction of chemotherapy, the patient suffered respiratory arrest and died.     

Antigen-specific allogeneic immunotherapy--selective augmentation of GVL effects

Advancement of chemotherapeutic agents and introduction of molecular-targeted therapy have been improving the prognosis of malignant tumors. However, allogeneic hematopoietic cell transplantation (allo-HCT) still remains the sole curative therapy against chemotherapy-resistant hematological malignancies. Once it was found that full engraftment of donor's immune cells could bring sufficient graft-versus-leukemia/lymphoma(GVL)effects, reduced intensity preconditioning regimens that focus only on suppression of the recipient's immune system so as to allow donor graft engraftment have been introduced into clinics. This has expanded the number of patients eligible for allo-HCT, including elderly patients. Nevertheless, overall survival of patients with high-risk malignancies has not been sufficiently improved. Simple enhancement of donor-derived immunity would result in the increased risk of graft-versus-host disease (GVHD). Here, current and future strategies to selectively enhance GVL effects without inducing detrimental GVHD will be discussed in parallel with their background information and basic concepts.     

Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells

Nuclear factor-kappa B (NF-kappaB) inhibits cell death through suppression of the caspase cascade, the c-Jun N-terminal kinase (JNK) pathway, and reactive oxygen species (ROS) accumulation. To suppress this antiapoptotic function of NF-kappaB might be a promising strategy to increase susceptibility of tumor cells to stress-induced cell death. We have recently shown that tumor necrosis factor (TNF)alpha induces caspase-dependent and -independent JNK activation and ROS accumulation in cellular FLICE-inhibitory protein (c-Flip)(-/-) murine embryonic fibroblasts (MEFs). To apply this observation to tumor therapy, we knocked down c-FLIP by RNA interference in various tumor cells. Consistent with the results using c-Flip(-/-) MEFs, we found that TNFalpha stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFalpha and Fas induced the cleavage of mitogen-activated protein kinase/ERK kinase kinase (MEKK)1, resulting in generation of a constitutive active form of MEKK1 leading to JNK activation in c-FLIP knockdown cells. Given that ROS accumulation and necrotic cell death enhance inflammation followed by compensatory proliferation of tumor cells, selective suppression of caspase-dependent ROS accumulation will be an alternative strategy to protect cells from ROS-dependent DNA damage and compensatory tumor progression.     

Nadifloxacin downmodulates antigen-presenting functions of epidermal Langerhans cells and keratinocytes

BACKGROUND: Nadifloxacin is an anti-microbial quinolone derivative widely used for the treatment of acne as a topical agent. This drug has been suggested to have not only anti-bacterial but also anti-inflammatory actions, which may have a beneficial effect on some aspects of inflammatory acne. OBJECTIVE: To further clarify its abilities to modulate skin immunity, we investigated whether nadifloxacin affects the hapten- and superantigen-presenting capacities of epidermal Langerhans cells (LC) and keratinocytes, respectively. METHODS: Immune lymph node CD4+ T cells from trinitrophenyl-sensitized BALB/c mice were cocultured with LC-enriched epidermal cells (LC-EC) that were freshly isolated from syngeneic mice and derivatized with trinitrophenyl hapten in the presence or absence of nadifloxacin. Alternatively, LC-EC were preincubated with nadifloxacin (NDFX), modified with the hapten, and cultured with immune T cells. The effects of nadifloxacin on the surface molecule expression in LC and keratinocytes were also tested by flow cytometry and cellular ELISA. RESULTS: LC-EC cultured with nadifloxacin at 10 microg/ml or more significantly suppressed the antigen-presenting function of LC for T cells. The ability of MHC class II+ keratinocytes to present a superantigen to T cells was suppressed by preincubation of keratinocytes with 30 microg/ml or more of nadifloxacin. These functional reductions in LC and keratinocytes reflected the decreased expression of MHC class II and/or costimulatory molecules. CONCLUSION: Nadifloxacin downmodulates cutaneous immunity by interfering with the antigen-presenting ability of epidermal cells.     

Primary cutaneous amyloidosis of the auricular concha: case report and review of published work

A 70-year-old Japanese female developed tiny papules on her bilateral ears 2 years previously. A histological study of a biopsy specimen revealed that amorphous materials were present in the widened dermal papillae. Because these materials were positive for both Congo red and Dylon, we diagnosed the lesion as primary cutaneous amyloidosis of the auricular concha. Immunohistochemically, the amyloid substance stained positively with 34betaE12 (cytokeratin 1/5/10/14), suggesting that it had an epidermal origin. Seven reported cases of this unique disorder were also reviewed.     

Synthetic prostacycline agonist,ONO-1301, ameliorates left ventricular dysfunction and cardiac fibrosis in cardiomyopathic hamsters

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood flow and increased collagen synthesis. Administration of growth factors was reported to attenuate left ventricular (LV) remodeling and dysfunction in animal models of dilated cardiomyopathy. We previously reported that ONO-1301, a synthetic prostacyclin agonist with thromboxane-synthase inhibitory activity, promotes production of hepatocyte growth factor and vascular endothelial growth factor from various cell types and ameliorate ischemia-induced LV dysfunction in mice and pigs. We evaluated therapeutic efficacy of ONO-1301 in the Syrian hamster (TO-2), a model of genetically determined dilated cardiomyopathy. Either vehicle or a slow releasing form of ONO-1301 (ONO-1301-PLGA, 10 mg/kg/3 weeks) was administered subcutaneously every 3 weeks to TO-2 hamsters from 24 to 32 weeks of age (n = 12 for each group). Age-matched F1B hamsters were used as a control. Plasma concentration of HGF was elevated in ONO-1301-PLGA group (p < 0.05). Echocardiographic study demonstrated that LV fractional shortening was significantly improved in the ONO-1301-PLGA group (25 ± 4%, p < 0.01) compared with that in the vehicle group (19 ± 2%). Cardiac fibrosis was significantly reduced by ONO-1301-PLGA (p < 0.05) as determined by Azan-Mallory staining. Capillary density of left ventricle was markedly reduced in TO-2 hamsters. ONO-1301-PLGA significantly increased capillary density in TO-2 group (p < 0.05). ONO-1301 improved LV dysfunction and reduced cardiac fibrosis in the hamster model of dilated cardiomyopathy. ONO-1301 might hold a therapeutic potential in the treatment of dilated cardiomyopathy.     

Bilateral single ectopic ureters with hypoplastic bladder: How should we treat these challenging entities?

Bilateral single ectopic ureters with hypoplastic bladder are rare and difficult to treat. Urinary diversion (e.g. by ileal conduit) is usually performed because of small bladder capacity. We report a case treated by staged operation without urinary diversion or bladder augmentation. The outcome shows that ureterovesicostomy between the dilated ureter and the bladder is a feasible method to increase capacity for bilateral single ectopic ureters with hypoplastic bladder.