A long-term survival case in Jehovah 's witness with simultaneous liver metastases of colon cancer by synchronous liver resection followed by a successful size reduction with chemotherapy

A bloodless surgery was required in the case of simultaneous liver metastases of colon cancer, one of which invaded at the confluence of left hepatic vein and inferior vena cava. In order to assure the safety and curability, hepatic arterial infusion chemotherapy aiming to size reduction was preceded to synchronous liver resection for a 53-year-old Jehovah's witness male. After gaining the reduction of tumor, synchronous liver resection was safely performed under a hemodilutional autotransfusion. The patient has been alive for 6 years under the withdrawal from chemotherapy.     

Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer

Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) or irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) has become a standard regimen for advanced or recurrent colorectal cancer. Numerous studies have reported that long-term use of FOLFOX or FOLFIRI leads to better survival for these patients. Thus, control of the toxicity of these drugs may be crucial to prolonging survival. Fucoidan is one of the major sulfated polysaccharides of brown seaweeds and exhibits a wide range of biological activities. In the present study, we analyzed the effect of fucoidan on suppressing the toxicity of anti-cancer drugs. A total of 20 patients with unresectable advanced or recurrent colorectal cancer scheduled to undergo treatment with FOLFOX or FOLFIRI were randomly allocated into a fucoidan treatment group (n=10) and a control group without fucoidan treatment (n=10). Results showed that fucoidan regulated the occurrence of fatigue during chemotherapy. Chemotherapy with fucoidan was continued for a longer period than chemotherapy without fucoidan. Additionally, the survival of patients with fucoidan treatment was longer than that of patients without fucoidan, although the difference was not significant. Thus, fucoidan may enable the continuous administration of chemotherapeutic drugs for patients with unresectable advanced or recurrent colorectal cancer, and as a result, the prognosis of such patients is prolonged.     

Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker

The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side-effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real-time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non-small-cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD-18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor-specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow-up in some lung cancer patients after surgical treatment.     

Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivin-derived peptide vaccine, in advanced colorectal cancer patients

We previously identified a human leukocyte antigen (HLA)-A24-restricted antigenic peptide, survivin-2B80-88, recognized by CD8+ cytotoxic T lymphocytes (CTL). Subsequently, we attempted clinical trials with this epitope peptide alone for some malignancies, resulting in clinical and immunological responses, although their potential was not strong enough for routine clinical use as a cancer vaccine. In the current study, to assess whether immunogenicity of the survivin-2B80-88 peptide could be enhanced with other vaccination protocols, we performed clinical trials in advanced colon cancer patients with two vaccination protocols: (i) survivin-2B80-88 plus incomplete Freund's adjuvant (IFA); and (ii) survivin-2B80-88 plus IFA and a type-I interferon (IFN), IFNα. Our data clearly indicated that, although the effect of survivin-2B80-88 plus IFA was not significantly different from that with survivin-2B80-88 alone, treatment with the vaccination protocol of survivin-2B80-88 plus IFA and IFNα resulted in clinical improvement and enhanced immunological responses of patients. Tetramer analysis of survivin-2B80-88 peptide-specific CTL demonstrated that such CTL were increased at least twofold after vaccination with this protocol in four of eight patients. In these patients, enzyme-linked immunosorbent spot (ELISPOT) results were also enhanced. Subsequent study of single-cell clone separation by cell sorting of peptide-specific CTL showed that each CTL clone was indeed not only peptide-specific but also cytotoxic against human cancer cells in the context of the expression of both HLA-A24 and survivin molecules. Taken together, these results indicate that vaccination of colon cancer patients with survivin-2B80-88 plus IFA and IFNα can be considered to be a very potent immunotherapeutic regimen, and that this protocol might work for other cancers.     

Tracheoesophageal Fistula Closed by Chemoradiotherapy in Lung Cancer

A 45-year-old man complaining of cough, dyspnea, and difficulty in swallowing was referred to our hospital. Chest CT scan showed a mediastinal mass compressing the trachea. He was diagnosed with poorly differentiated lung carcinoma by percutaneous needle biopsy. Bronchoscopy and upper gastrointestinal endoscopy revealed a tracheoesophageal fistula (TEF). Long-lasting febrile neutropenia made it impossible to continue chemotherapy, but a course of radiotherapy (total 61 Gy) was completed. The next endoscopy revealed closure of the TEF. Chemoradiotherapy (CRT) has been reported to close TEF in esophageal cancer, but the risk of a CRT-induced worsening of the fistula has dissuaded physicians from using CRT to treat TEF in lung cancer patients. CRT may serve as a palliative treatment for TEF in lung cancer as well as esophageal cancer.Key words: Chemoradiotherapy, Lung carcinoma, Tracheoesophageal fistula     

Occult neoplastic cells in the lymph node sinuses and recurrence/metastasis of stage III/Dukes' C colorectal cancer

Lymph nodes from patients with colorectal cancer were immunohistochemically stained for cytokeratin to investigate the relationship between the presence of occult neoplastic cells (ONCs) and recurrence/metastasis. A total of 80 patients with stage III/Dukes' C colorectal cancer were divided into 16 patients who developed recurrence/metastasis (recurrence group) and 64 patients without recurrence (non-recurrence group). ONCs were compared between the two groups with respect to i) single cells (≥ 3 floating ONCs), ii) clusters of cells (1 or more floating aggregates of 2-20 ONCs) and iii) single cells + clusters. When single cells were detected, the sensitivity for recurrence was 87.5% (14/16, p = 0.002), the positive predictive value (PPV) was 32.6% (14/43), the specificity was 54.7% (35/64) and the negative predictive value (NPV) was 94.6% (35/37). For clusters, the sensitivity was 87.5% (14/16, p<0.001), PPV was 41.2% (14/34), specificity was 68.8% (44/64) and NPV 95.7% (44/46). With single cells + clusters, the values were 87.5% (14/16, p<0.001), 48.3% (14/29), 76.6% (49/64) and 96.1% (49/51), respectively. These results suggest that the detection of single cells + clusters is a sensitive indicator of a high risk of recurrence/ metastasis, while ONCs are useful for identifying the low-risk group of patients with stage III colorectal cancer.     

Navigation surgery for Le Fort 1 osteotomy in a fibrous dysplasia patient

Orthognathic surgery is sometimes performed for fibrous dysplasia to correct malocclusion or facial asymmetry. However, Le Fort 1 osteotomy for this disease is difficult because of severe anatomical abnormality. Computerassisted surgery is a rapidly developing technique in oral and maxillofacial surgery that is helping to ensure the safety of the surgery. We report a case of polyostotic craniofacial fibrous dysplasia in which two-jaw orthognathic surgery was performed using a navigation system with the Le Fort 1 osteotomy procedure. A 29-year-old woman presented with swelling and asymmetry on the right side of her face. Craniofacial fibrous dysplasia on the right side had been previously diagnosed, and she had undergone conservative surgery several times before. The disease extended to the right mandible, maxilla, and zygomatic, temporal frontal, and orbital areas, including the skull base. We first performed conservative contouring around the frontal and orbital areas, and then Le Fort I osteotomy and sagittal split ramus osteotomy to correct the asymmetry and cant of the occlusal plane. A passive infrared navigation system (Vector Vision surgical navigation system) was used for the Le Fort I osteotomy. The postoperative course was stable, and the facial asymmetry and cant of the occlusal plane improved and remained suitable 2 years after surgery. Thus, Le Fort 1 osteotomy can be performed safely in fibrous dysplasia with the aid of a passive infrared navigation system.     

Diabetic retinopathy is associated with visceral fat accumulation in Japanese type 2 diabetes mellitus patients

The presence of diabetic retinopathy (DR) and increased of visceral fat accumulation (VFA) are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that DR is associated with insulin resistance and VFA in type 2 diabetes mellitus patients without insulin treatment. A total of 102 type 2 diabetes mellitus patients were divided into 2 groups: DR group (age, 60 ± 6 years [mean ± SD]; n = 31) and no diabetic retinopathy (NDR) group (59 ± 5 years, n = 71). The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment index, and hemoglobin A_1c. The fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. The body mass index and waist circumference were higher in the DR group than in the NDR group (P < .001 and P < .0005, respectively). Plasma levels of triglyceride were higher, whereas high-density lipoprotein cholesterol was lower, in the DR group than in the NDR group (P < .005 and P < .0001, respectively). Fasting plasma glucose (P < .0005), insulin concentrations (P < .0001), homeostasis model assessment index (P < .0001), and VFA (P < .0001) levels were higher in the DR group than in the NDR group. Multivariate logistic analysis revealed that DR was independently predicted by high VFA and insulin resistance. The results of this preliminary study indicate that the presence of DR was associated with high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus.     

The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor

Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumor-containing lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth.