Anti-NK cell treatment induces stable mixed chimerism in MHC-mismatched, T cell-depleted, nonmyeloablative bone marrow transplantation

OBJECTIVE: To clarify natural killer (NK) cell-mediated resistance under cytoreductive conditioning and T cell-depleted bone marrow transplantation, we investigated the effects of host NK cell depletion on engraftment and induction of stable mixed chimerism. METHODS: BALB/c mice (H-2kd) were injected intraperitoneally with anti-asialoGM1 antibody (anti-NK Ab) on day -1. On day 0, they received total body irradiation (TBI) at a dose of 500 cGy, followed by intravenous infusion of 2 x 10(7) T cell-depleted (TCD) bone marrow cells from C57BL/6 mice (H-2kb). Early engraftment and chimerism were determined by the relative ratio of peripheral blood (PB) lymphocytes expressing either H-2kd or H-2kb on day +21. Long-term engraftment and chimerism were evaluated on PB and spleen by multicolor flow cytometry. RESULTS: Although no recipients treated with TBI alone showed engraftment, all the recipients conditioned with anti-NK Ab and TBI showed successful engraftment as well as a donor-dominant pattern of mixed chimerism in both PB and spleen. Spleen cells from recipients with mixed chimerism showed specific tolerance to both host and donor strains, but not to a third party (C3H/He). None of the reconstituted mice showed signs of graft vs host disease, and all survived up to day +330. CONCLUSION: These observations indicate that host NK cell depletion may be used to reduce the intensity of conditioning regimens for engraftment of TCD grafts, and can contribute to establishment of stable mixed chimerism in major histocompatibility complex-mismatched nonmyeloablative transplantation.     

Primary metastatic neuroendocrine small cell bladder cancer: a case report and literature review

Small cell carcinoma of the urinary bladder (SCCUB) is a rare variant of neuroendocrine nonepithelial tumor. Clinically, SCCUB appears like a flat or ulcerated lesion and microscopically can cause microvascular invasion and necrosis. Small cell cancer, rarely found in the urogenital tract in a primitive form, usually coexists with urothelial bladder cancers. It has an incidence of 0.35-0.7% of all bladder neoplasms and survival at 5 years is estimated to be around 8%. A 60-year-old man who was a smoker was referred to our department with episodes of gross hematuria and pain in the lumbar region. After an extensive transurethral resection of the bladder, including of the muscular layer, the diagnosis of small cell carcinoma of the bladder was made. The neoplastic cells were positive with immunohistochemical staining for chromogranin A, paranuclear reactivity to cytokeratin and neuron-specific enolase. A total-body CT scan revealed lymph node involvement and hepatic, adrenal and lung metastases. Because of the advanced stage it was decided to avoid radical cystectomy and perform chemotherapy. The patient underwent two different cycles of cisplatin chemotherapy following international recommendations, but unfortunately without any response. After palliative therapy, the patient died in January 2010.     

Esophageal schwannoma of the upper mediastinum: report of a case

Esophageal schwannoma is extremely rare, and it is difficult to confirm a definitive diagnosis preoperatively. We report the case of a 67-year-old male with an asymptomatic esophageal schwannoma with a major axis of 6 cm. Computed tomographic angiography was very useful for determining a safe and efficient route of access to the tumor. Although high 18F-fluorodeoxyglucose uptake and high signal were revealed by diffusion-weighted images, a malignant potential was denied by low-grade clinical symptoms and surgical findings. The patient underwent tumor excision via a cervical collar incision and median sternotomy. This procedure was very useful and was shown to be safe for tumor exfoliation from the main blood vessel and nerve.     

Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening

Gallbladder cancer (GBC) is a highly fatal malignancy in humans. Genetic alterations in KRAS or TP53 as well as overexpression of ERBB2 have been shown to contribute to the development of certain types of GBC. However, many cases of GBC do not harbor such genetic changes, with other transforming events awaiting discovery. We here tried to identify novel cancer-promoting genes in GBC, with the use of a retroviral cDNA expression library. A retroviral cDNA expression library was constructed from a surgically resected clinical specimen of GBC, and was used to infect 3T3 fibroblasts in a focus formation assay. cDNA incorporated into the transformed foci was rescued by PCR. One such cDNA was found to encode free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor for short-chain fatty acids. The oncogenic potential of FFAR2 was confirmed both in vitro with the focus formation assay and by evaluation of cell growth in soft agar as well as in vivo with a tumorigenicity assay in nude mice. The isolated FFAR2 cDNA had no sequence alterations, suggesting that upregulation of FFAR2 expression may contribute to malignant transformation. Indeed, all of quantitative RT-PCR, in situ hybridization, and immunohistochemical analyses showed that the amount of FFAR2 mRNA and its protein product was increased in digestive tract cancer specimens. Furthermore, short-chain fatty acids potentiated the mitogenic action of FFAR2 in 3T3 cells. Our data thus, for the first time, implicate FFAR2 in carcinogenesis of the digestive tract. ( Cancer Sci 2009)     

Preclinical and clinical strategies for development of telomerase and telomere inhibitors

Background: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy.Design: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.     

Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer

We conducted a phase I study of paclitaxel and irinotecan (CPT-11) in advanced non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated doses (MTD). The pharmacokinetics of CPT-11 and its major active metabolite, SN-38, were also analysed. Patients received paclitaxel (day 1) followed by CPT-11 (days 1, 8 and 15), in a 4-week cycle, and paclitaxel and CPT-11 were escalated from 120 and 40 mg/m(2), respectively. 28 patients were enrolled, who were evaluated for toxicity. 2 of 6 patients at 210 mg/m(2) paclitaxel and 50 mg/m(2) CPT-11, and 2 of 4 at 180 and 60 mg/m(2) developed dose-limiting toxicity (DLT) (neutropenia, fever, neurotoxicity and diarrhoea). The area under the plasma concentration-time curve (AUC) of CPT-11 on day 1 was significantly higher than that on days 8 or 15 at each dose level (P=0.002). The AUC of SN-38 on day 1 was significantly increased using paclitaxel doses >or=150 mg/m(2). A preceding paclitaxel administration changed the pharmacokinetics of CPT-11 and SN-38. However, the toxicity was tolerable. Paclitaxel 180 mg/m(2) and CPT-11 50 mg/m(2) were the recommended doses for further phase II study of this combination.     

Middle ear cholesteatoma extending into the petrous apex: evaluation by CT and MR imaging

CT and MR imaging findings were reviewed in four cases of acquired cholesteatoma of the middle ear that extended medially into the petrous apex and middle cranial fossa. In one case the lesion further extended anteromedially into the sphenoid sinus. CT demonstrated the lesions as nonenhancing hypodense masses with bone destruction, extending medially from the middle ear cavity to the petrous apex region. On MR imaging, the lesion was slightly hypointense relative to brain on T1-weighted images and hyperintense on T2-weighted images. MR imaging clearly delineated the extraaxial location of the lesion and associated brain displacement. The medial extension of the cholesteatomas seems to have proceeded via a detour around the bony labyrinth into the petrous apex region by following normal pathways of temporal bone pneumatization.     

Fatty liver and uric acid levels predict incident coronary heart disease but not stroke among atomic bomb survivors in Nagasaki.

Relationships between fatty liver and coronary heart disease (CHD) and stroke risk remain ill defined. We investigated whether fatty liver is a predictor of CHD and stroke risk. Until December 2000 we followed 2,024 atomic bomb survivors (775 men: 62.0 +/- 9.9 years old; 1,249 women: 63.2 +/- 8.4 years old) who had basic examinations between November 1990 and October 1992 for clinical and laboratory CHD risk factors and fatty liver and who were initially free of CHD and stroke. Forty-nine cases of CHD and 84 cases of stroke were observed. At the time of the baseline examinations, significant clinical associations were found between fatty liver and obesity (p<0.001), hypertension (p<0.001), dyslipidemia (p<0.001), and glucose intolerance (p<0.001). A slight but nonsignificant association was found between fatty liver and hyperuricemia (p=0.07) as well. By using multiple Cox regression analyses, age (relative risk [RR] 1.05, 95% confidence interval [CI] 1.01-1.08), smoking (RR 2.20, 95% CI 1.02-4.74), hyperuricemia (RR 2.30, 95% CI 1.08-4.89), and fatty liver (RR 2.53, 95% CI 1.06-6.06) were shown to be significant predictors of CHD, whereas age (RR 1.08, 95% CI 1.06-1.10), smoking (RR 2.06, 95% CI 1.14-3.72), and hypertension (RR 2.14, 95% CI 1.38-3.30) predicted stroke risk. Fatty liver, which clusters clinical and laboratory CHD risk factors, is an independent predictor of CHD, but not of stroke. Fatty liver should be followed as a feature of metabolic syndrome, with the aim of preventing CHD.