Clinical experiences with intraluminal irradiation using 198Au grains in the treatment of bile duct carcinoma

Three cases of a bile duct carcinoma were treatment with radiotherapy, using intracatheterized 198Au grains. The intracatheter 198Au grains, placed in an inner tube, were inserted into a percutaneous transhepatic catheter. The number of 198Au grains used depended upon the length of the tumor. Tips of plastic were placed between the grains to improve the spatial and temporal dose allocation. The number of grains used can be changed quite easily, according to the length of the tumor, and the period of insertion in our cases was shorter than for a 192Ir wire. These three patients also received external irradiation and, since completion of treatment, two have continued to do well for the past 5 months. There have been no systemic or local complication.     

A gastric stromal tumor (GIST) with a prolonged partial response to a reduced dose of imatinib mesilate

A 78-year-old woman was admitted to our hospital because of tarry stools. A gastric stromal tumor with liver metastasis was diagnosed. Treatment with imatinib mesilate was begun in a dose of 400 mg daily. After 1 month, the primary tumor showed a partial response; the response of the liver metastasis was stable disease. However, grade 2 edema, leukocytopenia, and anemia developed, and the dose of imatinib mesilate was reduced to 200 mg daily. The adverse reactions resolved promptly, and a partial response of both the primary tumor and liver metastasis to imatinib mesilate has been maintained for 28 months. Strategies for lowering the dose of imatinib mesilate are reviewed.     

Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.     

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson’s disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.Cells transplanted into the nervous system could cure various forms of neurodegenerative disease and neural injury (1, 2), but most donor cells die without functional integration (3), and glial scar tissue is strongly inhibitory to axon regeneration (4). Glial scar tissue forms following conditions such as ischemia or mechanical trauma when reactive astrocytes increase proliferation, become hypertrophic, and up-regulate glial fibrillary acidic protein (GFAP) (5, 6). In this study, however, we demonstrate that if donor cells are delivered appropriately, they can interact successfully with the glial scar and restore lost neuronal function. We developed an in vivo model of the chronic gliotic environment in clinical patients by compressing the rat auditory nerve without breaching the fluid spaces that contain the sensory structures inside the cochlea (7–10). In this model, spiral ganglion cells (the auditory neurons) degenerate selectively, but hair cells are preserved both morphologically and functionally (7, 8, 10, 11). We then waited 5 wk before cell transplantation to allow the formation of a glial scar with the progressive degeneration of auditory neurons. We characterized the glial scar with several experimental measures. This characterization is an important element because experimental models for cell-based therapies for neurodegenerative diseases should include the chronic gliotic environment to simulate the appropriate clinical condition in patients.To compress the auditory nerve, the CNS portion was atraumatically exposed in the cerebellopontine angle cistern through right suboccipital craniectomy, a nerve hook was placed into the internal auditory meatus, and the nerve was injured by a single compression (Fig. 1 A and B and Fig. S1A). We used a murine auditory neuroblast cell line for transplantation (US/VOT-N33) (12). This cell line was derived from the ventral otocyst (inner ear anlage) of a mouse embryo at embryonic day ED10.5 and was selected because it expresses key markers for auditory sensory neurons and differentiates with the appropriate bipolar morphology in the ear both in vitro and in vivo (11, 12).Open in a separate windowFig. 1.Glial scar formation after auditory nerve compression. (A) The CNS portion (CNS-P) of the normal auditory nerve protrudes into the auditory nerve trunk and the transitional zone (TZ) at the boundary with the PNS is within the internal auditory canal (IAC). Mechanical compression (red arrow) applied to the CNS-P induced a glial scar. The red circle corresponds to that in Fig. S1A. BS, brainstem; CN, cochlear nucleus; Fs, fundus of the internal auditory canal; HC, hair cell; HP, habenula perforata; IAM, internal auditory meatus; PNS-P, PNS portion of the auditory nerve; SGC, spiral ganglion cells. (B) Auditory nerve (AuN) in sham-operated and compressed (Comp) ears. The compression site is marked with a double arrow. Distal extension of the GFAP domain is indicated by arrowheads. Spiral ganglion cells, labeled with Tuj1, were lost following compression (multiple single arrows). Asterisks indicate glial scar processes projecting into small bony canals beyond the fundus of the IAC. (C) Fluorescence image of glial scar formed 5 wk after auditory nerve injury, ChABC treated (Upper). The boxed area is enlarged in lower panels where confocal microscopy disclosed fine glial scar processes (arrowheads) past Rosenthal’s canal (R). The margin of the limbus was nonspecifically stained (arrows). bsl, mdl, ap: basal, middle, apical cochlear turn, respectively. (D) Expression of GFAP. PPA, positive pixel area (n = 4). (E) Western blot for GFAP. (F) Relative expression of GFAP mRNA after 1, 4, and 25 wk. (G) Expression of 1G2 (Neurocan) (n = 4). (H) Relative expression of Neurocan mRNA. (I) Relative expression of Nestin mRNA. (J) Nestin expression at compression site. Most of the glial scar processes were Nestin positive (arrowheads) and some were GFAP positive (arrows). The boxed area in the left panel is enlarged in the right. The asterisk indicates tissue loss due to compression injury. (K) The ChABC-digested auditory nerve was 2B6-positive (n = 4). (Scale bars, 200 μm in B and C, Upper; 100 μm in J; and 20 μm in C, Lower, D, G, and K.) All values represent mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.Open in a separate windowFig. S1.Techniques to induce glial scar in rat auditory system to transplant donor cells to gliotic auditory nerve and the primary antibodies used in this study. (A) Operative view of auditory nerve compression in the cerebellopontine angle (CPA). Red circle corresponds to that in Fig. 1A. Fundus, fundus of the internal auditory canal; IAM, internal auditory meatus; PB, petrous bone. (B) Donor cells were transplanted to gliotic auditory nerve by two different techniques: the intraneural method and the surface transplantation method. The tips of the syringes are indicated by circles. (C) Primary antibodies used to identify relevant endogenous and exogenous components of the auditory system (SI Materials and Methods).In the first experiments, we delivered cells into the auditory nerve via a thin fused silica tube (Fig. S1B), treating the nerve topically with chondroitinase ABC (ChABC) (13) soaked in a gelatin sponge at the time of nerve injury and then again immediately after cell transplantation. Three months later, we assessed the structural and functional recovery of the auditory nerve.During these experiments, we noticed that donor cells that spilled onto the surface of the nerve were apparently able to enter the ChABC-treated tissue and to survive. Thus, we reasoned that cell delivery onto the surface of the glial scar might be successful and less invasive. In this context, we designed an experiment to compare two methods of cell delivery. In the first, we applied the conventional method of intraneural infusion, and in the second, we delivered cells to the surface of the nerve without mechanical damage to its structure. We then compared the results in terms of cell morphology and functional recovery of the auditory system.     

Upper gastrointestinal complications associated with gemcitabine-concurrent proton radiotherapy for inoperable pancreatic cancer

Background

Little is known about acute upper gastrointestinal (GI) complications associated with gemcitabine-concurrent proton radiotherapy (GPT) for inoperable pancreatic cancer. We investigated acute GI complications following GPT in patients with inoperable pancreatic cancer using small-bowel endoscopy.

Methods

This prospective single center observational study was conducted at the Hyogo Ion Beam Medical Center from January 2010 to January 2012. Ninety-one patients who had clinically and medically inoperable pancreatic cancer treated by GPT were analyzed. Endoscopic examinations were performed before and after GPT to clarify the incidence rates of radiation-induced ulcers, GI hemorrhage, and GI perforation associated with GPT.

Results

Post-treatment endoscopic examinations revealed that 45 (49.4 %) patients had radiation-induced ulcers in the stomach and duodenum. Of those, many ulcerative lesions were found in the lower stomach (51 %) and horizontal part of the duodenum (39 %), regardless of the primary tumor site in the pancreas. Neither GI hemorrhage, nor perforation, was found in post-treatment endoscopy examinations.

Conclusion

Approximately half of the patients treated with GPT for inoperable pancreatic cancer exhibited radiation-induced ulcers in the stomach and duodenum.