Acceptability and feasibility of S-1 plus cisplatin adjuvant chemotherapy for completely resected non-small cell lung cancer: an open-label, single arm, multicenter, phase 2 trial.

BACKGROUND: Although platinum-based chemotherapy is accepted as adjuvant chemotherapy for resectable advanced non-small cell lung cancer (NSCLC), its completion rate is low due to severe adverse events. S-1 plus cisplatin is associated with relatively low toxicity and an unimpaired quality of life, and has been used for unresectable advanced lung cancer. We investigated the acceptability and feasibility of combination therapy with S-1 plus cisplatin as postoperative adjuvant chemotherapy following complete resection of pathological stage II-IIIA NSCLC. METHODS: Enrolled patients received oral S-1 at a dose depending on their body weight twice daily for 21 days with intravenous cisplatin 60 mg/m2 on day 8, with 1 cycle comprising 5 weeks and 4 cycles. Patients received standard precautions against adverse events and received standard treatment when adverse events occurred. The primary endpoint was completion rate; secondary endpoints included safety, status of drug administration, disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 19 patients [14 men, 5 women; mean age, 59.1 years; mean body surface area, 1.688 m2; 17 with an Eastern Cooperative Oncology Group performance status (PS) of 0 and 2 with a PS of 1; 7 (36.8%) with stage II disease and 12 (63.2%) with stage IIIA disease] were enrolled. The rate of completion of 4 cycles was 68.4%. Grade 3 adverse events that occurred in ≥10% of patients included neutropenia (21.1%), nausea (21.1%), and anorexia (15.8%). No grade 4 adverse events, febrile neutropenia, or treatment-related deaths occurred. The mean relative dose intensity (RDI) was 79% for S-1 and 80% for cisplatin. The 2-year DFS rate was 42.1%, and 2-year OS rate was 83.3%. CONCLUSIONS: This study demonstrated the acceptability and feasibility of using S-1 plus cisplatin as adjuvant chemotherapy. TRIAL REGISTRATION: This study was registered on the UMIN clinical study registration site (protocol ID: UMIN000016191) on December 1, 2015.

Pleural dedifferentiated liposarcoma: A case report.

The present case report describes a rare case of pleural liposarcoma. A 45-year-old Japanese man was hospitalized for increasing left chest pain. Imaging revealed a 10-cm pleural tumor and a 1.7-cm contralateral right pulmonary nodule. Biopsy specimens of the pleural tumor showed undifferentiated spindle-shaped and/or rounded sarcomatous features with myxoid stroma. The patient underwent embolization of the arteries feeding the left pleural tumor and palliative partial resection of the pleural tumor. The surgically removed specimens exhibited similar undifferentiated sarcomatous features. The left pleural tumor regrew aggressively, and the patient succumbed to mortality ~4.2 months following hospitalization. Autopsy demonstrated a 35-cm left pleural tumor, metastasizing to both adrenal glands and lumbar vertebral bones, and a 2.2-cm primary adenocarcinoma of the right lung. The majority of the left pleural tumor and its metastases consisted of undifferentiated sarcomatous elements, however, scattered or aggregated lipoblasts were identified in localized areas adjacent to the diaphragm. Immunohistochemically, these lipoblasts were diffusely positive for MDM2 and focally positive for S-100 protein. Undifferentiated sarcomatous tumor cells were focally positive for MDM2 but negative for S-100 protein. This case was diagnosed as pleural dedifferentiated liposarcoma. The local aggressiveness of the pleural liposarcoma directly contributed to the patient's mortality. A review of the literature indicated that the dedifferentiated subtype may serve as a factor that is indicative of a poor prognosis for pleural liposarcoma.

Focal positivity of immunohistochemical markers for pulmonary squamous cell carcinoma in primary pulmonary choriocarcinoma: A histopathological study.

Cytokeratin 5/6 (CK5/6), p63, and p40 are commonly used as immunohistochemical markers for squamous cell carcinoma (SqCC) of the lung. To elucidate their positivity in primary pulmonary choriocarcinoma (PPC), the present study examined 4 PPCs, including 1 surgically removed PPC and 3 postmortem PPCs. All PPCs consisted of nested cytotrophoblastic tumor cells and occasional syncytiotrophoblastic tumor cells although 1 surgically removed PPC was markedly affected by pre-operative therapy-associated necrosis and 3 postmortem PPCs coexisted with adenocarcinoma. In 1 surgical case, a pre-operative biopsy specimen of PPC contained a few polygonal tumor cells, which mimicked SqCC and exhibited focal p40+ features. Nuclear p63+ and p40+ features of cytotrophoblast-like polygonal tumor cells were focally observed in 3 PPCs (75%) and 2 PPCs (50%), respectively. CK5/6+ trophoblastic tumor cells were focally identified in 1 PPC. Additionally, in 2 other PPCs, CK5/6+ tumor cells were scattered in choriocarcinomatous areas, but possible intermingling of CK5/6+ adenocarcinoma cells could not be ruled out. The results emphasized that PPCs could mimic SqCC morphologically and immunohistochemically, although PPC was an extremely rare neoplasm. Surgical pathologists should be aware of this diagnostic pitfall when encountering a few squamous marker-positive polygonal tumor cells within hemorrhagic necrotic biopsy specimens from lung tumors.

Invasive form of ciliated muconodular papillary tumor of the lung: A case report and review of the literature.

We report a case of a 67-year-old woman with an invasive ciliated muconodular papillary tumor (CMPT) that developed in her right middle lobe. The current tumor was incidentally detected during a follow-up imaging examination for a large cell carcinoma that was resected 10 years previously. Partial removal of the middle lobe showed a 2 cm-sized, solid and myxoid tumor located in the peripheral region. Histologically, this tumor primarily consisted of ciliated columnar cells, mucous cells, and basal cells, all of which had relatively swollen nuclei and were proliferating in a lepidic or papillary/micropapillary manner. These features were consistent with those of previously reported CMPT. In addition, atypical spindle tumor cells with more swollen nuclei, which were partly continuous to less atypical basal tumor cells, were focally found and invaded fibrous stroma in a reticular fashion. Immunohistochemically, both basal cells and atypical spindle tumor cells were positive for pancytokeratin, cytokeratin 5/6, and p40. Increased p53 positivity was found in these invading spindle cells compared with basal tumor cells. Neither BRAF V600E nor V600K mutation was detected. We concluded that this tumor was an extremely rare invasive case of CMPT, possibly representing malignant transformation of basal tumor cell components of CMPT.

Non-sarcomatous spindle cell morphology in conventional lung adenocarcinoma: a clinicopathological study.

Non-sarcomatous spindle cell foci (N-SSCF) without aggressive invasiveness, also called morule-like lesions, occur occasionally in conventional lung adenocarcinoma, but their characteristics remain poorly understood. We identified N-SSCF in 7 (4.0 %) of 173 lung adenocarcinomas and examined their clinicopathological features. The patients were six men and one woman with a mean age of 57.0 years (range, 43-76 years). All tumors were papillary-predominant adenocarcinomas, ranging in size from 1 to 4.5 cm (mean, 2.7 cm). N-SSCF occupied 10-30 % of the tumors, and in all cases, there were focal or multifocal transitions between the two morphotypes. Most N-SSCF were plug-like nodules filling the spaces of cancerous alveoli/tubules or patchy insular nests. N-SSCF frequently contained mucin + lumina and were positive for cytokeratin 7, thyroid transcription factor 1, and Napsin A, but negative for cytokeratin 5/6 and vimentin, similar to the adenocarcinoma cells of the same tumor. Five cases (71 %) were at stage I or II, suggesting that N-SSCF can occur in an early phase of lung cancer. In an age-, sex-, and stage-matched control study, N-SSCF were not associated with prognosis (P = 0.471). We consider tumors with N-SSCF a distinct structural variant of adenocarcinoma without prognostic significance. They should be distinguished from true sarcomatous spindle cells and micropapillary components, which are associated with aggressive behavior.

Sebaceous-like clear cell changes in primary lung cancer.

We examined two cases of primary lung cancer with sebaceous-like clear cells (SLCCs), defined as clear carcinoma cells with microvacuolated cytoplasm and centrally located nuclei, which were selected from among 281 surgical/autopsy cases of lung cancer (2/281, 0.7%). Both cases were higher stage (stage IIA and IIIA), and SLCCs were intermingled with adenocarcinoma cells of usual type. They showed minute mucin staining, no evidence of glycogen, diffuse positivity for epithelial membrane antigen and carcinoembryonic antigen, focal positivity for thyroid transcription factor-1, and negativity for Napsin A and gross cystic disease fluid protein-15. Oil red O stain and ultrastructural examination in both cases failed to reveal lipid in SLCCs. SLCCs could represent non-specific changes of lung adenocarcinoma with a relatively advanced stage, and should be discriminated from true sebaceous differentiation.

Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion, resembling extraskeletal myxoid chondrosarcoma: Case report with a review of Literature.

Reported herein is an extremely rare case of primary pulmonary myxoid sarcoma (PPMS). A 31-year-old man presented with a 2.7 cm-sized pulmonary tumor surrounded by capsule-like fibrosis. The patient has been free of disease for 5.8 years after surgery. This tumor focally showed endobronchial features, and consisted of reticular cords of oval, short spindle, or polygonal cells with swollen vesicular nuclei accompanied by an abundant myxoid stroma, closely resembling extraskeletal myxoid chondrosarcoma. Tumor cells were diffusely positive for vimentin and focally positive for epithelial membrane antigen, but were negative for cytokeratin, TTF-1, Napsin A, S-100 protein, CD34, desmin, smooth-muscle actin, CD10, p63, calponin, h-caldesmon, c-kit, HMB-45, synaptophysin, or glial fibrillary acid protein. Our reverse transcription-polymerase chain reaction using the formalin-fixed, paraffin-embedded tumor tissues detected EWSR1-CREB1 fusion transcript, but could not demonstrate EWSR1-ATF1 fusion or EWSR1/TAF15/TFG-NR4A3 fusion. These findings indicate that the current tumor is an additional case of PPMS with EESR1-CREB1 fusion, recently reported by Thway et al. Some cases of PPMS can behave in an indolent manner.

[Bronchial carcinoid discovered due to repeated pneumonia in the lingular division of the left lung; report of a case].

Bronchial carcinoids are relatively rare, low-grade malignancies. Here we report a case of a bronchial carcinoid found by repeated pneumonia in the lingular division of the left lung. A 34-year-old man was referred to our hospital because of an abnormal shadow detected in an annual checkup. A chest computed tomography (CT) showed an infiltrative shadow in the lingular division. Two months later, a follow-up CT showed the shadow had remarkably improved. Two years after the 1st detection, an annual checkup revealed an abnormal shadow in the same lesion again. A chest CT showed not only an infiltrative shadow in the lingular division, but also a solid mass with calcification in the lingular bronchus. A bronchoscopy revealed an obstruction of the left upper lobe bronchus by a vascularized polypoid tumor. A transbronchial biopsy indicated a presence of a carcinoid, and a resection of the left upper lobe was performed. A histopathological examination showed that it was a typical carcinoid. The patient has been free of recurrence for 2 years since surgery. This is a case with repeated pneumonia and atelectasis caused by a bronchial carcinoid.

[A dialysis patient with advanced lung adenocarcinoma who was safely given biweekly gemcitabine therapy].

BACKGROUND: Although the number of advanced lung cancer patients on hemodialysis is expected to increase in the future, there has been no established treatment regimen yet. We report our experience with gemcitabine safely administered to an elderly patient requiring hemodialysis who had advanced lung adenocarcinoma. CASE: A 87-year-old man had been on dialysis for chronic renal failure. Left pleural effusions were detected in November 2007 and he was admitted to our hospital in January 2008. A diagnosis of Stage IIIB lung adenocarcinoma was made based on the findings of cytology from the pleural effusions and radiological examinations. After intrapleural cisplatin administration, he was given outpatient chemotherapy. Gemcitabine was administered every 14 days for 20 months. Adverse reactions observed included grade 1 neutropenia and grade 1 appetite loss. CONCLUSION: We described a dialysis patient with advanced non-small cell lung cancer who was given biweekly gemcitabine for 20 months. This regimen in a dialysis patient can be safely conducted on an outpatient basis.

Intercostal venous hemangioma presenting as a chest wall tumor.

Chest wall tumors are uncommon, but intercostal hemangioma is even more so: There have been only a handful of reports on it to date. We report on a 32-year-old man with a left-side chest wall mass detected on a chest roentgenogram and computed tomography scans. The tumor was completely resected by means of video-assisted thoracic surgery. Two years after the surgery, the patient is doing well with no evidence of recurrence.

Therapeutic angiogenesis induced by controlled release of fibroblast growth factor-2 from injectable chitosan/non-anticoagulant heparin hydrogel in a rat hindlimb ischemia model.

The addition of non-anticoagulant heparin [periodate-oxidized (IO4) heparin] and fibroblast growth factor (FGF)-2 to a viscous water-soluble chitosan (CH-LA) aqueous solution produces an injectable FGF-2/CH-LA/IO4-heparin hydrogel. The purpose of this study was to examine the ability of the injected FGF-2/CH-LA/IO4-heparin hydrogel to induce vascularization and fibrous tissue formation. FGF-2/CH-LA/IO4-heparin hydrogels (100 microL of hydrogel consisting of 20 mg/mL of CH-LA, 2 mg/mL of IO4-heparin, and 50 microg/mL of FGF-2) were subcutaneously injected into the backs of wound healing-impaired diabetic (db/db) mice. Furthermore, the effect of percutaneous injection of FGF-2/CH-LA/IO4-heparin hydrogel at eight sites (25 microL/site) into ischemic left lower limbs of rats was examined from day 4 to at least day 28 postinjection. The injection of FGF-2/CH-LA/IO4-heparin hydrogels into the backs of db/db mice resulted in significant increases in blood vessel formation, significant vascularization, and fibrous tissue formation near the injection site. Injection of FGF-2/CH-LA/IO4-heparin hydrogel into ischemic left lower limbs of rats also significantly recovered and increased blood flow and blood oxygen in the calf and thigh. These results indicate that the controlled release of biologically active FGF-2 molecules from FGF-2/CH-LA/IO4-heparin induces angiogenesis and possibly collateral circulation in db/db mice and the ischemic limbs of rats.

Controlled releases of FGF-2 and paclitaxel from chitosan hydrogels and their subsequent effects on wound repair, angiogenesis, and tumor growth.

A photocrosslinkable chitosan (Az-CH-LA) aqueous solution resulted in an insoluble hydrogel like a soft rubber within 30 sec of ultraviolet light (UV)-irradiation. The photocrosslinked chitosan hydrogel showed strong sealing strength and potential use as a new tissue adhesive in surgical application. Paclitaxel, which is an anti-tumor reagent and a vascularization-inhibitor, retained in the photocrosslinked chitosan hydrogel, and were gradually released from the photocrosslinked chitosan hydrogel in vivo upon the degradation of the hydrogel. The paclitaxel-incorporated photocrosslinked chitosan hydrogels effectively inhibited tumor growth and angiogenesis in mice. On the other hand, the fibroblast growth factor (FGF)-2 molecules also retained in both the photocrosslinked chitosan and an injectable chitosan/IO(4)-heparin hydrogels, and were gradually released from the hydrogels upon their in vivo biodegradations. The activity of FGF-2 in the hydrogels was stable for long time (more than 14 days). The controlled release of biologically active FGF-2 molecules from the hydrogels caused an induction of the angiogenesis and, possibly, collateral circulation occurred in the healing-impaired diabetic (db/db) mice and the ischemic limbs of rats. The purpose of this review is to describe the effectiveness of the chitosan hydrogels (photocrosslinkable chitosan hydrogel and chitosan/IO(4)-heparin hydrogel) as a local drug delivery carrier for FGF-2 and paclitaxel to control wound repair, tumor growth, and angiogenesis. It is thus proposed that the chitosan hydrogels may be a promising new local carrier for drugs such as FGF-2 and paclitaxel.

Noncontact vital sign monitoring system for isolation unit (casualty care system).

For measuring the vital signs of casualties inside an isolation unit, we developed a noncontact vital sign monitoring system using a microwave radar. The system was tested on eight healthy volunteers ranging in age from 30 to 48 years. The heart and respiratory rates derived by the microwave radar correlated with the heart and respiratory rates determined by electrocardiogram and respiratory sensor (r = 0.98, p < 0.0001 for heart rate; r = 0.84, p < 0.01 for respiratory rate). The exhaled CO and CO2, as a measure of trauma injury, were measured using an exhaled gas analyzer. The CO and CO2 concentrations were found to average 3.8 +/- 4.3 ppm and 2.9 +/- 0.4%, respectively. The expired air temperature and body temperature, as indicators of hemorrhagic hypothermia, averaged 31.8 +/- 1.7 degrees C and 36.2 +/- 0.4 degrees C, respectively. The results show that our system is promising for future prehospital application in determining casualty conditions for fluid infusions by the Casualty Care System intravenous lines.

Controlled release of fibroblast growth factor-2 from an injectable 6-O-desulfated heparin hydrogel and subsequent effect on in vivo vascularization.

We prepared a 6-O-desulfated (DS-) heparin (Hep) hydrogel as an excellent carrier for the controlled release of Hep-binding growth factors, such as fibroblast growth factor (FGF)-2. This material, which is partially derived from photoreactive groups, such as cinnamate, is easily crosslinked upon ultraviolet light (UV)-irradiation, resulting in a water-insoluble, viscous, and injectable hydrogel. In the present study, we examined the capacity of 6-O-DS-Hep hydrogel to immobilize FGF-2, as well as the controlled release of FGF-2 molecules from this hydrogel in vitro and in vivo. Only 10% of FGF-2 was gradually released from the FGF-2-containing 6-O-DS-Hep hydrogel (photocrosslinked 6-O-DS-Hep (4%; w/w) hydrogel containing 50 microg/mL FGF-2) into PBS (phosphate-buffered saline) within first 7 days. The 6-O-DS-Hep hydrogel in vitro maintained the original form through 1 weeks incubation in PBS, but it was gradually fragmented and could not maintain the original form by 2-3 week-washing. When the FGF-2-containing 6-O-DS-Hep hydrogel was subcutaneously injected into the back of rats, significant neovascularization and fibrous tissue formation were induced near the injected site from day 3 after the injection. And, the hydrogel had been biodegraded and completely disappeared from the injected sites in vivo within about 15-20 days after the injection. These findings indicate a controlled release of biologically active FGF-2 molecules together with fragmentation and biodegradation of 6-O-DS-Hep hydrogel and the subsequent induction of neovascularization in vivo.

Chitosan hydrogel as a drug delivery carrier to control angiogenesis.

An aqueous solution of photocrosslinkable chitosan containing azide groups and lactose moieties (Az-CH-LA) incorporating paclitaxel formed an insoluble hydrogel within 30 s of ultraviolet light (UV) irradiation. The chitosan hydrogel showed strong potential for use as a new tissue adhesive in surgical applications and wound dressing. The fibroblast growth factor (FGF)-2 molecules retained in the chitosan hydrogel and in an injectable chitosan/IO(4)-heparin hydrogel remain biologically active, and were gradually released from the hydrogels as they biodegraded in vivo. The controlled release of biologically active FGF-2 molecules from the hydrogels caused induction of angiogenesis and collateral circulation occurred in healing-impaired diabetic (db/db) mice and in the ischemic limbs of rats. Paclitaxel, which is an antitumor reagent, was also retained in the chitosan hydrogel and remained biologically active as it was released on degradation of the hydrogel in vivo. The chitosan hydrogels incorporating paclitaxel effectively inhibited tumor growth and angiogenesis in mice. The purpose of this review is to describe the effectiveness of chitosan hydrogel as a local drug delivery carrier for agents (e.g., FGF-2 and paclitaxel) to control angiogenesis. It is thus proposed that chitosan hydrogel may be a promising new local carrier for drugs such as FGF-2 and paclitaxel to control vascularization.

Significance of thymidylate synthase gene expression level in patients with adenocarcinoma of the lung.

BACKGROUND: Thymidylate synthase (TS) catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and is a key enzyme for DNA synthesis. High expression of TS is thought to be associated with poor prognosis in some kinds of cancers. However, this association has not been clarified for nonsmall cell lung carcinoma. In the current study, the authors investigated the clinicopathologic significance of TS mRNA levels and the correlation with cellular proliferation in patients with lung adenocarcinoma. METHODS: The expression levels of TS mRNA were measured in 47 lung adenocarcinoma tissues using the Taq-Man real-time reverse transcriptase-polymerase chain reaction (RT-PCR) method and examined the clinicopathologic significance of TS expression. To clarify the correlation between TS expression level and cell proliferation, the Ki-67 labeling index was also examined using immunohistochemical staining. RESULTS: A positive correlation was observed between the expression levels of TS mRNA and stage of disease, lymph node metastasis, or tumor differentiation (P = .015). The higher expression group of TS mRNA showed a significantly poorer prognosis than the group with lower expression (P = .042). Moreover, there was a strong correlation noted between the expression levels of TS mRNA and the Ki-67 labeling index (P = .009). CONCLUSIONS: The results of the current study demonstrated that TS may be associated with stage of disease, lymph node metastasis, tumor differentiation, prognosis, and tumor cell proliferation. These results suggest that the expression levels of TS mRNA may be useful for predicting the malignant potential in patients with lung adenocarcinoma.

Controlled release of paclitaxel from photocrosslinked chitosan hydrogels and its subsequent effect on subcutaneous tumor growth in mice.

A photocrosslinkable chitosan (Az-CH-LA) aqueous solution containing paclitaxel resulted in an insoluble hydrogel within 30 s of ultrtaviolet light (UV)-irradiation. About 35-40% of the paclitaxel was released from the paclitaxel-incorporated chitosan hydrogel into phosphate buffered saline (PBS) within 1 day, after which gradual release occurred during 3 days under in vitro non-degradation conditions of the hydrogel. The paclitaxel remaining in the chitosan hydrogel retained its biological activity in vitro for at least 21 days, and was released from the chitosan hydrogel in vivo upon degradation of the hydrogel. The paclitaxel-incorporated Az-CH-LA hydrogel inhibited the growth of subcutaneously induced tumors with Lewis lung cancer (3LL) cells more effectively than those treated with only Az-CH-LA, only paclitaxel, and a non-treated group (control) for at least 11 days. Furthermore, paclitaxel-incorporated chitosan hydrogel markedly reduced the number of CD34-positive vessels in subcutaneous 3LL tumors, indicating a strong inhibition of angiogenesis. These results suggested that application of paclitaxel-incorporated Az-CH-LA hydrogel has an inhibitory activity on angiogenesis and tumor growth.

Acceleration of wound healing in healing-impaired db/db mice with a photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2.

Application of ultraviolet light irradiation to a photocrosslinkable chitosan (Az-CH-LA) aqueous solution including fibroblast growth factor-2 (FGF-2) results within 30 seconds in an insoluble, flexible hydrogel. The FGF-2 molecules retained in the chitosan hydrogel remain biologically active and are released from the chitosan hydrogel upon in vivo biodegradation of the hydrogel. To evaluate the accelerating effect on wound healing of this hydrogel, full-thickness skin incisions were made in the backs of healing-impaired diabetic (db/db) mice and their normal (db/+) littermates. The mice were later killed, and histological sections of the wound were prepared. The degree of wound healing was evaluated using several histological parameters such as the rate of contraction, epithelialization, and tissue filling. Application of the chitosan hydrogel significantly advanced the rate of contraction on Days 0 to 2 in db/db and db/+ mice. Although the addition of FGF-2 into the chitosan hydrogel in db/+ mice had little effect, application of the chitosan hydrogel-containing FGF-2 further accelerated the adjusted tissue filling rate (Days 2 to 4 and Days 4 to 8) in db/db mice. Furthermore, the chitosan hydrogel-containing FGF-2 markedly increased the number of CD-34-positive vessels in the wound areas of db/db mice on Day 4. Thus, the application of chitosan hydrogel-containing FGF-2 onto a healing-impaired wound induces significant wound contraction and accelerates wound closure and healing.

Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/non-anticoagulant heparin hydrogel.

Addition of various heparinoids to the lactose-introduced, water-soluble chitosan (CH-LA) aqueous solution produces an injectable chitosan/heparinoid hydrogel. In the present work, we examined the capability of the chitosan/non-anticoagulant heparin (periodate-oxidized (IO(4)-) heparin) hydrogel to immobilize fibroblast growth factor (FGF)-2, as well as the controlled release of FGF-2 molecules from the hydrogel in vitro and in vivo. The hydrogel was biodegraded in about 20 days after subcutaneous injection into the back of a mouse. When the FGF-2-incorporated hydrogel was subcutaneously injected into the back of both mice and rats, a significant neovascularization and fibrous tissue formation were induced near the injected site. These results indicate that the controlled release of biologically active FGF-2 molecules is caused by biodegradation of the hydrogel, and that subsequent induction of the vascularization occurs.

Photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 stimulates wound healing in healing-impaired db/db mice.

Application of ultraviolet light (UV-) irradiation to a photocrosslinkable chitosan (Az-CH-LA) aqueous solution including fibroblast growth factor-2 (FGF-2) resulted within 30s in an insoluble, flexible hydrogel. About 20% of the FGF-2molecules were released from the FGF-2-incorporated chitosan hydrogel into phosphate buffered saline (PBS) within 1 day, after which no further significant release occurred under in vitro non-degradation conditions of the hydrogel. The FGF-2molecules retained in the chitosan hydrogel remained biologically active, and were released from the chitosan hydrogel upon the in vivo biodegradation of the hydrogel. In order to evaluate its accelerating effect on wound healing, full thickness skin incisions were made on the back of healing-impaired diabetic (db/db) mice and their normal (db/+) littermates. Application of the chitosan hydrogel significantly induced wound contraction and accelerated wound closure in both db/db and db/+ mice. However, the addition of FGF-2 in the chitosan hydrogel further accelerated wound closure in db/db mice, although not in db/+ mice. Histological examination also has demonstrated an advanced granulation tissue formation, capillary formation and epithelialization in wounds treated with FGF-2-incorporated chitosan hydrogels in db/db mice.