• Journal of Chest Surgery
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• v.39 no.11 s.268
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• pp.828-837
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• 2006

Background: Tissue hypoxia is characteristic of many human malignant neoplasm, and hypoxia inducible factor-1(HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increasing $O_2$ delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-$1{\alpha}$ has been reported in many human malignancies, but in non-small cell lung carcinoma the influence of HIF-$1{\alpha}$ on tumor biology, including neovascularization, is not still defined. In present study the relationship of HIF-$1{\alpha}$ expression on angiogenetic factors, relationship between the tumor proliferation and HIF-$1{\alpha}$ expression, interaction of HIF-$1{\alpha}$ expression and p53, and relationship between HIF-$1{\alpha}$ expression and clinico-pathological prognostic parameters were investigated. Material and Method: Archival tissue blocks recruited in this study were retrieved from fifty-nine patients with primary non-small cell lung carcinoma, who underwent pneumonectomy or lobectomy from 1997 to 1999. HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), and p53 protein expression and Ki-67 labeling index in tumor tissues were evaluated, using a standard avidin-biotin-peroxidase complex(ABC) immunohistochemistry. Relationship between the HIF-$1{\alpha}$ expression and VEGF, p53 overexpression and correlation between the HIF-$1{\alpha}$ expresseion and Ki-67 index were analyzed. Clinico-pathologic prognostic parameters were also analyzed. Result: HIF-$1{\alpha}$ expression in cancer cells was found in 24 of 59 cases of non-small cell lung carcinoma(40.7%). High HIF-$1{\alpha}$ expression was significantly associated with several pathological parameters, such as pathological TMN stage(p=0.004), pT stage(p=0.020), pN stage (p=0.029), and lymphovascular invasion(p=0.019). High HIF-$1{\alpha}$ expression was also significantly associated with VEGF immunoreactivity(p<0.001), and aberrant p53 expression(p=0.040). but was marginally associated with Ki-67 labeling index(p=0.092). The overall 5-year survival rate was 42.3%. The survival curve of patients with a high HIF-$1{\alpha}$ expression was worse than that of patients with low-expression(p=0.002). High HIF-$1{\alpha}$ expression was independent unfavorable factors with a marginal significance in multivariate analysis performed by Cox regression. Conclusion: It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway, and high HIF-$1{\alpha}$ expression could be associated with lymph node metastasis and post operative poor prognosis in patients with non-small cell lung carcinoma.

• Radiation Oncology Journal
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• v.20 no.3
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• pp.253-263
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• 2002

Purpose : In order to understand in vivo radiation damage modifying of bFGF on jejunal mucosa, bone marrow and the effect of bFGF on the growth of transplanted mouse sarcoma 180 tumor in mice. Materials and Methods : Mice were treated with $6\;{\mu}g$ of bFGF at 24 hours and 4 hours before exposing to 600 cGy, 800 cGy and 1,000 cGy total body irradiation (TBI), and then exposed to 3,000 cGy local radiation therapy on the tumor bearing thigh. Survival and tumor growth curve were plotted in radiation alone group and combined group of bFGF and irradiation (RT). Histologic examination was performed in another experimental group. Experimental groups consisted of normal control, tumor control, RT (radiation therapy) alone, $6\;{\mu}g$ bFGF alone, combined group of $3\;{\mu}g$ bFGF and irradiation (RT), combined group of $6\;{\mu}g$ bFGF and irradiation (RT). Histologic examination was peformed with H-E staining in marrow, jejunal mucosa, lung and sarcoma 180 bearing tumor. Radiation induced apoptosis was determined in each group with the DNA terminal transferase nick-end labeling method ($ApopTag^{\circledR}$ S7100-kit, Intergen Co.) Results : The results were as follows 1) $6\;{\mu}g$ bFGF given before TBI significantly improved the survival of lethally irradiated mice. bFGF would protect against lethal bone marrow syndrome. 2) $6\;{\mu}g$ bFGF treated group showed a significant higher crypt depth and microvilli length than RT alone group (p<0.05). 3) The bone marrow of bFGF treated group showed less hypocellularity than radiation alone group on day 7 and 14 after TBI (p<0.05), and this protective effect was more evident in $6\;{\mu}g$ bFGF treated group than that of $3\;{\mu}g$ bFGF treated group. 4) bFGF protected against early radiation induced apoptosis in intestinal crypt cell but might have had no antiapoptotic effect in bone marrow stem cell and pulmonary endothelial cells. 5) There was no significant differences in tumor growth rate between tumor control and bFGF alone groups (p>0.05). 6) There were no significant differences in histopathologic findings of lung and mouse sarcoma 180 tumor between radiation alone group and bFGF treated group. Conclusions : Our results suggest that bFGF protects small bowel and bone marrow from acute radiation damage without promoting the inoculated tumor growth in C3H mice. Improved recovery of early responding normal tissue and reduced number of radiation induced apoptosis may be possible mechanism of radioprotective effect of bFGF.

• Journal of Gastric Cancer
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• v.6 no.3
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• pp.146-153
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• 2006

Purpose: Gastrointestinal stromal tumorsm (GISTs) are the most common mesenchymal tumors that arise anywhere in the tubular GI tract. The prognosis for GSTIs is important because f GISTs may metastasiwx in the liver or the abdominal cavity in an early stage. For the reason we examined the tumor size, the mitotic number, ki 67, p53, and c-kit mutation as independent prognostic factor for GISTs. Materials and Methods: A retrospective study was conducted in 76 patients who had been re-evaluated for confirmation of diagnosis between Jan 1998 and Dec. 2001. at Catholic University of medicine. Results: There were significant difference between the turner size, mitotic indices, ki 67, c-kit mutations and the 5-years survival rates. Tumor size (${\geq}5\;cm$) and mitotic index (${\geq}5/50\;HPF$) were statistically related to a significantly poor prognosis (P=0.017 and P=0.042, respectively). c-kit mutations in exon 11 were found in 7 cases c-kit mutation was observed more frequently in high risk patients, and there was a significant difference between c-kit mutation and survival (P=0.037). Elevated ki 67 was noted in 34 out of the 76 cases. High risk patients showed elevated ki67 index more frequently and there was significant relation with the survival rate (P=0.0417). Conclusion: We think that tumor size, mitotic index, Ki 67 and c-kit mutation are as independent prognostic factors for GISTs, but more research is needed.

• Radiation Oncology Journal
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• v.10 no.1
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• pp.27-34
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• 1992

Cis-Platinum (DDP) was utilized as a radiosensitizer in a pilot study for stage III and IV squamous cell carcinoma between 1984-1987, and DDP 20 $mg/M^2$/day was administered for 4 days at 3 week interval with concurrent radiotherapy. This study consisted of three phases: cytoreduction phase, eradicative treatment phase and adjuvant phase. Total 59 patients were subjected to evaluate a tumor response and its toxicity. During the eradicative phase,27 patients underwent surgery (group I ), 29 patients were treated with radiotherapy only (group II) and 3 patients did not complete the second phase of therapy. At the cytoreduction phase, $95\%$ response rate with complete response (CR) $47.5\%$ and partial response (PR) $47.5\%$ was observed. Complete tumor clearance (CTC) rate following 2nd phase of therapy was $84\%$ (47/56) with 26/27($96\%$) in group I achieved CTC with surgery and 21/29 ($72\%$) patients In group II achieved CTC following 2nd phase. $67\%$ of primary lesions and $70\%$ of nodal diseases in group I showed no tumor in the surgical specimen. $34\%$ of patiets who achieved CTC at 2nd phase developed recurrence and median time to recur was 8 months. Actuarial disease free survival at 4 years was $59\%$ and $51\%$(24/27) of patients who achieved CTC at 2nd phase were alive without any evidence of disease at median follow-up 31 months (range, 10-48 months). There was no significant difference in overall and disease free survival between group I and II between CR and PR group following 1st Phase. Only significant Prognostic factor in this study was the complete tumor clearance following 2nd phase theapy. In general, toxicity was not excessive. Author concludes that this study confirmed the significant radiosensitizing effect of DDP with the acceptable toxicity and warrant the prospective study to determine optimum scheduling for DDP and radiotherapy which maximizes the therapeutic gain.

• Radiation Oncology Journal
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• v.6 no.1
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• pp.63-73
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• 1988

One hundred fifty-four patients with the carcinoma of the uterine cervix were studied retrospectively to assess the result and impact of treatment at Department of Radiation Oncology, Korea University, Hae-Wha Hospital from Feb 1981 through Dec. 1986. Prior to radiotherapy, the patients were evaluated and staged by recommendation of FIGO including physical examination, pelvic examination, cystoscopy, rectosigmoidoscopy, chest X-ray, IVP. Ba enema. Also, an additional pelvic CT scan was obtained for some of the patients. The patients were treated by radiotherapy alone or adjuvant postoperative irradiation; in case of radiation therapy only, whole pelvic irradiation was given with Co-60 teletherapy unit via AP and PA parallel opposing fields or 4-oblique fields, 180 cGy per day, 5 days per week and intracavitary insertion was performed. In satges Ia, Ib, and IIa with small primary lesion, external irradiation was initially given to pelvis up to $2,000\~3,000\;cGy/2frac{1}{2}\;-3frac{1}{2}$ weeks and then intracavitary insertion was performed using Fletcher-Mini-Declos Applicator with cesium-137 cources and followed by external irradiation of $1,000\~2,000\;cGy/1frac{1}{2}\;-2frac{1}{2}$weeks via AP and PA parallel opposing fields with midline shield to spare of bladder and rectum. However, if the primary lesion is large, external irradiation was given without midline shield. More than stages IIb, the patients were treated by external beam irradiation up to 5,400cGy/30f for 6 weeks via 4-oblique portals and at the dose of 5,040cGy/28f the field was cut 5cm from the top margin for spare of small bowel, and followed by intracavitary irradiation, If there was residual tumor an additional dose of $900\~l,200cGy/5\~7f$ was given to parametrium and/or residual tumor area. Total dose of radiation to A and B-point were as follows; A-point; In early stages, Ia, Ib, IIa; $8,000\~9,000$ B-point $5,000\~6,000 cGy$ A-point; In advanced stages IIb, IIIa, IIIb; $9,000\~10,000$ B-point $60,000\~7,000cGy$ The results were obtained and as fellows; 1 The patients distribution according to FIGO staging system were stage Ia 6, Ib 27, IIa 28, IIb 54, IIIa 12, IIIb 18, and stage IVa 9. 2. Value of CT scan were demonstration of cervix tumor mass, parametrial and pelvic side wall tumor spread, pelvic and inguinal lymph nodes metastases, and hydronephrosis. Three dimensional quantitative demonstration of tumor volume is also important in planning radiation therapy. Another advantage of CT scan was detection of recurrent tumor after radiation or surgery. 3. Local control rate of tumor according to the size was $91.3\%$ for less than 5cm in size and $44.6\%$ in tumor over 5cm (p<0.0068). 4. Thirty out of 50 recurrent sites has locoregional failures and 17 cases has distant metastases. And the para-aortic lymph nodes were the most common site for distant metastases. 5. The most common complication was temporal rectal bleeding which was controlled most by conservative management. However, 4 patients required for endoscopic cauterization. 6. The 5-year survival rates showed; stage la and Ib $95\%,\;stage\;IIa\;81\%\;stage\;lIb\;67\%,\;stage\;IIIa\;37.7\%,\;stage\;IIIb\;23\%$ and 3-year survival rate of stage IVa showed $11.6%$, retrospectively.

• Radiation Oncology Journal
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• v.20 no.2
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• pp.123-129
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• 2002

Purpose : The purpose of this study 띤as to determine the potential role of three-dimensional conformal radiotherapy (3D-CRT) in the treatment of primary unresectable hepatocellular carcinoma. The preliminary results on the efficacy and the toxicity of 3D-CRT are reported. Materials and Methods : Seventeen patients were enrolled in this study, which was conducted prospectively from January 1995 to June 1997. The exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child-Pugh classification C, tumors occupying more than two thirds of the entire liver, and a performance status of more than 3 on the ECOG scale. Two patients were treated with radiotherapy only while the remaining 15 were treated with combined transcatheter arterial chemoembolization. Radiotherapy was given to the field including the tumor plus a 1.5 cm margin using a 3D-CRT technique. The radiation dose ranged from $36\~60\;Gy$ (median; 59.4 Gy). Tumor response was based on a radiological examination such as the CT scan, MR imaging, and hepatic artery angiography at $4\~8$ weeks following the completion of treatment. The acute and subacute toxicities were monitored. Results : An objective response was observed in 11 out of 17 patients, giving a response rate of $64.7\%$. The actuarial survival rate at 2 years was $21.2\%$ from the start of radiotherapy (median survival; 19 months). Six patients developed a distant metastasis consisting of a lung metastasis in 5 patients and bone metastasis in one. The complications related to 30-CRT were gastro-duodenitis $(\geq\;grade\;2)$ in 2 patients. There were no treatment related deaths and radiation induced hepatitis. Conclusion : The preliminary results show that 3D-CRT is a reliable and effective treatment modality for primary unresectable hepatocellular carcinoma compared to other conventional modalities. Further studies to evaluate the definitive role of the 3D-CRT technique in the treatment of primary unresectable hepatocellular carcinoma are needed.

• Journal of Chest Surgery
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• v.37 no.8
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• pp.691-701
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• 2004

Background: Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1 a has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1 a on tumor biology, including neovascularization, is not still defined. Material and Method: The influence of HIF-1 a expression on angiogenic factors, correlation between the tumor proliferation and HIF-1 a expression, interaction of HIF-1 a expression and p53, and correlation between HIF-1 a expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1 a, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. Result: HIF-1 a expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1 a. High HIF-1 a expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1 a expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1 a expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1 a expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1 a expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis. Conclusion: It is suggested that (1) high HIF-1 a expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1 a expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1 a expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may playa role as biomarker for regional lymph node metastasis.

• Radiation Oncology Journal
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• v.27 no.3
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• pp.126-132
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• 2009

Purpose: We wanted to evaluate the prognostic factors for the pathologic N2 non-small cell lung cancer (NSCLC) patients who were treated by postoperative radiotherapy. Materials and Methods: We retrospectively reviewed 112 pN2 NSCLC patients who underwent surgery and postoperative radiotherapy (PORT) From January 1999 to February 2008. Seventy-five (67%) patients received segmentectomy or lobectomy and 37 (33%) patients received pneumonectomy. The resection margin was negative in 94 patients, and it was positive or close in 18 patients. Chemotherapy was administered to 103 (92%) patients. Nine (8%) patients received PORT alone. The median radiation dose was 54 Gy (range, 45 to 66), and the fraction size was 1.8~2 Gy. Results: The 2-year overall survival (OS) rate was 60.2% and the disease free survival (DFS) rate was 44.7% for all the patients. Univariate analysis showed that the patients with multiple-station N2 disease had significantly reduced OS and DFS (p=0.047, p=0.007) and the patients with an advanced T stage ($\geq$T3) had significantly reduced OS and DFS (p<0.001, p=0.025). A large tumor size ($\geq$5 cm) and positive lymphovascular invasion reduced the OS (p=0.035, 0.034). Using multivariate analysis, we found that multiple-station N2 disease and an advanced T stage ($\geq$T3) significantly reduced the OS and DFS. Seventy one patients (63.4%) had recurrence of disease. The patterns of failure were loco-regional in 23 (20.5%) patients, distant failure in 62 (55.4%) and combined loco-regional and distant failure in 14 (12.5%) patients. Conclusion: Multiple involvement of mediastinal nodal stations for the pN2 NSCLC patients with PORT was a poor prognostic factor in this study. A prospective study is necessary to evaluate the N2 subclassification and to optimize the adjuvant treatment.

• Radiation Oncology Journal
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• v.8 no.1
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• pp.85-93
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• 1990

A series of 25 patients with residual, recurrent, and unresectable gastric cancer received various combination of surgery, radiotherapy (RT), chemotherapy (CT), and hyperthermia (HT). They were placed into 7 categories; 1) CT and HT-14 patients; 2) RT and HT-15 patients; 3) surgery, RT and HT-2 patients; 4) surgery, RT, HT and CT-1 patient; 5) RT, HT and CT -1 patient; 6) RT and CT-1 patient; 7) RT alone-1 patient. Three patients had curative resection. 21 patients received irradiation with tightly contoured portals to spare as much small bowel, kidney and marrow as possible. Hyperthermia was applied regionally once or twice a week for 23 patients using 8 MHz radiofrequency capacitive heating device (Thermotron RF-8). HT was given approximately 30 min after RT 7 patients were treated with CT: 4 patients received HT and concomitant Mitomycin-C; 3 patients received HT and sequential 5-FU+Adriamycin+Mitomycin-C. There was not any treatment related deaths. There was also no evidence of treatment related problems with liver, kidney, stomach, or spinal cord except only one case of transient diabetic ketoacidosis. The tumor response was evaluable in 22 patients. None achieved complete remission.11 ($50\%$) achieved partial remission. The response rate was correlated with total radiation dose and achieved maximum temperature. 9 of 14 ($64\%$) received more than 4000 cGy showed partial remission; especially, all 3 patients received more than 5500 cGy achieved partial response.8 of the 12 patients ($67\%$) who achieved maximal temperature more than $41^{\circ}C$ showed partial response in comparing with $25\%$ (2 of 8 patients, below $41^{\circ}C$). The numbers of HT, however, was not correlated with the response. 3 of the 25 patients ($12\%$) remain alive. The one who was surgically unresectable and underwent irradiation alone is in progression of the disease with distant metastases. The remaining two patients with curative resection are alive with free of disease, 24 and 35 months, respectively. The median survival by response are 11.5 months in responders and 4.6 months in non-responders.

• Nuclear Medicine and Molecular Imaging
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• v.40 no.4
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• pp.205-210
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• 2006

Purpose: FDG uptake on positron omission tomography (PET) has been considered a prognostic indicator in non-small cell lung cancer (NSCLC). The aim of this study was to assess the clinical significance of maximum value of SUV (maxSUV) in recurrence prediction in patients with surgically resected NSCLC. Materials & methods: NSCLC patients (n=42, F:M =14:28, age $62.3{\pm}12.3$ y) who underwent curative resection after FDG-PET were enrolled. Twenty-nine patients had pathologic stage 1, and 13 had pathologic stage II. Thirty-one patients were additionally treated with adjuvant oral chemotherapy. MaxSUVs of primary tumors were analyzed for correlation with tumor recurrence and compared with pathologic or clinical prognostic indicators. The median follow-up duration was 16 mo (range, 3-26 mo). Results: Ten (23.8%) of the 42 patients experienced recurrence during a median follow-up of 7.5 mo (range, 3-13 mo). Univariate analysis revealed that disease-free survival (DFS) was significantly correlated with maxSUV (<7 vs. $\geq7$, p=0.006), tumor size (<3 cm vs. $\geq3$ cm, p=0.024), and tumor tell differentiation (well/moderate vs. poor, p=0.044). However, multivariate Cox proportional analysis identified maxSUV as the single determinant for DFS (p=0.014). Patients with a maxSUV of $\geq7$(n=10) had a significantly lower 1-year DFS rate (50.0%) than those with a maxSUV of <7 (n=32, 87.5%). Conclusion: MaxSUV is a significant independent predictor for recurrence in surgically resected NSCLC. FDG uptake can be added to other well-known factors in prognosis prediction of NSCLC.